Human germline genetic engineering, modifications and enhancements

This is a collection of human germline genetic modifications that has been collected over a period of more than 10 years now. It's the largest collection on the internet, and we welcome most contributions. Check the ?hplusroadmap if you want.

Please note that many of these candidate mutations need to be re-checked, double checked, and further studied. Be aware that sometimes the statistical power is somewhat lacking, study designs are sometimes bad, and such. Other times, there are very well known mutations that will definitely work. There's no magic short cut other than doing the work and figuring it out. Sometimes a referenced study is actually for mouse or rat, although this doesn't mean the result does or does not translate to human. Another theoretical issue is with regards to multiple simultaneous changes and whether effects can be preserved when making simultaneous changes. Just like there are "off-target" effects in CRISPR, there can be "off-target" effects of protein mutations or modifications that may interfere with natural biology natural function or otherwise interfere with other attempted modifications. In some cases, there might even be an unintended beneficial effect from two or more modified proteins that were modified for different intents but for some reason produce a (possibly unrelated) beneficial effect (or, in many more cases, likely a negative effect). Various problems with GWAS study design and epistemology should be more rigorously identified and reasoned about. Some changes can be experimentally verified in cell models, others may require rodent or primate verification. And finally, sometimes the best way to find out is in human cell culture or human embryo development.

Radiation resistance

CD47 suppression provides gobs of radiation resistance. prevent binding of thrombospondin to CD47 with a drug, inhibits NO production and somehow this prevents radiation damage and kills cancer cells. antisense CD47 RNA should do the trick permanently.

((Add better summary here))

• http://www.washingtonsblog.com/2014/01/can-high-tech-medicine-render-radiation-harmless.html

• http://www.dotmed.com/news/story/10571

• http://en.wikipedia.org/wiki/CD47#Angiogenesis

Other radiation resistance: "What about radiation resistance? Here's a case in the literature where radiation resistance was improved 100,000-fold. 10-fold using e14-deletion. 50-fold using recA. 20-fold using yfjK. And 10-fold using dnaB. See Ecoli, Byrne et al, eLife 2014 ("Evolution of extreme resistance to ionizing radiation via genetic adaptation of DNA repair"). This only requires 4 mutations. There is a wide variation in natural organisms, but the only difference here is those 4 mutations."

• Directed evolution of ionizing radiation resistance (2009)
• PprA radioresistance protein from radiodurans
• bacterial heterologous NHEJ pathway could be introduced into cells as an alternative double-strand break repair pathway?

P53 overexpression

As the "guardian of the genome", p53 is missing in many cancers, and has been investigated as a gene therapy option for cancer. Introducing a separate copy, or copies of the gene from the wild-type could reduce the incidence of knockout mutations that normally lead to cancer.

p53 is highly relevant in longevity, see the longevity section later on this page.

Other anti-cancer pathways should be up-regulated and enhanced.

Lower cardiovascular disease and lower coronary disease

milano allele: "Apolipoprotein A-1 Milano (also ETC-216, now MDCO-216) (ApoA-1 milano) is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA1 Milano was first identified by Dr. Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels."

Those with the PCSK5 gene have 88 percent lower coronary disease.

Also, PCSK9 loss-of-function (according to George Church) is also capable of lowering susceptibility to coronary disease and causes lifelong low LDL-C.

https://en.wikipedia.org/wiki/ApoA-1_Milano

Protective mutations for heart attacks

• PCSK9 - 80% lower risk
• NPCILI - 53% lower risk
• LPA - 24% lower risk
• APOC3 - 40% lower risk
• ANGPTL3 - 34% lower risk
• ANGPTL4 - 53% lower risk
• ASGR1 - 34% lower risk

See here and ref.

PCSK9 deletion may cause atherosclerosis protection.

increase compatibility with pacemakers, optogenetic pacemakers (use optogenetic ion channels), heart implants, artificial valves, etc.

Protection against Alzheimer's disease

"More than 50 different mutations in the APP gene can cause early-onset Alzheimer disease, which begins before age 65."

Amyloid precursor protein

The impact of rare genetic variants on Alzheimer disease (2025)

Protective genetic variants against Alzheimer's disease (2025) is a review of germline protective variants (including APP A673T, RELN-COLBOS, and APOE protective alleles).

Immune system

Blood type

ABO locus on chr 9q34.2 (9q34.1‑34.2).

universal donor: ?

universal recipient: ?

what about: Rh complex? kell? duffy (DARC)? diego (band 3)? kidd (JK)? MNS (glycophorin A/B)? Lewis?

TODO:

• blood types modulation

• blood type antigen knockout (universal blood donor, give blood type O-) (can use CRISPR for this). express blood antigens only on non-blood cells. Do not express blood antigens in blood. Add expression of some of the blood antigens into the liver.

• blood type antigen expression to become a universal blood type recipient?

Allergy

• rs2101521
• rs9266772
• rs7720838
• rs10497813
• rs9860547
• rs6021270
• rs17388568
• rs1998359
• rs17533090

ref

allergen-encoding bone marrow to reduce allergies, or antigen-encoding bone marrow

Norovirus (stomach flu) resistance

Those with double FUT2 are resistant to stomach flu.

rs601338

see also https://news.ycombinator.com/item?id=14863351

nonsense/inactivating FUT2 alleles block gut HBGA expression and confer near-complete resistance to major norovirus strains (not all genotypes). Might be linked to Crohn's.

Malaria resistance

DARC - rs2814778

HBB - i3003137

G6PD - rs1050828

HIV resistence and plague resistance

CCR5 knockout provides resistance to HIV and plague. Increases risk from West Nile virus, but who cares about West Nile virus?

CCR5 delta 32-bp deletion mutation provides resistance to HIV-1 infection (especially in homozygotes).

See also HCP5 (rs2395029) and CCL3L1.

see also rs333 for other details.

Anti-leprosy

TLR1 I602S (hypofunction) provides protection from mycobacterial disease (TB/leprosy).

Autoimmune disease protection

TYK2 P1104A (rs34536443) shows broad protection across many autoimmune diseases. Hypomorphic TYK2 allele lowers risk for multiple disorders (T1D, MS, RA, IBD, thyroid autoimmunity, psoriasis); homozygosity can increase tuberculosis risk. See also ref.

Various other protection against autoimmune disease via PTPN22 mutation including T1D and rheumatoid arthritis.

Anti-type-1-diabetes

dominant HLA class II protection: HLA-DQB1*06:02, typically carried on the DRB115:01-DQA101:02-DQB1*06:02 (DR15-DQ6) haplotype, confers dominant protection across the pre-symptomatic stages and against clinical type 1 diabetes. It's present in less than 1% of people who develop type 1 diabetes.

protect against type 1 diabetes by increasing thymic insulin expression and increasing central tolerance to insulin.

IFIH1 (MDA5): multiple loss-of-function/low-expression variants reduce T1D risk

TYK2: the P1104A hypomorphic allele is protective across many autoimmune diseases, including T1D.

in mice:

• transgenic thymic expression of proinsulin in NOD mice prevents insulitis and prevents diabetes
• β-cell–targeted overexpression of PD-L1 (B7-H1) in NOD mice prevents or markedly delays diabetes
• β-cell overexpression of the sialyltransferase ST8Sia6
• reduce diabetogenesis via some MHC stuff that i don't understand
• there is virus-triggered type 1 diabetes? wtf

See also diabetes.

Wild ideas for upgrading the immune system

• Donor MHC-specific thymus vaccination allows for immunocompatible allotransplantation perhaps possible to encode this into the genome instead. For example, encode and express the complete donor MHC class I and class II regions (or selected classical loci such as H-2Kb, Db, Ab). Restrict expression to thymic epithelial precursors if necessary. Any donor whose MHC class I and II sequences match the ectopically expressed transgenic donor-MHC casette would be tolerated. This could open up acceptance to tissue grafts and organ donation from those donors with matching MHC regions.

• germline encode BCR data for earlier head-start immunity against common antigens. "genomic vaccination"? See cell therapy for more information about this idea.

• TODO: DRACO for cellular apoptosis instead of leaking interferon everywhere for an immune response. Immediately kills any cell that a virus infects.

• TODO: improved anti-cancer apoptosis stuff

• TODO: downloadable immunity via germline-delivered genetic program to accept lysosome or exosomes carrying antibody fragment plasmids, incorporate into B cells or immune system to generate antibodies based on the given antibody fragment. Use infrastructure outside the human body to develop these antibody fragment plasmids, or find someone who has antibodies for a specific target, then deliver to germline modified humans.

• Cas9 immunity, Cas9 tolerance (be permissive or restrictive about future CRISPR dosages), possibly via dCas9 expression in bone marrow, possibly also want to express deactivated versions of the other CRISPR systems too...

• TODO: make B and T cells more easily reprogrammable in vivo, such as through DREADD targeting or something gating a natural competence pore, or some other technique.

• endogenous cellular CRISPR immune system? nah...

• TODO: reduce acute inflammatory shock like closed airways?

• transgenic cathelicidin for protection against Acinetobacter baumannii, Staphylococcus aureus; ulcer size reduction. Various cathelicidins from various animals like porcine, crocodile, alligator... Chinese alligator As-CATH8 cathelicidin kills both Gram-positives (S. aureus) and Gram-negatives (A. baumannii, E. coli, Pseudomonas) at lower minimum inhibitory concentration than human LL-37 cathelicidin. Unlike human cathelicidin, As-CATH8 has additional antimicrobial bacterial DNA binding activity. Generally croc cathelicidin is more salt resistant and serum-resistant than human LL-37 cathelicidin. LL-37 should be kept for human wound healing and immune signaling reasons? Some mouse studies have done overexpression of xenobiotic cathelicidin in skin or epithelium. Consider inducible expression of cathelicidin upon infection or inflammation, or restrict expression to non-gut tissue such as respiratory epithelium.

• shark IgNAR single-chain (heavy-chain-only) variable domain is smaller than human antibody multi-chain. Smaller antigens could be detected, and these antibodies might be more heat resistant. Unfortunately to switch to these small antibodies might require substantial genetic changes across the whole immune system including B cells, central and perpheral tolerization, B-cell selection, thymus positive/negative selection would have to be considered.

• "Variable Lymphocyte Receptors" are likely better than human antibody for binding to linear, repetitive, or carbohydrate-rich antigens like glycans, polysaccharides, and repetitive epitopes.

• better defense against bacterial infection via horshoe crab blood cell amebocyte protein "Factor C" (a serine protease zymogen that acts as a bacterial endotoxin sensor). Trace amounts of bacterial lipopolysaccharides bind and activates Factor C, setting off a "proteolytic cascade" which promotes downstream clotting factors like Factor B and proclotting enzyme which converts clotting protein coagulogen into coagulin. Coagulin molecules rapidly polymerize into insoluble strands, creating a gel-like clot. This gel physically traps bacteria and seals off the site of infection or injury. This is a direct enzymatic method compared to the human approach where immune cells (macrophages, dendritic cells, and monocytes) expressing TL4 pattern recognition receptor detect gram-negative bacterial lipopolysaccharides then triggers upregulation of inflammation, cytokine release, and immune cell recruitment to the infection site. Unclear if coagulin would need to be engineered for human physiological parameters and whether rapid polymerization can still be made to occur in this context. Also enzymatic dissolution of these polymerized clots is something to be considered.

• immunity to HIV, but express a little bit in saliva or different tissues as a venomous defense?

Digestion

branching carbohydrates

Alpha-galactosidase expression for the digestion of branching carbohydrates.

Humans are unsuited to digesting some types of branching carbohydrates, which then pass through the intestines and feed annoying bacteria. Not a huge priority, but with the increased metabolic demands from the muscle-enhancing therapies, it can't hurt.

Lactose tolerance and lactase persistence

http://snpedia.com/index.php/Rs4988235 http://snpedia.com/index.php/Rs4988235(C;C)

Also known as "C/T(-13910)", and located in the MCM6 gene but with influence on the lactase LCT gene, rs4988235 is one of two SNPs that is associated with the primary haplotype associated with hypolactasia, more commonly known as lactose intolerance in European Caucasian populations. [PMID 11788828], [PMID 15114531]

In these populations, the rs4988235(T) allele is both the more common allele and the one associated with lactase persistence; individuals who are rs4988235(C;C) are likely to be lactose intolerant. In populations of sub-Saharan Africans, though, the rs4988235(T) allele is so rare that it's unlikely to be predictive of lactase persistence, and other SNPs are predictive instead. [PMID 15106124, PMID 17159977]

Phytate

Phytic acid or inositol hexaphosphate is a phosphate storage ring used by plants to sequester minerals in seeds. Increased use of phosphate fertilizers has caused overproduction of phytic acid and inadvertently caused mineral nutrients to be locked up in a non-bioavailable form called phytate, making it an anti-nutrient. Degrading the ring releases the minerals so that they can be absorbed, as well as the phosphorus.

• phytase salivary secretion as in Enviropig™

Metabolism

Anti-obesity

ref

• rs763727 chr16 pos:83342301 CDH13
• rs726553 chr2 pos:226016494 intergenic
• rs10817737 chr9 pos:100306267 TMOD1
• rs3050 chr6 pos:150923115 PLEKHG1

• rs1278895 chr14 32400170 intergenic

• "Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin" http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=10480614

• RCAN1 "Regulator of Calcineurin 1 helps coordinate whole‐body metabolism and thermogenesis" ref

• try over-expression of FST, SIM1, MC4R

• GLP-1 receptor downregulation?

• essential fructosuria - "lack of the primary enzyme needed to metabolize fructose", help prevents obesity (ref)

• uricase knock-in (prevent gout and obesity and hypertension, uric acid is not needed with increased vitamin C levels, possible decrease/increase in reaction time) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495042/

• increase fertility in obesity (ref)

• suppression of AgRP neurons (in the arcuate nucleus of the hypothalamus) reduces appetite. Activation causes intense "voracious" feeding.

• stimulation of POMC neurons in arcuate nucleus causes appetite suppression; maybe a genetic alteration in the excitability of these POMC neurons?

• increase activation of thirst neurons (in organum vasculosum of the lamina terminalis, median preoptic nucleus) to drive drinking behavior.

Resistance to weight gain from high-fat diets (APOA5)

rs662799 increases risk of heart attack, but contributes towards preventing weight gain from high fat diets.

body fat distribution SNPs - ref

lipodystrophy is a disease where the body cannot store fat properly at all leading to near-total absence of adipose tissue. Congenital Generalized Lipodystrophy (extremely low body fat, severe insulin resistance, muscle hypertrophy, heaptomegaly fatty liver, hypertriglyceridemia) is associated with mutations in AGPAT12 and BSCL2 (which encodes seipin, which is critical for adipocyte development).

Destroy chemical toxins

paraoxon is some cholinesterase inhibitor / nerve gas similar to the organophosphate insecticide parathion.

paraoxonase-1 (PON1) degrades paraoxon and other organophosphate pesticides. the PON1-Q variant has higher activity against organophosphates such as sarin.

PON1 also has lipid peroxide degrading activity via hydrolysis. the PON1-R variant has higher activity against lipid peroxides.

PON1 is found on the surface of small lipid transport particles returning their cholesterol to the liver to be reused. these small particles have a high surface area and are exposed to greater lipid peroxidation per unit lipid than on the forward journey when the particle is larger and full of lipids. lipid peroxides likely cause a large variety of diseases of modernity such as heart disease, diabetes, alzheimers, cancer, etc. due to their destructive effects on cell membranes and inflammatory reactions needed to prevent more peroxidation, since it's a chain reaction. fragile and reactive polyunsaturated seed oils are a feature of modern industrial farming and food science, and we should adapt to this fact instead of dying.

PON1 activity is associated with reduced atherosclerosis and heart disease, by blocking the formation of oxHDL and oxLDL.

Serum PON1 activity in a given population can vary by 40-fold.

PON1 is activated by PPAR-γ. (PPARG)

• increase PON1 expression.

  • The 55L allele results in significantly higher PON1 mRNA and serum protein levels and therefore activity compared to the 55M allele. (ref)(doi:10.1016/s0306-3623(98)00028-7)
  • The 108C allele has greater promoter activity than the 108T allele which results in different serum activities. (same refs)

• add a copy of both PON1-Q and PON1-R since they each preferentially degrade different substrates

  • PON1-Q192R polymorphism determines a substrate dependent effect on activity

Increased metabolism

PGC-1alpha Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism

Smell, olfactory perception, hyperosmia, macrosmia

rs6591536 - detection of β-ionone (floral) fragrance

rs1953558 - sensitivity to sweaty odor (isovaleric acid)

TODO: other hyperosmia (increased odor sensitivity) alleles? other hyperosmia in general?

TODO: see IRC logs for more information about olfactory neurons, olfactory cells, receptors, and canine olfactory receptor genetics that could be copied over to human.

Olfaction in humans is molecularly mediated by GPCRs (olfactory receptors). In insects, olfactory receptors are an unrelated group of ligand-gated ion channels.

Olfaction bypasses the thalamus and goes straight to cortical and limbic areas. Olfactory receptor neurons -> olfactory bulb -> piriform cortex and amygdala etc

Kv1.3 -/- mice have a 1,000- to 10,000-fold lower threshold for detection of odors and an increased ability to discriminate between odorants

TODO: simple transplantation of olfactory receptor genes from elephant or dog.

TODO: machine learning or computational design of olfactory receptor genes and insert a few thousand of these into the human genome. Instead of relying on existing olfactory genes found in nature, we could target various compounds that are of high human interest.

number of olfactory receptor genes by species: cow 1186, opossum 1188, rat 1207, elephant 1948, koala 1500, human 400, dogs 1100, pigs 1100; dogs, which are reputed to have good sense of smell, do not have the largest number of functional olfactory receptor genes.

dog:

• dog macrosmia might be due to airflow in the nasal cavity.
• "1/8 of a dog's brain is devoted to analyzing smells"
• "canine olfactory bulb is 40x larger than in humans (relative to total brain size)"
• "A bloodhound can detect 1 part per 10 trillion, roughly equivalent to detecting a single drop of blood diluted in 20 olympic-sized swimming pools."
• if the canine olfactory limit is one part per trillion for certain molecular targets, then the operational scent threshold limit might be closer to one part per billion or worse depending on dog training, dog/handler teamwork efficiency, distractions, etc.
• olfactory imprinting and neural coding of olfactory signals to neural discrimination puts a damper on neuralink olfactory sensor plans? this seems like an easy one or two orders of magnitude performance improvement on scent tracking tasks if by using neuralink you can decouple signal detection from animal behavior.

TODO: Develop a recombinase-driven genetic circuit that enables olfactory sensory neurons to stochastically assemble novel olfactory receptor variants from modular gene segment, analogous to immune V(D)J recombination. Make a biologically plausible strategy to generate in vivo receptor diversity and systematically enhace odor sensitivity and selectivity. Can we make a way to perceive viruses by smelling their protein capsid shell? Can we make a way to smell new nano-objects that were not genomically encoded via our pre-exisitng olfactory receptors? Take inspiration from in vivo affinity maturation, V(D)J recombination, CRISPR bacterial immune system memory, (synthetic recombineering) diversity-generating retroelements, (synthetic) shufflons (site-specific recombinase card shuffles), PilV pilus tip reprogramming, pilus sequence recombination schemes in bacteria, segmental gene conversion from silent cassettes, antigenic variation schemes, CRISPR-X, TRACE / T7-RNAP-guided mutagenesis, CoMuTER (Type I-E Cas3 mutagenesis), various base editor and prime editor randomization toolkits... possibly there are some in vivo continuous evolution and mutagenesis schemes that might be appropriate, but many seem to either have an in vitro step or are intended for in vitro environments instead of in living animal, like in vivo affinity maturation of edited B cell repetoires (BCRs)... We need in vivo affinity maturation for non-antibody targets.

relevant IRC logs:

• https://gnusha.org/logs/2017-09-01.log
• https://gnusha.org/logs/2023-01-16.log
• https://gnusha.org/logs/2025-07-02.log
• https://gnusha.org/logs/2025-09-14.log

other:

• this is a generalized molecular sensor. everyone should have one of these in their homes, labs, at work, etc.
• see A scalable, multiplexed assay for decoding receptor-ligand interactions.
• intranasal stem cell paper, deliver stem cells with hyaluronidase which makes connective tissue more permeable
• if you snort enough canine olfactory stem cells would your sense of smell change? see: Cell-based therapy restores olfactory function in an inducible model of hyposmia
• Poor human olfaction is a 19th century myth
• odor prediction: A principal odor map unifies diverse tasks in olfactory perception

Taste

sweetness - TAS1R2

umami - TAS1R1

T1R generally covers both sweet and umami flavor

saltyness - ENaC

sourness - PKD2L1, TRPM5

spiciness - TRPV1

signal - GNAT3, TRPM5, PLCB2

bitterness - T2R - TAS2R4, TAS2R5, TAS2R16, TAS2R8, TAS2R38, TAS2R48 see also ref

Taste is GPCRs (G-protein coupled receptors) and some ion channels. Taste perception goes from receptors -> cranial nerves VII, IX, X -> solitary nucleus -> thalamus -> gustatory cortex. Actually that might be wrong, see https://gnusha.org/logs/2025-10-02.log for more details. For hedonic reward from taste: parabrachial nucleus interneurons need to be modified for hedonic reward association against endocrine-linked nutrient sensors on those neurons. Positive hedonic gustatory value is encoded here by "high gamma phase locking" with ~something in VPMpc/BLA that starts a timing window initialized by orofacial sensorimotor pattern generator, anyway they watch for an expected spike and if it's late a FoxP2+ GABAergic interneuron in VPMpc is already depolarized or something. Maybe better to modify VPMpc interneurons to couple spike decision with internal nutritional deficiency status sensing?

TODO: look at olfactory perception enhancement proposals on this page and apply to taste as well? The actual circuit for hedonic value of olfactory perception has not been documented here yet.

let a new era of total gluttony now commence.

Pain and pain insensitivity

You probably don't want full lifelong pain insensitivity. It's called a pathology for a very good reason.

rs6269: http://snpedia.com/index.php/Rs6269

chronic back pain - rs12310519 in SOX5, rs7833174 between CCDC26 and GSDMC, and rs4384683 in DCC ref

"A novel human pain insensitivity disorder caused by a point mutation in ZFHX2" https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awx326/4725107

A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain

"low pain" allele of SCN9A (ref) - "nonsense mutations in Nav1.7 result in loss of Nav1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain". At this point there are now several different mutations discovered in SCN9A for pain insensitivity.

SCN9A mutations from ref:

• p.Ser459Ter (S459X) c.1376C>G in exon 10, nonsense mutation
• p.Ile767Ter (I767X) c.2298del in exon 13 (single-base deletion causing a frameshift and reinterpretation of a premature stop codon at 767)
• p.Trp897Ter (W897X) c.2691G>A in exon 15, nonsense mutation

other scn9a mutations causing pain insensitivity:

• p.Arg1488Ter (R1488*) (ref)
• splice-site variants (ref)
• dozens of SCN9A loss-of-function alleles underlying autosomal-recessive congenital pain insensitivity, most are truncating (nonsense/frameshift) or splicing changes (ref)
• all CIP-causing SCN9A variants are biallelic, loss-of-function disruptions in NaV1.7 expressed in nociceptors; affected individuals typically have lifelong pain absence and often anosmia, with otherwise intact large-fiber modalities.

FAAH pseudogene microdeletion leading to pain insensitivity and forgetfulness ref; "We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH." (however, please note that FAH-OUT doesn't seem to be real from looking at UK biobank data)

PRDM12 also plays a role in congenital insensitivity to pain (CIP), especially the syndrome often called PRDM12-related HSAN type VIII. PRDM12 ("PR domain zinc finger protein 12") is a transcriptional regulator. PRDM12 structure includes a PR domain (related to SET methyltransferases), several zinc fingers, and a poly-alanine tract. PRDM12 is expressed in nociceptor (pain-sensing) neuron precursors during development, and continues to be expressed in mature nociceptors. Here are some articles pertaining to PRDM12-linked congenital insensitivty to pain: PRDM12 missense mutation in exon 3, PRDM12 splicing error, and other PRDM12 congenital insensitivty to pain variants. Loss of PRDM12 leads to absence or severe reduction of nociceptor neurons / nerve fibers (both small myelinated Aδ and unmyelinated C fibers) in the skin. Thus, the physical substrate for pain detection is missing or under‐developed. Disruption of downstream developmental programs: PRDM12 regulates expression of neurotrophic receptor NTRK1 (TrkA), among others. Without PRDM12, TrkA levels drop, leading to poor survival of nociceptor precursors.

opiod receptors (μ, δ, κ) are a common target for analgesics. glycine receptor anesthetics are targeted for immobility. there are many other targets for anesthetics and analgesics to consider.

TODO: specialty ligands to target cells such that we can turn on/off sensitivity to pain? instead of having total insensitivity 100% of the time.

TODO: various pain management things, including anesthetics, analgesics, pain killer compatibility, toxicity? knock-in of GABA-A subunits that have higher affinity to anesthetics? or reduce metabolizers of anesthetics to prolong effect?

Ocular system

Eye color (iris color)

green eye color - rs7495174

blue eye color - rs12913832

loss of SLC45A2 reduces melanosome pH and lightens pigmentation.

OCA2-HERC2 region on chromosome 15, which tunes melanosome pH and tyrosine activity

melanogenesis enzymes - TYR/TYRP1/DCT

transporters that set melanosome ion balance - OCA2, SLC45A2, SLC24A

PMEL organelle scaffolding proteins play a role here too.

In the back of the eye, the fundus color comes from melanin in the retinal pigment epithelium (RPE) and choroid, plus the macula's yellow carotenoids (lutein/zeaxanthin) that are taken up by receptors like SCARB1 and CD36.

iris melanocytes: the iris looks brown when iris melanocytes have lots of eumelanin. With very little stromal melanin, shorter wavelengths are scattered in the collagenous stroma (Tyndall/Rayleigh scattering), so eyes look blue/gray even though there’s no blue pigment. Intermediate amounts and some long wavelengths reflectance produce green/hazel iris. (ref)

TYRP1 and DCT/TYRP2 steer eumelanin chemistry. TYR (tyrosinase) is rate-limiting for eumelanin production. Severe loss of TYRP1, DCT/TYRP2 causes forms of oculocutaneous albinism with very light irides.

OCA2 (P protein) forms/controls an anion conductance on the melanosome and raises lumenal pH; reduced OCA2 function acidifies melanosomes, suppresses TYR, and lightens color. The famous enhancer SNP rs12913832 in HERC2 intron 86 lowers OCA2 expression in iris melanocytes and is the strongest common predictor of blue/light eyes. SLC45A2 (MATP) also helps neutralize melanosome pH; reduced function lightens pigmentation. SLC24A4 (NCKX4), a cation exchanger, is associated with eye color in GWAS and phenotyping panels.

transcriptional control of melanogenesis is via MITF, an enhancer variant near IRF4 alters TFAP2A/MITF cooperation and modulates TYR expression in melanocytes, and therefore impacts pigmentation.

PMEL builds the fibrillar matrix on which eumelanin is deposited; disrupting PMEL affects melanosome maturation and visible pigment density. PMEL disruption causes inefficient pigment deposition leading to a lighter colored iris.

TPC2 (two-pore channel) tends to acidify melanosomes. higher TPC2 activity could reduce TYR activity.

brown iris color: high TYR pathway throughput + neutral-ish melanosome pH (OCA2/SLC45A2 set to "on"), densely melanized melanosomes leading to strong absorption. more melanin synthesis including TYR, TYRP1, DCT.

blue/gray iris color: low stromal melanin; structural scattering dominates in the stroma. blue is caused by lowers OCA2, while more OCA2 leads to darker pigmentation. less melanin synthesis for blue/gray.

green/hazel/amber: intermediate melanin + scattering; subtle shifts in eumelanin/pheomelanin balance and stromal optics.

melanosome pH (transporter) SLC45A2 (MATP) knockdown or mutation causes more acidification and therefore lighter iris color.

melanosome cation balance via SLC24A4 (NCKX4) mutations modulates pigment output.

negative pH regulator TPC2, a channel that tends to acidify melanosomes, at higher activity level causes less melanin biogenesis.

more carotenoids like SCARB1, CD36 or receptors transporting lutein/zeaxanthin into retina causes denser macular yellow coloration.

For human eye color it is mostly about quantitative tuning of melanin plus stromal light scattering.

Anti-myopia

see http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003299 "Sixteen of the novel associations are in or near genes implicated in eye development, neuronal development and signaling, the visual cycle of the retina, and general morphology: BMP3, BMP4, DLG2, DLX1, KCNMA1, KCNQ5, LAMA2, LRRC4C, PRSS56, RBFOX1, RDH5, RGR, SFRP1, TJP2, ZBTB38, and ZIC2".

Spectrum expansion and tetrachromacy

introduce an additional, spectrally distinct cone pigment (e.g., deliver an L-opsin into a subset of M-cones, or vice-versa; or add a tuned variant).

adult primate brains can exploit a new cone class without developmental rewiring. AAV L-opsin delivery; therefore, is a germline change required? taking hundreds of gene therapies is probably not ideal, so including extra L-opsin in the genome could make sense.

engineer amino-acid substitutions that shift peak absorption (λmax) of L/M opsins to widen separations based on known tuning sites in primate opsins.

some human females are heterozygous for L opsin variants

ultraviolet vision spectrum: ultraviolet-sensitive SWS1, and reduce UV filtering by the lens/cornea (humans strongly block UV). UV is phototoxic to the retina and would require mitigation.

lots of available opsins from other animals, like tetrachromatic reptiles or birds.

Near-infrared vision

TRP has been added to mouse retinal cells for near-infrared vision, but not infrared vision. TRPV1 in human retinal organoids also for near-infrared.

often temperature-gated TRP channels (TRPA1 and TRPV1) are used in combination with gold nanorods to get near-infrared vision.

near-infrared vision in humans can be done by upconversion nanoparticles or lenses that convert infrared to visible light. Can these upconversion nanoparticles be proteins produced by human retinal cells?

Infrared vision

Pit viper snakes like pythons and boas have specialized infrared-detecting pit organs with TRPA1 (transient receptor potential ankyrin 1) gene variants. These thermoreceptive TRPA1 channels are highly thermal sensitive that can detect temperature differences as small as 0.003 celsius. these receptors probably need to sit far away from vasculature so that they respond to radiant heat instead of internal body temperature variations.

The thermosensitive pit organ in snake has an external face membrane that looks out toward the air, and an internal face membrane that looks toward the underlying air-filled chamber. Warm arterial blood is prohibited from reaching the membrane. The temperature difference across the two faces is what the snake's thermosensitive receptors are measuring.

Fire-seeking jewel beetle (Melanophila acuminata) carries arrays of photo-mechanosensitive "infrared sensilla". Infrared warms a nanostructure, causing tiny mechanical changes that gate a mechanoreceptor. The principle is based on thermal expansion of many small dome-enclosed fluid-filled cavity converting infrared flux into a mechanosensory signal transduced via stretch-activated ion channels on a protein-chitin receptor membrane. Beetles can detect forest fires from many kilometers away. Various other insects have similar thermoception capabilities.

The infrared sensilla of the fire-seeking jewel beetle Melanophila acuminata are dome-shaped cuticular depressions, 12–15 µm in diameter, each housing a single, 200 µm-long, fluid-filled sensory organ composed of ≈70 mechanosensory neurons whose dendrites terminate on a thin (≈200 nm) protein–chitin receptor membrane that is mechanically deformed by the rapid (≈5 ms) thermal expansion of a fluid-filled cavity beneath the dome, converting minute (≈25 mK) infrared flux into a mechanosensory signal transduced via stretch-activated ion channels.

A microbolometer is a tiny, uncooled thermal sensor that detects infrared radiation by measuring the temperature-induced resistance change in a suspended microstructure. Can we make one out of proteins attached to an ion channel? infrared optogenetics? possibly a protein for this purpose could be evolved via in vitro directed evolution. could an aptamer do it? use knowledge of protein engineering, optogenetics, cytochrome C, chlorophyll, photosystems, etc.

maybe thermoresponsive elastin-like polypeptide (ELP) can be attached to a mechanosensitive channel (Piezo1). these ELPs have been used as genetically encoded thermosensors (ELP-TEMP) and as thermogenetic actuators in cells.

cytochrome c protein as a potential sensing material for long-wavelength bolometers -- "We simulated and experimentally proved high infrared absorption of cytochrome c in the wavelength between 8 μm and 14 μm."

maybe use triplet-triplet annihilation in a protein assembly like in "Photon upconversion supramolecular assemblies", however this seems to be mostly near-infrared-excitable not infrared-excitable.

Other ocular

include day-specific vision changes, night-specific changes, maybe choose one per eye?

extra eye, retina and optic nerve

more axons in the optic nerve: Bcl-2 overexpression (anti-apoptotic) causes increased global neuron survival, more axons. In mice, this causes 40-50% more neurons in several CNS/PNS populations (including facial motor nucleus, retinal ganglion cells) and more axons in the facial and optic nerves.

more retinal ganglion cells, increase visual acuity? lense-related enhancements?

See biosight for more ocular enhancement notes.

Hearing

SNPs related to hearing loss

perfect pitch - rs3057 near 8q24

increase inner hair cell (IHC) nerve synapses: boosting neurotrophin-3 (Ntf3/NT-3) in the cochlea increases IHC ribbon-synapse density and the amplitude of sound-evoked neural potentials. In mice, this causes better auditory processing relative to wildtype mice.

increase resistance to acoustic injury via overexpression of the α9 nicotinic receptor subunit on outer hell cells (OHCs).

hair cell regeneration, ATOH1 gene therapy?

Sox2 overexpression alleviates noise-induced hearing loss by inhibiting inflammation-related hair cell apoptosis.

prestin modifications for ultrasonic hearing? various other mechanotransduction components. increase mechanosensitivity of hair cells?

increase hearing range? various outer hair cell (OHC) mechanotransduction tweaks, like hair stiffness, resonance, and ion channel kinetics in stereocilia on hair cells. Grow a wider range of hair types, including shorter hairs and longer hairs.

engineer various variants of the mechanosensors.

engineered prestin motor protein kinetics. copy from bat?

consider bat-derived actin-binding proteins or espin, fascin-2, or beta-actin variants knocked into human OHCs.

in OHCs, replace TMC1/2 isoforms with fast-gating variants from dolphins or echolocating bats.

for tectorial membrane stiffness modification, can this be done surgically? collagen-based hydrogel as a replacement maybe? basal turn implants?

Hair

Hair color

https://www.snpedia.com/index.php/Redheads - MC1R SNPs like rs1805009(C;C), known as Asp294His or D294H; the most common variant associated with red hair and poor tanning ability in one study; rs1805007(T;T), known as Arg151Cys or R151C; associated with red hair, and in redheaded females, linked to being more responsive to the anesthetics pentazocine, nalbuphine, and butorphanol, often used by dentists; rs1805008(T;T), known as Arg160Trp or R160W; associated with red hair in an Irish population;

red hair SNPs from 23andme blog post:

• rs34474212 C S83P
• rs1805006 A D84E
• rs11547464 A R142H
• rs1110400 C I155T
• i3002507 C D294H

MC1R rs1805005, known as Val60Leu or V60L, associated with light blond hair in one study (PMID 9302268).

MC1R variants may be associated with skin cancer and reduced effectiveness of painkillers. geneticlifehacks

MC1R knockout resulted in gold mice with black eyes, but some mice had white coats with red eyes.(ref)

MC1R is also mentioned elsewhere on this page in other contexts, including skin and aging.

Hair color is superfluous because hair coloring dyes work.. but if you really want a germline genetic intervention for hair color, keep reading.

The visible color of a hair shaft is set by the amount, type, and distribution of melanin granules (melanosomes) packed into cortical keratinocytes as the hair is formed. Dark hair contains more, larger, ellipsoidal eumelanosomes (black/brown eumelanin); red/blond hair has fewer, smaller, more spherical pheomelanosomes (yellow/red pheomelanin). Melanosomes are produced in hair bulb melanocytes, then transferred into matrix keratinocytes and ultimately into the hair cortex; this transfer can occur via exocytosis–phagocytosis, shed vesicles, or filopodial/membrane-fusion routes. After uptake, keratinocytes position melanin into supranuclear caps and retain it within the growing hair cortex.

MC1R pathway: α-MSH -> MC1R -> cAMP promotes eumelanin; antagonism by ASIP (agouti) shifts toward pheomelanin. Human genetics and mouse models establish MC1R as a key determinant of red/blond phenotypes. (ref)

Melanosome pH/ion handling tunes TYR activity and eumelanin:pheomelanin ratio. OCA2 and SLC45A2 help alkalinize maturing melanosomes; TPC2 (a two-pore channel) modulates melanosomal ion flux and is associated with blond hair variation in humans. (ref)

PMEL forms the fibrillar melanosome matrix; mutants alter melanosome shape and reduce black pigment. Peripheral melanosome transport in melanocytes requires the Rab27a-Mlph-MyoVa complex; loss causes pigment dilution. (ref)

gray hair is from loss of melanocyte support from keratinocyte-derived SCF. graying can also be from local oxidative stress, H2O2 accumulation, loss of catalase/MSR enzymes, melanocyte stem cell failure in the follicle bulge, etc.

pheomelanin-rich to get yellow/red in mice. Red hair contains pheomelanin and low-molecular-weight benzothiazine/benzothiazole derivatives historically called trichochromes, derived from cysteinyldopa chemistry.

in human: OCA2/HERC2 (an enhancer modulating OCA2), SLC45A2, SLC24A5, TYR, KITLG, IRF4, and TPCN2. Large GWAS/meta-analyses in Europeans and multi-ancestry cohorts repeatedly implicate these loci; the IRF4 rs12203592 enhancer variant influences TYR via an MITF/TFAP2A-dependent mechanism and has also been linked to graying. (ref)

melanosome size, shape, packing, and total granule load within hair-shaft keratinocytes strongly influence perceived color depth and brightness. (ref)

Hair follicles and hair growth

• Colossal demonstrated editing genes associated with wooly hair in wooly mammoths with multiplex-edited mouse models with loss of function mutations in Tgm3, Fzd6, Astn2, Fam83g, Fgf5, Tgfa and Mc1r and missense mutations in keratin genes Krt25 and Krt27.

• a mutation in P2YR5 (a G protein-coupled receptor) is associated with woolly hair

• trichohyalin (TCHH) (a single-stranded α-helical protein with two or three highly repetitive regions) strengthens the hair follicle; TCHH mutants are associated with straight hair in europeans. possibly rs17646946, rs11803731, rs4845418, rs12130862. Some smaller effects seen by WNT10A and FRAS1. TCHH is a major structural protein of the inner root sheath (IRS) and medulla.
• Asian-specific alleles of the EDAR and FGFR2 genes are associated with thick straight hair; EDAR is associated with hair thickness. EDAR V370A is associated with straight and thick hair. Gain-of-function variant in ectodysplasin-A receptor enhances NF-κB signaling in ectodermal appendages, increasing fiber thickness and biasing toward straight hair.
• straighter hair in latin americans and east asians via PRSS53 Q30R (a serine protease).
• repetin (RPTN)

• KRT71 / KRT74 / KRT25 are keratins of the inner root sheath, missense variants destabilize keratin intermediate filaments and change shaft molding. woolly/curly phenotypes (KRT71 AD woolly hair; KRT74 AD woolly hair; KRT25 AR woolly hair).

• Long-hair phenotypes / anagen prolongation - FGF5, a catagen trigger; human loss-of-function causes trichomegaly (very long eyelashes) and generally prolongs anagen.

some other things to consider doing:

• knock-down androgen receptors in dermal papilla cells in scalp
• 5-α-reductase deficienc but only in hair: reduce SRD5A2 (type-2 5-α-reductase) in dermal papilla, connective tissue sheath, outer root sheath.
• block the production of DKK1 (a Wnt antagonist) in dermal papilla cells, or block its action in epithelial LRP5/6. DHT induces DKK1 in balding DP, and DKK1 drives keratinocyte apoptosis and anagen to catagen regression.
• block or reduce expression of IL-6 and TGFB1 in dermal papilla cells in scalp, or block their receptors in matrix/bulge keratinocytes.
• lower PTGDS (PGD2 synthase) locally and/or block GPR44 on follicular cells

hair pro-growth pathways:

• boost Wnt/beta-catenin in dermal papilla cells or epithelium. blocking secreted Wnt inhibitors (SFRP1, DKK1) enhances human hair growth ex vivo.
• in the follicular epithelium, human FGF5 loss-of-function leads to trichomegaly (long hair)
• increase local VEGF expression for angiogenesis in outer root sheath keratinocytes around baldness-prone follicles.
• in bulge or outer root sheath epithelium, JAK initiates anagen in mice and boosts growth signals in human follicles ex vivo.

baldness SNPs - rs6152 and rs1160312

TODO:

• hair growth rate modulation? human hair follicles grow at a rate of about 10,000 nm/hour. can we pattern hair types, growth rates, etc, to different skin patches or regions? hair where we want it, and not where we don't?
• what about: TET-expression control of inducible hair follicle coloration?
• genetic inducible hair follicle style switching (switch between curly, wavy, woolly, straight, thick, etc.)
• what about using hair follicle coloring as a molecular sensor of metabolites, drugs, hormones, or other circulating blood factors?
• human hair drug testing is already a thing; hair drug testing is also used in wildlife and livestock (ref).
• what about a lineage tracing system that works in the hair follicle bulb, or hair matrix, such that the matrix generates cells that encode information about the molecular environment, and then that information is then transferred into keratin filaments inside each of those cells that ultimately make up the human hair follicle? or otherwise makes the data available via DNA sequencing (although a system where a simple optical microscope can extract information would be better).
• what about using modified keratin filaments inside of cortical keratinocytes as a protein molecular recording device of cellular state, then use protein sequencing (or optical microscope?) to extract information about cellular history, see analog recording of gene regulation dynamics over weeks using intracellular protein tapes. Can this be done with keratin filaments instead? or as an alternative to keratin filaments inside hair follicles? or done with stereocilia, chitinous chaeta, etc? "CytoTape is a living "protein ticker-tape" molecular memory device: a long intracellular protein filament or thread that grows continuously from one end made up of multiple sections or beads. Each bead can carry a short, unique peptide tag whose appearance is dictated by a chosen promoter. When the promoter is active, the tag is made, it is then threaded onto the growing tip, and it is then locked in place. Because growth proceeds at a steady nanometers-per-hour rate, distance from the tip automatically encodes elapsed time. Multiple events can be recorded in parallel on the same filament using simultaneous recording of five distinct tags. After days or weeks the cell is fixed, the filament is stained with tag-specific antibodies conjugated to distinct fluorophores, and a diffraction-limited microscopy line scan converts spatial position (distance from the tip) into a temporal trace of each promoter's activity. This yields multiplexed, single-cell analog recordings."
• in insects and arthropods, epidermal trichogen cells generate a "cellular hair", like for mechanosensory hairs; these hairs are chitinous chaeta or cuticular outgrowths.
• human inner ear "hair cells" produce hair which is not a keratinocyte type hair follicle; each hair cell carries or protrudes a hair bundle made of dozens of stereocilia (actin-based microvili) and not keratin shafts. there's stereocilia (unbranched actin filaments), kinocilium (microtubule-based cilium), and outer hair cells. Various studies have used cellular hair protrusions as a biosensor recorder: ref, ref, kidney cilia, in vivo cilia labeling, ciliary targeting sequences for transmembrane proteins, bacterial flagellar filaments with flagellin that travels through a 2 nm central hole, amyloid fibers, ... this gets you cilium-based expression profiling or recording.
• what about using tunneling nanotubes (TNTs) for recording cellular information?
• In cancer biology, microtentacles are extremely thin, actin-rich membrane projections that form on the surface of detached or circulating cancer cells. These are not classical filopedia or invadopedia; instead, microtentacles are tubulin-based structures enriched in detyrosinated α-tubulin and EB1. Microtentacles extend for tens of micrometers from the cell body and persist for hours or days.
• what is the longest single cell hair that has been produced or discovered? very long cilia? very long chitinous growth from a cell?
• neurons: use cellular cilia extrusion length segment types to record information about neuronal cell internal/external microenvironment.
• could single hair protrusions or cilium be used for protein purification? just collect the cilia from the cells?
• ribosome-level cellular event recorder using promiscuous codons (or a subet of promiscuous codons that are based on cell expression activity) to incorporate data into a growing amino acid chain

Skin

Albinism is probably the easiest way to go here https://en.wikipedia.org/wiki/Oculocutaneous_albinism#Types

Vitiligo seems to be related to a mutation in tyrosinase (TYR), similar to albinism. In vitiligo, there is a destruction of melanocytes.

melanosome transfer disorder, creating localized spots of depigmentation - https://en.wikipedia.org/wiki/Nevus_depigmentosus

"Melanin is produced within the skin in cells called melanocytes and it is the main determinant of the skin color of darker-skinned humans. The skin color of people with light skin is determined mainly by the bluish-white connective tissue under the dermis and by the hemoglobin circulating in the veins of the dermis. Humans with naturally occurring light skin have varied amounts of smaller and scarcely distributed eumelanin and its lighter-coloured relative, pheomelanin. The concentration of pheomelanin varies highly within populations from individual to individual, but it is more commonly found among East Asians, Native Americans, and Northern Europeans with red hair."

"Organelles which contain pigments, called melanosomes, are smaller and less numerous in light-skinned humans."

• "Inhibition of melanosome transfer results in skin lightening" ref
• albinism genetics - OCA1, OCA2; "A mutation in the human TRP-1 gene may result in the deregulation of melanocyte tyrosinase enzymes, a change that is hypothesized to promote brown versus black melanin synthesis."

"Variations in the KITL gene have been positively associated with about 20% of melanin concentration differences between African and non-African populations. One of the alleles of the gene has an 80% occurrence rate in Eurasian populations. The ASIP gene has a 75–80% variation rate among Eurasian populations compared to 20–25% in African populations. Variations in the SLC24A5 gene account for 20–25% of the variation between dark and light skinned populations of Africa, and appear to have arisen as recently as within the last 10,000 years. The Ala111Thr or rs1426654 polymorphism in the coding region of the SLC24A5 gene reaches fixation in Europe, but is found across the globe, particularly among populations in Northern Africa, the Horn of Africa, West Asia, Central Asia and South Asia. Whilst not all of these genes directly affect melanin production, most of them code for proteins that may play a significant role in melanogenesis and control melanin concentration. Some of these genes are found to be more prevalent in certain population than others."

"the SLC24A5 gene account for 20–25% of the variation between dark and light skinned populations of Africa"

"The characteristic of fair skin, red hair, and freckling is associated with high amount of pheomelanin, little amounts of eumelanin. This phenotype is caused by a loss-of-function mutation in the melanocortin 1 receptor (MC1R) gene. However, variations in the MC1R gene sequence only have considerable influence on pigmentation in populations where red hair and extremely fair skin is prevalent. The gene variation’s primary effect is to promote eumelanin synthesis at the expense of pheomelanin synthesis, although this contributes to very little variation in skin reflectance between different ethnic groups. Melanocytes from light skin cells cocultured with keratinocytes give rise to a distribution pattern characteristic of light skin."

• "Genetics of dark skin in mice" ref
• "A genome-wide association study identifies the skin color genes IRF4, MC1R, ASIP, and BNC2 influencing facial pigmented spots" ref including IRF4, MC1R, RALY/ASIP, and BNC2 which "contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production"
• "Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans" ref including HERC2, MC1R, IRF4, TYR, OCA2, ASIP, UGT1A (hue), BNC2 (saturation)

• "A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation" ref including IRF4 loci, SLC24A4 loci, hair color, MATP variant for hair color, HERC2, MC1R red hair color alleles.

• rs12896399

• BNC2 alleles

• rs10765819 located in the first intron of the BNC2 gene previously associated with (saturation of) human skin color

• "Physiological factors that regulate skin pigmentation" ref -- "More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1 and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2 and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including α-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins."

• Skin hair: "Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development" ref

• see other references on page for "skin youthfulness" and "skin aging"

• instead of merely picking existing human alleles, specific expression in melanocytes or skin epithelium cells for custom pigmentation?

Anti-acne

https://www.ebi.ac.uk/gwas/search?query=acne

Skin perception

Human skin tactile resolution is approximately 10 nm at the high end.

goals: enhance sensory mechanoreceptors in human skin like touch-sensitive cells, mechanical prssure sensor, high resolution spatial tactile detail detection. lamellar receptors for deep pressure sensory modification. better receptors. more receptors. more sensory neurons. more nerve fibers.

increase cutaneous mechanoreceptor/afferent supply or Merkel-cell numbers. increase innervation, hyperinnervation.

Merkel cell neurite complexes and Meissner corpuscles are located superficially and contribute mainly to light touch and flutter. For the sensation of firm, steady pressure instead consider lamellated (Pacinian) corpuscles and the Ruffini endings.

in mice:

target-derived neurotrophins overexpressed in epidermis (K14 promoter):

• Neurturin (NRTN) overexpression in skin: increased numbers of cutaneous sensory neurons with phenotypic shifts and heightened mechanical sensitivity in glabrous skin on behavioral testing.
• NT-3 (K14-NT3) overexpression: more dorsal root ganglion (DRG) sensory neurons, larger touch domes, more Merkel cells per dome, and denser innervation of touch domes and hair follicles. enhanced touch dome innervation.
• BDNF overexpression in skin: altered cutaneous sensory innervation, including increases in specific mechanosensory endings.
• NGF overexpression in skin (K14-NGF): hyperinnervation and expansion of NGF-dependent sensory populations, skewing toward nociceptors and increases epidermal nerve supply.
• artemin (ARTN) overexpression in epidermis: increased density of TRPV1+/CGRP+ cutaneous fibers and robust behavioral hypersensitivity.
• sensory neuron Neuropilin-1 deletion causes defasciculation and exuberant spread of sensory (and follower motor) axons in limb; more, mis-bundled fibers reaching/beyond the plexus

Increase merkel cell numbers by transcriptional programming via epidermal Atoh1 ectopic expression.

Expand sensory-neuron populations via apoptosis blockade: Bax knockout (Bax-/-) prevents developmental culling, leading to more DRG neurons and cutaneous hyperinnervation. LTMR receptive fields can shrink to accommodate the larger population, implying finer tiling. Also shows enhanced mechanical sensitivity (mostly studied in nociception context).

Piezo2 is the principal transducer for LTMRs and Merkel-cell complexes. Sensitization studies exist using Piezo2 knock-in but mainly these studies focused on pain.

epidermal ephrin down-tuning might increase local nerve fiber entry.

STOML3 (mechanotransduction scaffold) overexpression to increase LTMR sensitivity.

Height

Height SNPs

• "Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies"

ref

refs:

• "Defining the role of common variation in the genomic and biological architecture of adult human height" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250049/
• "Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide" http://www.pnas.org/content/95/5/2337.short
• "ADAM12‐S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation" https://onlinelibrary.wiley.com/doi/full/10.1359/jbmr.060502
• "A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation" http://dev.biologists.org/content/142/5/817.full

• "Identification of novel genes significantly affecting growth in catfish through GWAS analysis" https://link.springer.com/article/10.1007/s00438-017-1406-1

• mice, transgenic overexpression of metallothionein growth hormone, mice grew dramatically larger in body size and length.

• SOCS2 knockout -- proportional overgrowth with increased body and long-bone length; GH hypersensitivity via SOCS2 loss.
• FGFR3 knockout or loss of function -- overgrowth of long bones and vertebrae.
• cGMP pathway: CNP overexpression in chondrocytes (Nppc Tg)
• cGMP pathway: NPR2 activation (non-dephosphorylatable Npr2 7E/7E knock-in), increased bone elongation by maintaining guanylyl cyclase activity
• BNP/CNP family and clearance receptors: BNP (Nppb) overexpression causes skeletal overgrowth with elongated limbs/paws.
• BNP/CNP family and clearance receptors: Npr3 (clearance receptor) mutations/deficiency causes skeletal overgrowth; also replicated by osteocrin (OSTN) overexpression that limits CNP clearance.
• CNP regulates endochondral bone growth
• IGF axis & chondrocyte/ECM drivers: cartilage-specific CCN2/CTGF overexpression accelerates endochondral ossification and increases long-bone length.
• IGF axis & chondrocyte/ECM drivers: IGF1 and IGF2 and mouse growth review
• PI3K–AKT signaling: Pten deletion in osteo-chondroprogenitors (Col2a1-Cre) increased skeletal size (notably vertebrae) with growth-plate changes.
• HMGA2 gain-of-function/overexpression causes "somatic overgrowth" and "giant" phenotype
• a review of regulation of long bone growth in vertebrates
• insights into the regulation of growth plate (2014)

For primates, very risky to do GH/GHRH upregulation or SOCS2 loss of function for GH hypersensitivity.

In human, FGFR3 partial loss of function and NPR3 loss of function both increase height but come with skeletal disproportions.

Instead, consider CNP-NPR2 signaling like with NPR2 gain-of-function or CNP related changes.

Focus genetic modifications on epiphyseal growth-plate chondrocytes, espcially the columnar proliferative and pre-hypertrophic zones, because that is where endochrondal elongation is programmed. Activating NPR2 increases stature and CNP analogs raise growth velocity assuming open plates.

Try to avoid premature plate exhaustion.

Growth plate resting zone chondrocytes (the stem cell pool) has cells like PTHrP⁺ chondrocytes with stem-like properties that feed the columnar compartment, and modulating them can extend the duration and supply of growth, not just the rate, which could be a target if the goal is to prolong the growth window (delay senescence/closure) rather than simply speed up elongation, but has some risk of dysplasia or niche exhaustion.

For bone width or growth plate supply, consider perichondrial groove of ranvier or perichondrium to widen plates and feed progenitors. Might trigger neoplasias or cartilage tumors, bone tumors in mice?

osteoblast lineage cells (periosteal or endosteal) set diameter, cortical thickness, and mass. They don't control the rate of endochondral elongation, which is chondrocyte-driven.

Extra strong bones

Those people with the LRP5 gene have extra strong bones.

also take a look at mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) which enhances bone formation.

Height TODO

items to incorporate into this document later:

• rs4788196 near MAPK3, height-increasing allele correlates to decreased expression of MAPK3.
• bone length vs other aspects
• investigate extra expression of various growth hormones for extra height
• bovine growth hormone?
• IGF1 overexpression in bones and PAPP-A transgenics show potential for increasing body size and bone length.
• CNP overexpression also contributes to longer bones
• NPR3 knockout
• NPR2 activation increases height
• knockout of GPC3 leads to overgrowth
• mutations like SOCS2 knockout and Pten knockout affect skeletal development
• FGFR3?
• CDKN1C knockout
• STATS5b overexpression may increase growth
• consider embryological development and timing of relevant progenitors or precursors, or chondrocyte proliferation
• are there any benefits from congenital dwarfism?
• separate bone-related section for strong bones (LRP5), marrow enhancements

Lungs

• GPR126 variation impacts carbon monoxide uptake (DLCO) per alveolar volume (DLCO/VA), ref
• protease-antiprotease balance: lung-directed alpha-1 antitrypsin (AAT) protects against elastase and cigarette smoke injury
• boost antioxidant defenses: (pharmacologic but probably also genetic) activation of NRF2 is lung-protective against smoke exposure, maybe we need a elastase biosensor to activate and upregulate NRF2 expression.
• tame bronchoconstriction: airway-smooth-muscle RGS4 overexpression reduces hyperreactivity and improves airway resistance under challenge
• Hippo-YAP/TAZ is a lung organ size rheostat. Hippo also has involvement in ovary fertility. Epithelial YAP/TAZ drive progenitor proliferation and distal patterning; perturbing Hippo (Mst1/2–Mob1) or YAP/TAZ alters lung growth/size and architecture. Increased activiation of YAP/TAZ increases the lung progenitor cells. (mouse)
• lung volume GWAS

speculative:

• make lungs bigger via embryological development: boost FGF10-FGFR2b (branching), keep YAP/TAZ appropriately active during development, and ensure TBX4/FOXF1 dosage is intact.
• increase gas exchange surface area: promote secondary septation via PDGF-A/PDGFRα pathway, septal elastogenesis, and properly tuned YAP/TAZ.

High altitude adaptation

High-altitude human adaptation targets the hypoxia-sensing axis: EPAS1 (HIF-2α) and EGLN1 (PHD2) variants tune ventilatory/hematologic responses and are associated with population differences in oxygenation at altitude.

• EPAS1 prevents high-altitude blood-thickening process, and is responsible for the Sherpa people being able to survive in high altitude environments (ref1ref2)
• EGLN1 has another high altitude mutation
• MTHFR mutation for high altitude

Intelligence, cognitive ability, learning and memory

• TKTL1 increases basal radial glial cell abundance, which increases cortical neuron production, implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals
• genes implicated in learning include COMT, SLC6A3 (DAT1), DRD4, DRD2, PPP1R1B (DARPP32), MAOA, LMX1A, and BDNF
• FADS2 polymorphisms may modify the effect of breastfeeding on iq see rs1535

• Variation in longevity gene KLOTHO is associated with greater cortical volumes see rs9536314 and the KL gene; related to the KL gene variants is rs9527025. Low dose klotho protein enhances memory in aged nonhuman primates. Positive long-term effects from AAV-induced secreted klotho in wildtype mice.

• DRD2 C957T - "flow proneness"

• CRHR1 rs17689882, greater intracranial volume

• AKT1 - rs1130214

• BDNF - rs6265
• BDNF - BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects "The met-BDNF allele was associated with an 11% reduction in the volume of the hippocampal formation."
• CAMTA1 - rs4908449
• CLSTN2 - rs6439886 - associated with increased episodic memory performance
• COMT - rs4680 ("The valine-to-methionine amino-acid substitution involved in (a certain COMT) polymorphism reduces the activity of this dopamine-degrading enzyme, and the polymorphism is thought to affect dopamine function in the prefrontal cortex. This is responsible for only 0.1% of the heritability of IQ score results.")
• CTSD - rs17571
• DAOA - rs3918342, rs1421292
• HTR2A - rs6314
• KIBRA / WWC1 - rs17070145, "Carriers of KIBRA rs17070145 T allele had 24% better free recall performance 5 min after word presentation (P = 0.000004) and 19% better free recall performance 24 hours after word presentation (P = 0.0008) than did noncarriers."
• NRG1 - rs35753505, rs6994992, SNP8NRG433E1006
• SorCS1 - rs10884402, rs7078098, rs950809, see Impact of genetic variation in SORCS1 on memory retention and The sorting receptor SorCS1 regulates trafficking of neurexin and AMPA receptors
• DTNBP1 - not rs2619522
• hippocampus volume - TESC - rs7294919, see Identification of common variants associated with human hippocampal and intracranial volumes
• intracranial volume - HMGA2 - rs10784502
• FADS2
• PRKCA
• NRXN3 and other neurexins
• IMMP2L
• CHRM2
• GRIN2B overproduction for high learning and memory
• CTNNBL1 (beta-catenin-like protein 1)
• TOMM40
• FASTKD2
• SEMA5A
• rs11074779 ??
• various dopamine D2 receptor changes
• APOE - alzheimers related? rs4420638 is associated with poorer delayed recall performance.
• SPOCK3 - (nearby?) rs6813517 - paragraph delayed recall - poor performance
• HS3ST4 - (nearby?) rs11074779 - paragraph delayed recall - poor performance
• ALDH5A1 SSADH rs2760118 maybe (ref)
• CHRM2 rs324650 maybe

• GWAS ADHD loci ref; rs11420276, rs1222063, rs9677504, rs4858241, rs28411770, rs4916723, rs5886709, rs74760947, rs11591402, rs1427829, rs281324, rs212178.

• FNBP1L rs236330 - intelligence (ref) (ref)

• FOXP2 - related to language acquisition (ref for various language development disorders)

• AKAP6 rs17522122 (ref) ... "T was associated with worse baseline performance in episodic memory, working memory, vocabulary and perceptual speed, but it was not associated with cognitive change in any domain." and: "AKAP6 is highly expressed in various brain regions and cardiac and skeletal muscle where it binds to the regulatory subunit of protein kinase A (PKA) and anchors PKA to the nuclear membrane or sarcoplasmic reticulum. The cAMP-dependent PKA signalling pathway, in turn has been shown to be involved in short- and long-term memory and working memory (Bernabeu et al. 1997; Taylor et al. 1999)."

• MIR211 rs10457441 (ref) ... "associated with accelerated decline in episodic memory"

• SPOCK1 (rs1012694, rs11743006, rs17778739 and rs17777541) association with mathematics ability. The SPOCK1 gene is located on chromosome 5q31.2 and encodes a highly conserved glycoprotein testican-1 which was associated with tumor progression and prognosis as well as neurogenesis. (ref)

• rs733722, near the choline acetyltransferase CHAT gene, -- controls whether galantamine can help fight mental decline in Alzheimer's disease

Exceptional episodic memory (see ref):

• rs9321334
• MOXD1 (Monooxygenase, DBH-like 1) rs6902875 (when lacking an APOE ε4 allele); see also rs9321334 and rs4897574.

"DAB1. An adaptor protein that is an obligate effector of the Reelin signaling pathway, and is essential for laminar organization of multiple neuron types of the cerebral cortex [61]. Increased activation of DAB1 by Reelin signaling pathway is correlated with increased dendritic spine density and enhanced performance in associative and spatial learning and memory [62]." (from ref)

"CNR1. This gene encodes for the type 1 cannabinoid receptor, a presynaptically expressed Gi/Goprotein-coupled receptor that is densely localized to the hippocampus, amygdala, prefrontal cortex, striatum, and cerebellum [70]. It binds and reacts to both natural and synthetic cannabinoids. Several polymorphisms in this gene affect the efficiency of memory [71, 72] and procedural learning in human [73, 74]. For example, a variant on promoter of the CNR1 (rs2180619) moderates the effect of valence on working memory [70]."

upregulation of ADRB2 increases learning and memory (Gibbs, M. and Summers, R., Neuroscience, 1999, vol. 95, no. 3, pp. 913–922.) rs1042713 and rs1042714; (Junkiert-Czarnecka, A. and Haus, O., Postepy Hig. Med. Dosw. (Online), 2016, vol. 70, pp. 590–598.)

Educational attainment: rs9320913, rs11584700, rs4851266

cognitive performance: rs1487441, rs7923609, rs2721173 (Common genetic variants associated with cognitive performance identified using the proxy-phenotype method)

intelligence: rs10457441 rs1872841 rs10119 rs12204181 rs9375195 rs1487441 rs1906252 rs12202969 rs17522122 rs9388171 rs9401634 rs12206087 rs9375225

anti-depression: rs3787138, rs3787138, rs1044396, rs3787140, see also ref

COMT rs4680 - higher frequency of complaint reporting? something about placebo effect? met/met more likely to respond to morphine than val/val allele.

• DRD4 promoter variant rs3758653 ("A dopamine receptor genetic variant enhances perceptual speed in cognitive healthy subjects"); "To our knowledge, this is the first report implicating the same DRD4 polymorphism in cognitively European healthy individuals with a sample size >1000. In a smaller sample (n = ∼500 healthy Chinese adults), a correlation between this SNP and the speed of processing of the Tower of Hanoi task was reported [71]. Regarding the functional implications of the gene's promoter variants, it has been shown that the DRD4 gene's polymorphisms lead to the difference in how well the receptors bind with dopamine and similar compounds [72], and therefore it has been assumed this basic difference leads to the differences observed in the phenotypes."

• neurite growth - NFASC (neurofascin)

Other associations (from ref table 2):

Reference abilities	gene	snp
episodic memory	GABRA4	rs4695183
episodic memory	GRIN2B	rs2192977
episodic memory	GRIN2B	rs12829455
reasoning	SLC6A11	rs2581206
reasoning	SLC6A11	rs1881354
reasoning	CDKL3	rs326626
reasoning	NR3C1	rs6877893
reasoning	EPHA1	rs11767557
reasoning	ADRA1A	rs2644627
reasoning	NTRK2	rs11795386
reasoning	CH25H	rs11203006
reasoning	MAPT	rs8079215
reasoning	GALR1	rs2717164
speed	GABRA4	rs1398176
speed	GABRB1	rs971353
speed	RP1L1	rs4841401
speed	DRD4	rs3758653
speed	CHRNA5	rs7180002
speed	SLC6A2	rs36008
speed	GALR1	rs2717164
speed	GRIK1	rs457474
vocabulary	CREB1	rs2551640
vocabulary	LPCAT1	rs3756450
vocabulary	EPHA1	rs11767557
vocabulary	SLC18A1	rs2270641
vocabulary	TPH2	rs1352250
vocabulary	GABRB3	rs2114217
vocabulary	CRHR1	rs12938031

Hippocampus

Hippocampus stuff:

Some loci associated with hippocampal volume found in genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8), enzymes targeted by new diabetes medications (DPP4), and neuronal migration (ASTN2).

• DPP4 - rs6741949 - G allele, smaller hippocampus vlume
• ASTN2 - rs7852872 - C allele, smaller hippocampus volume
• rs7294919, located on 12q24 between HRK and FBXW8, T allele, smaller hippocampus volume
• rs17178006 - smaller hippocampus volume
• rs6581612, between WIF1 and LEMD3, smaller hippocampus volume
• IL1RAPL1 - IL-1 signaling in hippocampus, IL-6R other interluekin receptors related to intelligence (Carrié, A., Jun, L., Bienvenu, T., Vinet, M.-C., McDonell, N., Couvert, P., Zemni, R., Cardona, A., van Buggenhout, G., and Frints, S., Nat. Genet., 1999, vol. 23, no. 1); (Humeau, Y., Gambino, F., Chelly, J., and Vitale, N., J. Neurochem., 2009, vol. 109, no. 1, pp. 1–14.) (Zhao, M., Kong, L., and Qu, H., Sci. Rep., 2014, vol. 4.)

extra IGF-1 has been shown to increase hippocampus size.

optimization of ubiquitin metabolism in hippocampus ? The deubiquitinating enzyme USP46 regulates AMPA receptor ubiquitination and trafficking. Also influences glutamate receptors.

• hippocampus volume (ref): rs11979341 (7q36.3) 200 kb upstream of SHH (sonic hedgehog) crucial for neural tube formation, rs7020341 (9q33.1) in ASTN2 (astrotactin 2), rs2268894 (2q24.2) in an intron of DPP4, rs2289881 (5q12.3) in an intron of MAST4 which modules microtubule scaffolding, rs7492919, rs17178006.

Working memory

The polymorphisms rs1800497 and rs2283265 (also known as the Taq1a polymorphism) near the dopamine receptor 2 (DRD2) gene are associated with improvements during working memory training. (rs1800497(C;C) better avoidance of errors). However this polymorphism comes with serious tradeoffs: antisocial, borderline, dissocial, and avoidant personality disorders, addictive and impulsive behaviors such as binge eating, pathological gambling, and drug abuse. (more)

Other genes and polymorphisms associated with working memory improvements are listed on page 5 table 1: SLC6A3 (DAT1) rs27072 rs40184 rs3863145; DRD4 rs11246226 rs936465 rs7124601; PPP1R1B (DARPP32) rs3764352; MAOA rs6609257; ANKK1 rs1800497 (TAQ1A); DRD2 rs2283265; LMX1A rs4657412; BDNF rs6265; COMT rs4680

(in ADHD) CDH13 alleles associated with improved verbal working memory performance, see CDH13 intronic SNP rs11150556 and a nearby region (ref)

DRD2: "DRD2 A1/A1 genotype had a significantly higher intelligence than A2/A2 carriers [81]. In addition, a relationship between the striatal dopamine receptor D2 and verbal intelligence quotient was found [82]." (Tsai, S.-J., Yu, Y.W.-Y., Lin, C.-H., Chen, T.-J., Chen, S.-P., and Hong, C.-J., Neuropsychobiology, 2002, vol. 45, no. 3, pp. 128–130.) (Guo, J.F., Yang, Y.K., Chiu, N.T., Yeh, T.L., Chen, P.S., Lee, I.H., and Chu, C.L., Psychol. Med., 2006, vol. 36, no. 4, pp. 547–554.)

"... our results indicate that the human genes encoding adenylyl cyclase 8 (ADCY8), the γ catalytic subunit of cAMP-dependent protein kinase (PRKACG), the γ subunit of calcium/calmodulin-dependent protein kinase II (CAMK2G), 2a and 2b subunits of the ionotropic NMDA glutamate receptor (GRIN2A, GRIN2B), metabotropic glutamate receptor 3 (GRM3), and protein kinase C α (PRKCA) are important for human memory function, because variability among these genes was specifically associated with memory performance and with activation in memory-related brain regions." (ref: Identification of a genetic cluster influencing memory performance and hippocampal activity in humans (2006))

• investigate hippocampus structural alterations vs molecular tweaks
• heritability of long-term memory? heritability of short-term memory?

Activation of the cAMP/PKA intracellular pathway in the striatum is sufficient to increase working memory capacity in mice. This has been achieved with optogenetics in mice to increase measured working memory capacity from 6 to 8 (30% increase). They also found that decreasing the activity of Parvalbumin interneuron activation in the striatum mPFC-STR pathway can improve working memory capacity in some circumstances. "These findings align with pre-clinical and clinical studies on the effects of cortical and striatal phosphodiesterase inhibitors (which increase cAMP levels) in regulating working memory." For germline there are several options such as inhibitory optogenetics of the parvalbumin interneurons to not otherwise infringe on higher working memory capacity. Driving or increasing the cAMP/PKA pathway in striatum is another option for germline intervention from this article. Again this is in mice.

SNAP25

SNPs in the SNAP25 gene were initially linked to intelligence but have failed to replicate. While now suspect, the original work can be found here.

• rs363039
• rs363043

• rs353016

• The SNAP25 gene is linked to working memory capacity and maturation of the posterior cingulate cortex during childhood

• Variants in SNAP25 are targets of natural selection and influence verbal performances in women
• DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex

Memory enhancement in mice

from Genes and signaling pathways involved in memory enhancement in mutant mice:

Excitatory synaptic transmission:

Mutant	Memory phenotypes	LTP phenotypes
NR2B (GluN2B) transgenic	Enhanced in Morris water maze, contextual fear conditioning, object recognition test, non-match place to task	Enhanced CA1 LTP
Cdk5 conditional knockout	Enhanced in contextual fear conditioning, reversal learning in Morris water maze	Enhanced CA1 LTP
p25 transgenic	Enhanced in Morris water maze, contextual fear conditioning	Enhanced CA1 LTP
Kif17 transgenic	Enhanced in Morris water maze, delay matching to place task	Not determined
ORL1 knockout	Enhanced in Morris water maze, contextual fear conditioning, PA	Enhanced CA1 LTP
Hgf transgenic	Enhanced in Morris water maze	Not determined
Cavβ3 knockout	Enhanced in Morris water maze	Enhanced CA1 LTP
Dao knockout	Enhanced in Morris water maze	Enhanced CA1 LTP

Presynaptic function:

Mutant	Memory phenotypes	LTP phenotypes
H-ras transgenic	Enhanced in Morris water maze, contextual fear conditioning	Enhanced CA1, cortical LTP
Ncx2 knockout	Enhanced in Morris water maze, contextual fear conditioning, object recognition test	Enhanced CA1 LTP
Cbl-b knockout	Enhanced in Morris water maze (remote memory)	No change in CA1 LTP
Gap43 transgenic	Enhanced in Morris water maze	Enhanced CA1 LTP

Inhibitory synaptic transmission:

Mutant	Memory phenotypes	LTP phenotypes
GABAAR α4 (Gabra4) knockout	Enhanced in contextual fear conditioning, trace fear conditioning	Not determined
Magl knockout	Enhanced in Morris water maze, object recognition test	Enhanced CA1 LTP
Pkr (Eif2ak2) knockout	Enhanced in Morris water maze, contextual fear conditioning, auditory fear conditioning	Enhanced CA1 LTP
GABAAR α5 (Gabra5) knockout	Enhanced in Morris water maze	Trend of enhanced CA1 LTP
Grpr knockout	Enhanced in contextual fear conditioning, auditory fear conditioning	Enhanced amygdala LTP

Network activity:

Mutant	Memory phenotypes	LTP phenotypes
Bec1 knockout	Enhanced in Morris water maze, y-maze	No change in CA1 LTP; Impaired LTP in Tg
Kvβ1.1 knockout	Enhanced in Morris water maze (aged mice only)	Enhanced CA1 LTP (aged mice only)
Hcn1 knockout	Enhanced in Morris water maze	Enhanced perforant path LTP

Transcriptional regulation and its upstream molecules:

Mutant	Memory phenotypes	LTP phenotypes
CREB-Y134F transgenic	Enhanced in Morris water maze, contextual fear conditioning, social recognition, "CD" (contextual discrimination?)	Enhanced CA1 LTP
CREB-DIEDML transgenic	Enhanced in contextual fear conditioning, social recognition	Not determined
eIF2αSS1A knock-in	Enhanced in Morris water maze, contextual fear conditioning, auditory fear conditioning	Enhanced CA1 LTP
Gcn2 knockout	Enhanced in Morris water maze, impaired in contextual fear conditioning	Enhanced CA1 LTP
ATF4, C/EBP conditional inhibition	Enhanced in Morris water maze	Enhanced CA1 LTP
CamkIV transgenic	Enhanced in contextual fear conditioning	Enhanced CA1 LTP
Ac1 transgenic	Enhanced in object recognition test	Enhanced CA1 LTP
Ap oa1 transgenic	Enhanced in contextual fear conditioning, object recognition test	Enhanced CA1 LTP
Pde4d knockout	Enhanced in Morris water maze, radial arm maze, object recognition test	Not determined but see reference
Pde8b knockout	Enhanced in Morris water maze, contextual fear conditioning	Not determined
Calcineurin conditional inhibition	Enhanced in Morris water maze, auditory fear conditioning, object recognition test	Enhanced CA1 LTP
PP1 conditional inhibition	Enhanced in Morris water maze, object recognition test	Enhanced CA1 LTP
FXR1P knockout (PR)	Enhanced in Morris water maze, reversal probe test	Enhanced GluA2 LTP

Translational regulation:

Mutant	Memory phenotypes	LTP phenotypes
Paip2a knockout	Enhanced in Morris water maze, object location test, contextual fear conditioning	Enhanced CA1 late phase LTP
Fkbp12 knockout	Enhanced in contextual fear conditioning	Enhanced CA1 late phase LTP

Epigenetic regulation:

Mutant	Memory phenotypes	LTP phenotypes
Hdac2 knockout	Enhanced in contextual fear conditioning, auditory fear conditioning, non-match place to task	Enhanced CA1 LTP

miRNA biogenesis:

Mutant	Memory phenotypes	LTP phenotypes
Dicer1 knockout	Enhanced in Morris water maze, contextual fear conditioning, trace fear conditioning	Enhanced CA1 LTP

Extracellular molecules:

Mutant	Memory phenotypes	LTP phenotypes
Mmp9 transgenic	Enhanced in Morris water maze, object recognition test	Enhanced CA1 LTP
tPA (Plat) transgenic	Enhanced in Morris water maze	Enhanced CA1 LTP
HB-GAM (Ptn) transgenic	Enhanced in Morris water maze	Enhanced CA1 LTP

Other manipulations:

Mutant	Memory phenotypes	LTP phenotypes
Ncs-1 transgenic	Enhanced in Morris water maze, object recognition test	Enhanced perforant path LTP
Rgs14 knockout	Enhanced in Morris water maze (learning), object recognition test	Enhanced CA2 LTP
5-HT3R transgenic	Enhanced in contextual fear conditioning	Not determined
Maoa knockout	Enhanced in contextual fear conditioning, auditory fear conditioning	Not determined
Hdc knockout	Enhanced in Morris water maze, contextual fear conditioning, auditory fear conditioning	Enhanced CA1 LTP
Def45 knockout	Enhanced in Morris water maze, object recognition test	Not determined
EC-SOD transgenic	Enhanced in Morris water maze, impaired contextual fear conditioning	Enhanced CA1 LTP
S100b knockout	Enhanced in Morris water maze, contextual fear conditioning	Enhanced CA1 LTP

Intelligence

from "Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence" n=78308 table 1 (note that these only explain at most one IQ point or something):

rsID	Annotation	Locus	Ref	Alt	Ref frequency (UK Biobank)	z	P value	Direction	n	nGWS
rs2490272	FOXO3 intronic	6q21	T	C	0.63	7.44	9.96 x 10^-14	++++−+++	78307	28
rs9320913	Intergenic	6q16.1	A	C	0.48	6.61	3.79 x 10^-11	++++−+++	78307	13
rs10236197	PDE1C intronic	7p14.3	T	C	0.63	6.46	1.03 x 10^-10	+++++−++	78286	35
rs2251499	Intergenic	13q33.2	T	C	0.26	6.31	2.74 x 10^-10	++++++++	78307	22
rs36093924	CYP2D7 ncRNA_intr	22q13.2	T	C	0.46	−6.31	2.87 x 10^-10	?−−?????	54119	100
rs7646501	Intergenic	3p24.2	A	G	0.74	6.02	1.79 x 10^-9	?++−++++	65866	5
rs4728302	EXOC4 intronic	7q33	T	C	0.60	−5.97	2.42 x 10^-9	−−−+−−+−	78307	45
rs10191758	ARHGAP15 intronic	2q22.3	A	G	0.61	−5.93	3.06 x 10^-9	?−−?????	54119	17
rs12744310	Intergenic	1p34.2	T	C	0.22	−5.88	4.20 x 10^-9	?−−−−−−−	65866	28
rs66495454	NEGR1 upstream	1p31.1	G	GTCCT	0.62	−5.75	9.08 x 10^-9	?−−?????	54119	1
rs113315451	CSE1L intronic	20q13.13	A	ATTAT	0.43	5.71	1.15 x 10^-8	?++?????	54119	1
rs12928404	ATXN2L intronic	16p11.2	T	C	0.59	5.71	1.15 x 10^-8	++++++++	78307	19
rs41352752	MEF2C intronic	5q14.3	T	C	0.97	−5.68	1.35 x 10^-8	?−−?????	54119	1
rs13010010	LINC01104 ncRNA_intr	2q11.2	T	C	0.38	5.65	1.56 x 10^-8	++++++++	78308	11
rs16954078	SKAP1 intronic	17q21.32	A	T	0.21	−5.55	2.84 x 10^-8	?−−−−+−−	65866	7
rs11138902	APBA1 intronic	9q21.11	A	G	0.54	5.49	4.12 x 10^-8	+++++−++	78307	1
rs6746731	ZNF638 intronic	2p13.2	T	G	0.43	−5.46	4.88 x 10^-8	−−−−−+−−	78307	1
rs6779302	Intergenic	3p24.3	T	G	0.37	−5.45	4.99 x 10^-8	?−−?????	54119	1

• CON2 copy number variations seem to increase IQ as the number of CON2 copies go up, see Olduvai protein domain and DUF1220

• copy number variants of DUF1220 (ref) for cognitive ability and brain size (but also a schizophrenia and autism risk factor)

• 1q21.1-1q21.2 DUF1220 copy number variations correlated with brain size etc and is very human-specific. The DUF1220 domain is also called (or has been reamed to) Olduvai domain.

from "A genome-wide association study for extremely high intelligence" (2018):

• chromosome 10 high IQ via ADAM12 mutants rs4962322, rs4962520, and rs10794073 explaining up to 1% of high IQ but it may have no impact on IQ in the normal range. ADAM12 can "shed" HB-EGF, an EGFR ligand. HB-EGF/EGFR signaling supports hippocampal plasticity and learning. ADAM12 cleaves IGF-binding proteins (IGFBP-3/-5), increasing free IGF available to activate IGF1 receptors. IGF1 signaling is strongly implicated in synaptic plasticity, LTP and memory across animal and human studies. Reports exist of ADAM12 expression in oligodendrocyte lineage cells and during demyelination.
• X chromosome gene SH2D1A is associated with high IQ.

• plexins gene family showed a significant association with high IQ. Plexins are transmembrane proteins which act as receptors to semaphorins. The plexin-semaphorin pathway has been linked to axon guidance, neural connectivity, axon regeneration in the central nervous system, mental disability, bone disorders, cancer, and inflammatory diseases. Consider regulation of semaphorin receptor activity. Consider different expression in brain-expressed genes and their regulatory reasons, instead of whole body.

• TODO: incorporate results from "GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence" like ZNF638 rs1804020, TMEM89 rs9834639, SLC26A6 rs13324142, BSN rs34762726, CCDC36 rs13068038, C3orf62 rs13077498, MST1 rs3197999, RNF123 rs34823813, TSNARE1 rs79460462

from "A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence" (2019):

• 0.71 IQ point explanation power: NEGR1 intron rs34305371 (chr1:72.73Mb). NEGR1 is a neuronal cell-adhesion molecule in the IgLON family and NEGR2 promotes neurite outgrowth, connectivity, and synaptogenesis in models (FGFR2-linked signaling, ADAM10-regulated shedding).
• 0.5 IQ point explanation power: IP6K1 intronic rs7618501 (chr3:49.77Mb). IP6K1 makes inositol pyrophosphates (like 5-IP7) that influence synaptic vesicle release and neuronal signaling. IP6K1 affects presynaptic function and neuronal migration in models.
• 0.5 IQ point explanation power: intergenic allele (nearest SUMO2P2 pseudogene) rs11793831 (chr9:23.36Mb). might be related to SUMO/ubiquitin pathways.
• 0.4 IQ point explanation power: ATXN2L intronic allele rs8049439 (chr16:28.84Mb). ATXN2L (ataxin-2-like) is a stress-granule and RNA-metabolism protein related to ATXN2. ATXN2/ATXN2L influence RNA handling and neuronal stress responses. General theme here is post-transcriptional/RNA-granule control in neurons.
• 0.4 IQ point explanation power: STAU1 intergenic allele rs2426132 (chr20:47.72Mb). STAU1 encodes an RNA-binding protein that mediates dendritic mRNA transport and local translation, important for long-term synaptic plasticity.

• oligodendrocyte differentiation is involved in intelligence differences via structure and maintenance of white matter in the brain.

• from "Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function" such as mutations in GATAD2B (NuRD complex transcriptional repressor; neurodevelopmental regulator), SLC39A1 (zinc transporter related to ion homeostasis), and AUTS2 (broad brain neurodevelopment regulator and transcriptional control during brain development); ATXN1/ATXN1L/ATXN2L/ATXN7L2 (ataxin-like genes possibly related to RNA processing/chromatin in neurons); DCDC2 (doublecortin-domain protein) associated with neuronal migration and associated with normal variation in reading and spelling; reaction time and brain region volumes have been correlated with MAPT, WNT3, CRHR1, KANSL1, and NSF; etc. TTBK1 (neuron-specific tau kinase, regulates tau phosphorylation, related to axonal/synaptic maintenance pathways), CWF19L1 (related to spliceosome and neuronal survival), RBFOX1 (regulator of alternative splicing in neurons; neuronal RNA splicing factor, interacts with ATXN2), RAI1 (transcriptional regulator), NMNAT2 (axon survival/Wallerian degeneration), FOXO3 (longevity transcription factor).

• CHRFAM7A: Human restricted CHRFAM7A gene increases brain efficiency (2024) -- "CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p = 0.027) ... direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function."; CHRFAM7A is also mentioned in "lineage-specific copy number variations article".

• Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes -- "[...] a duplication at 2q12.3 associated with higher cognitive performance. [...] We identified a novel association between a duplication at 2q12.3 and positive effects on cognitive ability [...] EDAR, SH3RF3, SEPT10, SOWAHC [..] The 865 kb duplication .. equivalent to 6.5 points of intelligence quotient (IQ). Given that the median age of our dataset is 60.7 years, it is possible that this duplication may be associated with a neuroprotective effect. We suspect that many more CNVs associated with higher cognitive ability will be identified in the future as sample sizes increase,"

• Identification of a unique, de novo MYCBP2 variant in an individual with highly superior autobiographical memory -- "Using whole exome sequencing of the HSAM individual and their unaffected parents, we identified a unique de novo missense variant in MYCBP2, which encodes an E3 ubiquitin-protein ligase. To explore the potential behavioral consequences of this variant, we introduced the homologous variant into C. elegans, which resulted in reduced forgetting and increased membrane-bound glutamate receptor in relevant neuronal cells." See the deubiquitin theory.

• RIMS1 allele causing blindness but also significantly increased verbal intelligence. Note that the RIMS1/RIM1 result is now questioned and may be instead related to PROM1: "a later re-analysis of the same ophthalmic pedigree concluded the retinal disease was explained by PROM1, casting doubt on the original assignment of the ocular phenotype to RIMS1". It is not clear to me whether the improved cognitive phenotype is linked to RIMS1, PROM1, both, or neither.

• The human cognition-enhancing CORD7 mutation increases active zone number and synaptic release -- here is a drosophila electrophysiology study of the RIMS1/RIM1 mutation.

• Enhanced learning and memory in patients with CRB1 retinopathy -- reminds me of the RIMS1/RIM1 retinopathy verbal intelligence (VIQ) boost. CRB1 retinopathy seems to be different.

Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development -- "Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1, an important gene for brain development and brain evolution. Brain-image and tissue-section analyses indicated an altered pattern of neural-cell differentiation, resulting in a delayed neuronal maturation and neural-fiber myelination of the transgenic monkeys, similar to the known evolutionary change of developmental delay (neoteny) in humans. Further brain-transcriptome and tissue-section analyses of major developmental stages showed a marked human-like expression delay of neuron differentiation and synaptic-signaling genes, providing a molecular explanation for the observed brain-developmental delay of the transgenic monkeys. More importantly, the transgenic monkeys exhibited better short-term memory and shorter reaction time compared with the wild-type controls in the delayed-matching-to-sample task. The presented data represent the first attempt to experimentally interrogate the genetic basis of human brain origin using a transgenic monkey model and it values the use of non-human primates in understanding unique human traits."

BEC1/KCNH3 knockout enhances cognitive function -- "The K+ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K+ channel genes are expressed in the CNS. The therapeutic potential of K+ channel blockers for cognitive enhancement has been discussed, but the contribution each K+ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K+ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K+ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K+ channel that contributes preferentially and bidirectionally to cognitive function."

SP0535: A human-specific de novo gene promotes cortical expansion and folding -- "Here, a human-specific de novo gene, SP0535, is identified that is preferentially expressed in the ventricular zone of the human fetal brain and plays an important role in cortical development and function. In human embryonic stem cell-derived cortical organoids, knockout of SP0535 compromises their growth and neurogenesis. In SP0535 transgenic (TG) mice, expression of SP0535 induces fetal cortex expansion and sulci and gyri-like structure formation. The progenitors and neurons in the SP0535 TG mouse cortex tend to proliferate and differentiate in ways that are unique to humans. SP0535 TG adult mice also exhibit improved cognitive ability and working memory. Mechanistically, SP0535 interacts with the membrane protein Na+/K+ ATPase subunit alpha-1 (ATP1A1) and releases Src from the ATP1A1-Src complex, allowing increased level of Src phosphorylation that promotes cell proliferation. Thus, SP0535 is the first proven human-specific de novo gene that promotes cortical expansion and folding, and can function through incorporating into an existing conserved molecular network."

NOTCH2NL overexpression: Human-specific notch2nl genes expand cortical neurogenesis through delta/notch regulation; NOTCH2NLB overexpression leads to clonal expansion of human cortical progenitors. -- "The cerebral cortex underwent rapid expansion and increased complexity during recent hominid evolution. Gene duplications constitute a major evolutionary force, but their impact on human brain development remains unclear. Using tailored RNA sequencing (RNA-seq), we profiled the spatial and temporal expression of hominid-specific duplicated (HS) genes in the human fetal cortex and identified a repertoire of 35 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among them NOTCH2NL, human-specific paralogs of the NOTCH2 receptor, stood out for their ability to promote cortical progenitor maintenance. NOTCH2NL promote the clonal expansion of human cortical progenitors, ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL function by activating the Notch pathway through inhibition of cis Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes active during human corticogenesis and reveals how human-specific NOTCH paralogs may have contributed to the expansion of the human cortex."

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• IGF-2 (insulin-like growth factor 2), but only for memory consolidation

"The role of non-coding RNA in memory formation has been reported in a number of publications [46, 47]. RNA-mediated “memory transfer” was recently demonstrated in the marine mollusk Aplysia [48]. Total RNA was extracted from neurons of Aplysia subjected to sensitization training by tail electroshock and injected into neurons of naive mollusks. Snails injected with the RNA of the trained snails showed higher levels of siphon withdrawal reflex as compared to the control group. These data confirm the epigenetic hypothesis of memory formation and can be used in future studies on the possibility of memory stimulation."

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• TODO: "Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence" (2018) (biorxiv)
• TODO: "Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals" (2018)

• TODO: "Identification of novel loci associated with infant cognitive ability"

• rs768023 (related to FOXO3, LACE1) is strongly correlated with cognitive ability or intelligence

• intelligence gwas results in gwas catalog (there's a few thousand associations)

• consider rs11793831-T, rs2013208-T, rs6906737-A, rs7646366-A, rs62037363-T, rs28888764-A, rs6931604-T, rs2426132-C, rs6019535-A, rs6019537-A, rs2624839-T, rs1343775-A, rs4587178-T, rs6931604-T, rs34811474-A, rs942353-T

• memory - APOC1, APOC1P1, PVRL2, APOE, TOMM40, GLI3, LOC102723536, LOC105371152, PHBP14, RN7SL776P, CECR1, CECR3, etc.

• 1q21.1-1q21.2 DUF1220 copy number variations correlated with brain size etc and is very human-specific

• "HYDIN2... This part of 1q21.1 is involved in the development of the brain. It is assumed to be a dosage-sensitive gene. When this gene is not available in the 1q21.1 area it leads to microcephaly. HYDIN2 is a recent duplication (found only in humans) of the HYDIN gene found on 16q22.2." See 1q21.1 microduplication causing disparity between non-verbal performance and verbal performance ref.

• neuronal apoptosis inhibitory protein (NAIP or BIRC1) on 5q13 (try increasing the strength of the inhibitory effect?). There is at least one copy of this gene in the human genome. It may have a dose-specific effect.

• "Several other genes implicated in lineage-specific copy number variations in humans include: a neurotransmitter transporter for γ-aminobutyric acid (GABA) (SLC6A13), a leucine zipper-containing gene highly expressed in brain (KIAAA0738), α7 cholinergic receptor/Fam7 fusion gene (CHRFAM7A), a p21-activated kinase (PAK2), a Rho GTPase-activating protein (SRGAP2), a Rho guanine nucleotide exchange factor (ARHGEF5) that is a member of the rhodopsin-like G protein-coupled receptor family, and Rho-dependent protein kinase (ROCK1)."

• "Another gene showing an HLS copy number increase, USP10, encodes a ubiquitin-specific protease, an enzymatic class implicated in learning and memory and in synaptic growth (DiAntonio et al. 2001). Overexpression of the USP10 homologue in Drosophila leads to uncontrolled synaptic overgrowth and elaboration of the synaptic branching pattern (DiAntonio et al. 2001), raising the possibility that the human-specific copy number increase for USP10 could be relevant to expanded synaptic growth in humans."

more on deubiquitinalization and learning:

• The deubiquitination theory of enhanced cognitive ability
• The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability

• USP8 deubiquitinates SHANK3 to control synapse density and SHANK3 activity-dependent protein levels

• NR2B overexpression (enhanced maze solving in mice, "Doogie mice" 1999) (NR2B subunit of the NMDA receptor) (notably, memory performance of "Doogie" mice was retained in advanced age, see: Maintenance of superior learning and memory function in NR2B transgenic mice during ageing (2007); or this ref about NMDA receptor 2b (NR2B) overexpression)

• NR2A overexpression (Hobbie-J mice) ref
• see also GRIN2B overexpression and various mutations of GRIN2B mentioned elsewhere on this page such as episodic memory SNPs (GRIN2B rs2192977 and GRIN2B rs12829455).

"Chemical upregulation of the NR2B subunit with magnesium L-threonate and/or D-cycloserine also resulted in memory enhancement in animals and humans" (from "Enhancement of declarative memory (2018))

• Wang, D., Jacobs, S. A., and Tsien, J. Z. (2014) Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline, Expert Opin. Ther. Targets, 18, 1121-1130
• Kalisch, R., Holt, B., Petrovic, P., De Martino, B., Kloppel, S., Buchel, C., and Dolan, R. J. (2009) The NMDA agonist D-cycloserine facilitates fear memory consolidation in humans, Cereb. Cortex, 19, 187-196

"Most genetic manipulations that potentiate NMDA-related molecular mechanisms were found to enhance memory performance. Thus, transgenic mice overexpressing KIF17 (protein that transports NR2B along the microtubules) exhibited enhanced learning and memory in the Morris water maze task [9]."

• Wong, R. W.-C., Setou, M., Teng, J., Takei, Y., and Hirokawa, N. (2002) Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice, Proc. Natl. Acad. Sci. USA, 99, 14500-14505

"α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors functionally coupled with NMDA receptors are other popular targets in the studies on memory strengthening. Chemical activation of AMPA receptors by ampakines (benzamides, benzothiadiazines, biaryl propylsulfonamides, 3-trifluoromethylpyrazoles) have been found to facilitate memory (for detailed review, see [10]). AMPA receptors are regulated by the protein kinase Mζ (PKMζ), a product of the PKCζ gene in the brain, that has been shown to affect the long-term memory storage in invertebrates and vertebrates (see review [11]). For example, overexpression of PKMζ in the rat neocortex enhanced long-term memory, whereas the dominant negative PKMζ with amino acid substitution in the active site disrupted memory [12]. In monkeys, higher levels of PKMζ were associated with more accurate recognition memory [13]. "

"Another popular target in the memory improvement studies is cAMP response element-binding protein (CREB), a transcription factor that regulates expression of immediate early genes, such as c-Fos and zif268. In general, any manipulation that that leads to the upregulation of CREB expression results in memory enhancement. To give a few examples, local overexpression of CREB in the basolateral amygdala enhanced memory in the classic fear conditioning [14] and social defeat [15] tests. Overexpression of calcium/calmodulin-dependent protein kinase IV (CAMKIV) that directly regulates CREB in the forebrain of mice improved memory in the social recognition and Morris water maze tests [16, 17]. CCAAT/enhancerbinding protein (C/EBP), a product of the early C/EBP gene, is involved in the activation of late response genes in synaptic plasticity. Upregulation of C/EBP expression enhances memory performance. Thus, suppression of the negative C/EBP regulator, ATF4, improved performance of the experimental animals in the Morris water maze test [18]."

"Among many attempts to find chemical agents potentiating CREB-mediated pathways, the most productive approach to memory enhancement in AD patients involved modulation of phosphodiesterase (PDE) that negatively regulates the cAMP/CREB pathway by hydrolyzing cAMP. Hence, PDE inhibitors should enhance memory. Indeed, some PDE inhibitors, namely Rolipram and Sildenafil, have shown positive result in AD mouse models. Cilostazol a selective inhibitor of PDE3, partially prevents cognitive decline and memory loss in AD patients [19]. For more detailed information on the inhibitors on CREB-dependent pathways, see the review [20]."

"... ENSG00000205704, in human neural progenitor cells. Notably, knock-out or over-expression of this gene in human embryonic stem cells accelerates or delays the neuronal maturation of cortical organoids, respectively. The transgenic mice with ectopically expressed ENSG00000205704 showed enlarged brains with cortical expansion." (ref)

Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor

Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity (in mice) (2011) -- "α1-adrenergic receptors (α1ARs) activation was recently shown to increase neurogenesis... Here, we studied the effects of long-term α1AAR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α1AAR. CAM-α1AAR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α1AAR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α1AAR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the α1AAR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α1AAR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α1AAR mice was 10% longer than that of WT mice. Our results suggest that long-term α1AAR stimulation improves synaptic plasticity, cognitive function, mood, and longevity."

TrkB (RTK): Postnatal neuronal TrkB overexpression activated PLCγ1 signaling and improved multiple learning tasks despite reduced CA1 LTP. See: Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLCgamma pathway, reduced anxiety, and facilitated learning (2004).

mineralocorticoid receptor overexpression in mouse forebrain using CaMKIIα promoter. See: Forebrain mineralocorticoid receptor overexpression enhances memory, reduces anxiety and attenuates neuronal loss in cerebral ischaemia (2007).

TrkC (NT-3 receptor) (Ntrk3) overexpression in mice

possible evidence for mouse transgenic overexpression of GAP-43 (the axonal protein kinase C substrate)? See Enhanced learning after mouse genetic overexpression of a brain growth protein GAP-43 (2000). "... dramatically enhanced learning and long-term potentiation in transgenic mice. If the overexpressed GAP-43 was mutated by a Ser-to-Ala substitution to preclude its phosphorylation by protein kinase C, then no learning enhancement was found. These findings provide evidence that a growth-related gene regulates learning and memory and suggest an unheralded target, the GAP-43 phosphorylation site, for enhancing cognitive ability."

AAV overexpression of IGF-2 in hippocampus of aged mice preserved/boosted CA1 spine density and improved hippocampal memory (ref); pharmacological/peptide IGF-2 also acts as a memory enhancer. Some evidene for adult neurogenesis neuron survival and maturation with IGF-1. Maybe activate neuronal expression of IGF-2 or IGF-1 at different times during development or aging via custom genetic circuits?

CRTC1 (CREB co-activator): overexpressing constitutively active CRTC1 in dorsal hippocampus enhanced long-term memory and was accompanied by enlargement of dendritic spines (ref, 2014)

auditory fear memory enhancement and memory consolidation by increasing the function or overexpression of BAF53b (2017), a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex.

overexpression of valosin-containing protein (VCP)/p97 (AAA+ ATPase) to increase (hippocampal?) dendritic spine density and formation (spinogenesis), modulating contextual fear memory and social interaction. Also shows contextual memory and social behavior restored by leucine supplementation. "... These findings indicate that leucine supplementation likely enhances mitochondrial activity and protein trafficking/transportation and increases the expression of cytoskeleton molecules to support dendritic spine formation in Nf1+/– mice."

negative results in mice:

• CREB is not indicated; overexpression of CREB in mice does not seem to enhance memory formation: ref, ref.
• possibly conflicting evidence for BDNF overexpression? possibly need more timing-controlled BDNF overexpression, like during development or aging? possibly BDNF overexpression in mice improves motor coordination.

growth hormone overexpression in hippocampus in mice seems to improve memory in certain assays?

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in transgenic mice, stabilized beta-catenin causes markedly enlarged brains with increased cortical surface area and even sulci/gyri–like folds.

beta-catenin expression: Regulation of cerebral cortical size by control of cell cycle exit in neural precursors -- "Transgenic mice expressing a stabilized beta-catenin in neural precursors develop enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. [...] Compared with wild-type precursors, a greater proportion of transgenic precursors reenter the cell cycle after mitosis. These results show that beta-catenin can function in the decision of precursors to proliferate or differentiate during mammalian neuronal development and suggest that beta-catenin can regulate cerebral cortical size by controlling the generation of neural precursor cells."

ARHGAP11B and human cortex size, see "Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset) and "Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion -- "Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex."

pharmacological inhibition of mitochondria permeability transition pore (mPTP) opening via cyclosporine A mimics basal progenitor expansion by ARHGAP11B; bacteria-derived mitochondrial toxin bongkrekic acid (BKA) inhibits adenine nucleotide translocase (ANT) function which also mimics basal progenitor expansion by ARHGAP11B. See Human-specific ARHGAP11B acts in mitochondria to expand neocortical progenitors by glutaminolysis for more information about what makes human ARHGAP11B cause mammalian brains to grow so much larger.

((there's also an ARHGAP15 intronic SNP rs10191758 (A-to-G) at 2q22.3 associated with a small variation in IQ. is that related?))

cyclin-dependent kinase inhibitor (CKI) member p27kip1 when knocked out from mouse neural progenitor cells causes a higher basal level of neural progenitor cell proliferation, and also has high NPC proliferation after adult ischemia incidents. p27kip1 constrains proliferation of neural progenitor cells. See also:

• Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996;85:707–720. doi: 10.1016/s0092-8674(00)81237-4.
• Kiyokawa H, Kineman RD, Manova-Todorova KO, et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996;85:721–732. doi: 10.1016/s0092-8674(00)81238-6.

PTEN regulates neuronal arborization and social interaction in mice -- deletion of PTEN in "limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta."

possibly some studies doing AAV-Cre-mediated PETN loss in adult cortex causing cortical thickening and neuronal hypertrophy in the targeted area?

Cdk4/CyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors (2009) -- "During mouse embryonic development, neural progenitors lengthen the G1 phase of the cell cycle and this has been suggested to be a cause, rather than a consequence, of neurogenesis. To investigate whether G1 lengthening alone may cause the switch of cortical progenitors from proliferation to neurogenesis, we manipulated the expression of cdk/cyclin complexes and found that cdk4/cyclinD1 overexpression prevents G1 lengthening without affecting cell growth, cleavage plane, or cell cycle synchrony with interkinetic nuclear migration. Specifically, overexpression of cdk4/cyclinD1 inhibited neurogenesis while increasing the generation and expansion of basal (intermediate) progenitors, resulting in a thicker subventricular zone and larger surface area of the postnatal cortex originating from cdk4/cyclinD1-transfected progenitors. Conversely, lengthening of G1 by cdk4/cyclinD1-RNAi displayed the opposite effects. Thus, G1 lengthening is necessary and sufficient to switch neural progenitors to neurogenesis, and overexpression of cdk4/cyclinD1 can be used to increase progenitor expansion and, perhaps, cortical surface area."

Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming -- ".. Transient Yamanaka factor (YF) expression during development expands neocortex; YF-treated mice show enhanced cognitive skills; Intermittent YF expression is tolerated by adult principal hippocampal neurons. [..] Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF induction led to progenitor expansion, an increased number of upper cortical neurons and glia, and enhanced motor and social behavior in adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus." There are many other ways to genetically cause cortex expansion and proliferation besides Yamanaka factors. See morphogenesis for more advanced synthetic biology techniques.

Sonic hedgehog (Shh) signaling enhancement (ligand) increases HOPX-positive outer radial glial cells and also increases cerebral cortical folding in gyrencephalic ferret cortex (ref)

PSD-95 overexpression - intracerebroventricular injection for postsynaptic density scaffolding protein 95 (PSD-95) overexpression, previously developed an epigenetic editing strategy where a zinc finger DNA-binding domain targeting the Dlg4/PSD95 gene promoter was fused to the transactivation domain VP64 and driven under a CMV promoter. AAV-PhP.B-mediated delivery of this artificial transcription factor (ATF) CMV-PSD95-6ZF-VP64 improved cognition in [an intentionally impaired] mouse model."

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fetal microinjection of FGF2 into embryonic ventricles (mouse E11.5) induces cortical gyrification (Cortical gyrification induced by fibroblast growth factor 2 in the mouse brain) -- "Gyrification allows an expanded cortex with greater functionality to fit into a smaller cranium. However, the mechanisms of gyrus formation have been elusive. We show that ventricular injection of FGF2 protein at embryonic day 11.5—before neurogenesis and before the formation of intrahemispheric axonal connections—altered the overall size and shape of the cortex and induced the formation of prominent, bilateral gyri and sulci in the rostrolateral neocortex. We show increased tangential growth of the rostral ventricular zone (VZ) but decreased Wnt3a and Lef1 expression in the cortical hem and adjacent hippocampal promordium and consequent impaired growth of the caudal cortical primordium, including the hippocampus. At the same time, we observed ectopic Er81 expression, increased proliferation of Tbr2-expressing (Tbr2+) intermediate neuronal progenitors (INPs), and elevated Tbr1+ neurogenesis in the regions that undergo gyrification, indicating region-specific actions of FGF2 on the VZ and subventricular zone (SVZ). However, the relative number of basal radial glia—recently proposed to be important in gyrification—appeared to be unchanged. These findings are consistent with the hypothesis that increased radial unit production together with rapid SVZ growth and heightened localized neurogenesis can cause cortical gyrification in lissencephalic species. These data also suggest that the position of cortical gyri can be molecularly specified in mice. In contrast, a different ligand, FGF8b, elicited surface area expansion throughout the cortical primordium but no gyrification. Our findings demonstrate that individual members of the diverse Fgf gene family differentially regulate global as well as regional cortical growth rates while maintaining cortical layer structure."

BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus (2002) -- "Utilizing transgenic mice where BDNF overexpression was controlled by the β-actin promoter, we evaluated the effects of long-term overexpression of BDNF on the dendritic structure of granule cells in the hippocampal dentate gyrus. BDNF transgenic mice provided the opportunity to investigate the effects of modestly increased BDNF levels on dendrite structure in the complex in vivo environment. While the elevated BDNF levels were insufficient to change levels of TrkB receptor isoforms or downstream TrkB signaling, they did increase dendrite complexity of dentate granule cells. These cells showed an increased number of first order dendrites, of total dendritic length and of total number of branch points. These results suggest that dendrite structure of granule cells is tightly regulated and is sensitive to modest increases in levels of BDNF. [..] previous in vitro observations that BDNF influences synaptic plasticity by increasing complexity of dendritic arbors."

Neuroligin-1 overexpression in newborn dentate granule cells in vivo -- "To examine the role of neuroligins as synapse-inducing molecules in vivo, we infected dividing neural precursors in adult mice with a retroviral construct that increased neuroligin-1 levels during granule cell differentiation. By 21 days post-mitosis, exogenous neuroligin-1 was expressed at the tips of dendritic spines and increased the number of dendritic spines. Neuroligin-1-overexpressing cells showed a selective increase in functional excitatory synapses and connection multiplicity by single afferent fibers, as well as an increase in the synaptic AMPA/NMDA receptor ratio. In contrast to its synapse-inducing ability in vitro, neuroligin-1 overexpression did not induce precocious synapse formation in adult-born neurons. However, the dendrites of neuroligin-1-overexpressing cells did have more thin protrusions during an early period of dendritic outgrowth, suggesting enhanced filopodium formation or stabilization. Our results indicate that neuroligin-1 expression selectively increases the degree, but not the onset, of excitatory synapse formation in adult-born neurons."

Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat -- "We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 day estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain." and another study suggests that endogenous hippocampus estradiol not peripheral estradiol is responsible for female rat "novel object recognition" skill, however they only tested this via inhibition of the production of hippocampal estradiol via microinjection of letrozole (an aromatase inhibitor) into the hippocampi of rats.

intracortical infusion or injection for the purposes of proliferation & neurogenesis:

• EGF (ICV infusion) — robust SVZ proliferation; expands migratory cells along RMS; note reports of hyperplastic SVZ “polyp” lesions with prolonged dosing in rats. Journal of Neuroscience, PLOS, Liebert Publishing
• TGF-α (EGF-family; ICV) — SVZ hyperproliferation and parenchymal recruitment (documented alongside EGF; caution for dysplasia). gupea.ub.gu.se
• HB-EGF (ICV infusion) — increases BrdU+ cells in SVZ and dentate gyrus. MDPI
• Betacellulin (BTC) (EGF-family ligand; ICV) — increases V-SVZ proliferation in adult rodents. Cell
• BDNF (ICV infusion) — drives new neurons beyond OB/RMS into striatal, septal, thalamic, hypothalamic parenchyma. Journal of Neuroscience
• NGF (chronic ICV) — increases DG proliferation & new neuron survival; cognitive benefits reported. PubMed, ScienceDirect
• IGF-1 (ICV) — restores/boosts hippocampal neurogenesis in aged rats. PubMed
• IGF-2 (intrahippocampal protein injection) — enhances memory with evidence for synaptic and neurogenic support. PMC
• VEGF (ICV) — neurogenic and angiogenic effects in adult rodent brain (hippocampus). ResearchGate
• EPO (erythropoietin) (ICV) — increases hippocampal neurogenesis, improves outcomes post-injury. ScienceDirect

intracortical injection or infusion for the purposes of dendritic branching, dendritic spine density, and synaptogenesis:

• Reelin (acute protein supplementation/injection to hippocampus or cortex) — causes increased dendritic spine density, increased CA1 LTP, cognitive enhancement; rescues synaptic plasticity in deficit models. PubMed, PMC -- reelin injection boosts NMDAR function and promotes AMPAR insertion via ApoER2/VLDLR signaling.
• BDNF (ICV) — causes increased neurogenesis and widely reported increased dendritic complexity/spines; related to activity-dependent synaptogenesis. Journal of Neuroscience
• VGF-derived peptide TLQP-62 (intrahippocampal) — causes increased dendritic branching & synaptic potentiation via BDNF/TrkB-dependent mechanism; enhances memory. Journal of Neuroscience, MDPI
• Neuregulin-1 (NRG1) (ICV) — rescues dendritic spine density and ameliorates synaptic deficits via ErbB signaling. Cell
• CXCL12/SDF-1 (ICV) — promotes dendritic spine formation and cognitive recovery after neuroinflammation. PubMed
• Growth hormone (GH) (ICV) — causes increased spine density & dendritic length in hippocampus; improved memory. bioRxiv

• Hevin/SPARCL1 (astrocyte-secreted matricellular protein) — potent excitatory synaptogenic organizer in visual/cortical circuits in vivo. PMC

• intrahippocampal injection of insulin, IGF-2, IGF-1, etc; insulin increases NMDAR surface delivery/phosphorylation and modulates AMPAR trafficking.

• intrahippocampal injection of BDNF increases GluA1/GluA2 levels/trafficking and GluA1 phosphorylation; BDNF-driven plasticity is NMDAR/TrkB-linked.
• intrahippocampal injection of glucose
• direct hippocampal lactate infusion enhanced spatial memory and increased plasticity markers (e.g., Arc/Arg3.1); a large body of work shows astrocyte-to-neuron lactate transport is required for LTP and long-term memory.
• hippocampal pyruvate infusions

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consider the possibility of:

• possibly some brain size gains from reducing developmental apoptosis (like via Apaf1, caspase pathway mutants, or other apoptosis escape) of surplus neural precursors escaping programmed cell death?
• yamanaka factor direct injection into cortical areas? in utero? in adult?
• various cell cycle control factors either genomically encoded and expressed, or via intracortical injection
• injection of kalirin-7 (a regulator of spine plasticity)
• consider maybe: Chondroitinase ABC (protein enzyme; intracortical infusion) — digests CSPGs/PNNs, reopens adult visual-cortex plasticity, enabling new synaptic connections and circuit re-wiring.
• consider maybe: Otx2 homeoprotein (protein delivered to visual cortex) — modulates PV-cell/PNN state to reopen or shift critical-period plasticity, facilitating structural/synaptic remodeling. PMC
• consider maybe: intrahippocampal injection of APP-alpha - improved motor learning and memory in mice.
• hippocampus or amygdala injection of Tat-GluA2_3Y peptide (block AMPAR endocytosis and keep AMPARs at synapses)
• intracortical delivery of exosomes or extracellular vesicles? intracerebral intraparenchymal mitochondria injection?
• oxygen-loaded microbubbles and ultrasound targeting (sonoperfusion), perfluorocarbon oxygen carriers emulsions to increase cerebral oxygenation and mitochondrial function, etc
• Intracerebral injection of extracellular vesicles from mesenchymal stem cells
• faster action potentials. faster recovery. more dendrites per neuron. more receptors per synapse (davidad says estimates are 150 to 300 receptors per human synapse), less ubiquitin, more DUB, more basal radial glia cells.

faster action potentials:

• Kv3 channel mechanisms: Kv3.1/3.2 enable ultra-fast action potential repolarization; transfection/overexpression of Kv3.1 makes normally slow neurons capable of high-rate firing.
• BK channel β4 (KCNMB4) loss narrows action potentials and alters excitability in dentate granule cells

need to double check and confirm these mouse results:

• overexpression of neuronal caveolin-1 (SynCav1) to increase dendritic arborization and synaptic preservation in aging mice?
• Cdk4 + Cyclin-D1: increasing expression of these cell-cycle genes in adult dentate gyrus expands neural stem/progenitor pools, increases adult neurogenesis, and improves memory.
• TLX (Nr2e1, orphan nuclear receptor): TLX expression expands adult hippocampal stem/progenitor cells (increased AHN) and has been linked to enhanced learning/memory in mice.

possible engineering targets:

• deubiquitinization efficiency?
• neurotransmitter receptors, binding efficiency, regulation, lifecycle stuff (production, membrane localization, (thermo)stability, destruction)
• agonists, antagonists
• copy number variations of deubiquitinization
• spinogenesis, synaptogenesis, synapse pruning, axon growth, dendritic growth, neurites, mitochondria modifications

possibly it would be better to focus on the engineering of entire systems of growth and pruning rather than just growth, unless existing pruning mechanisms can accommodate irrelevant-needs-to-be-pruned overgrowth. It is not clear if there is a specific balance or synaptic plasticity rate, or synaptogenesis rate to pruning rate etc, that needs to be hit in order to have significantly improved cognitive ability or learning.

how to better increase the information density of neurons or synapses?

• Evolution of cortical neurons supporting human cognition has a nice overview of what makes human cortical pyramidal neurons different, in particular very extensive dendritic trees and neurite growth. The highest most protracted overproduction of human synapses (up to third decade of life) was described for associative layer IIIC pyramidal neurons in the human dorsolateral prefrontal cortex. Also indicated is action potential speed of information transfer and overall cortical neuron metabolic efficiency.
• Large and fast human pyramidal neurons associate with intelligence
• Human neocortical expansion involves glutamatergic neuron diversification
• Comparative transcriptomics reveals human-specific cortical features
• Molecular mechanisms of the specialization of human synapses in the neocortex
• Human voltage-gated Na+ and K+ channel properties underlie sustained fast action potential signaling

modulated alcohol cravings - rs1799971

rs4680 "worrier/warrior" cognitive effects

Note that for overexpression of either receptors in neurons or modulated expression, either upregulated or downregulated, in any neuron can have different performance and behavioral outcomes depending on the region or type of neuron in which this different gene expression program is executed. It may be interesting to look at transcription factors and synthetic transcription factors or other promoters that are cell type specific or cell fate specific in order to get a specific effect in a specific type of neuron or in specific circuits. Likewise, modulated expression in every cell throughout the body is likely non-ideal.

Sleep

See also sleep.

4-5 hours of sleep/night, plus resistance to sleep deprivation -- see http://gnusha.org/logs/2016-11-25.log

Warning: the identified genetics of short sleep humans may not be accurate: https://forum.effectivealtruism.org/posts/nSwaDrHunt3ohh9Et/cause-area-short-sleeper-genes?commentId=GCQf5qjG4LyEdEJov

• hSIK3 - A mutation in salt-induced kinase 3 (hSIK3-N783Y) is identified in a human subject exhibiting the natural short sleep duration trait.

• "The transcriptional repressor DEC2 regulates sleep length in mammals" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884988/ (hDEC2-P385R)

• DEC2 BHLHE41 Y362H (a second DEC2 mutation) is also associated with short sleep and resistance to sleep deprivation, see "A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans" https://go.aastweb.org/Resources/journalclub/journalcluboctober2014.pdf

• BHLHE41 - rs121912617

NPSR1 - Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation pop article

ADRB1 - Mutation in Beta1-Adrenergic Receptor Affects Sleep/Wake Behaviors pop article; the ADRB1 short sleep mutation seems to still be in play?

Resisting sleep deprivation by breaking the link between sleep and circadian rhythms

"TNFα G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467999/

Inactivation of the DREAM complex mimics the molecular benefits of sleep

Mitochondrial origins of the pressure to sleep (not a human study)

here is what gpt-o3 says about sleep pressure invulnerability: "Candidate mechanisms, supported by transgenic or knockout studies, include: (1) overexpression of adenosine kinase (ADK), which accelerates adenosine clearance and blunts its accumulation; (2) loss-of-function or dominant-negative mutations in adenosine A1 or A2A receptors, rendering sleep-promoting regions insensitive to adenosine's somnogenic signal; (3) hyperactive ENT1 transporters, which remove adenosine too efficiently from synapses; (4) mutations in mitochondrial respiratory proteins that reduce electron leak, thereby weakening the redox trigger for pressure buildup; and (5) loss of prostaglandin D2 synthesis (e.g., in PTGDS), blocking the immune-to-sleep cascade that normally amplifies pressure. Each of these could be tested via CRISPR in mice by introducing: a promoter duplication for ADK (upregulate or otherwise promote expression); a single-point mutation in Adora2a or Adora1 disrupting G-protein coupling; a gain-of-function allele in Slc29a1 (ENT1); a stabilized complex I subunit (e.g., Ndufs4) mimicking tighter coupling; or a nonsense mutation in Ptgds." .... it also says: "A microdeletion affecting the 5' regulatory region or a non-critical exon of ADK might lead to a benign, inherited suppression of sleep pressure, causing minimal systemic disruption while significantly reducing brain adenosine accumulation." but I thought adenosine kinase was used everywhere? maybe not?

• sleep duration - PAX8, VRK2 (vaccinia related kinase 2) (rs62158211, rs17190618, rs1380703), rs3768984

• GNB3 - rs1047776 A allele and the rs2238114 C allele

• ARNTL - rs10766071 "has been associated with shorter sleep duration"

• ABCC9 - rs11046205 - A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila "rs11046205 explains ~5% of the variation in sleep duration. The A allele was associated with longer sleep duration, while the G allele was associated with shorter sleep duration"

• ADA - rs73598374 (higher quality sleep)

• CLOCK - rs12649507

• FTO - rs9939609 - something about short sleep duration and weight gain in children?

• morning person / "morningness": rs12736689 near RGS16, rs9479402 near VIP, rs55694368 near PER2, rs35833281 near HCRTR2, rs11545787 near RASD1, rs11121022 near PER3, rs9565309 near FBXL3; others reported in GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person ..

• insomnia - ref

• there are various optogenetic studies for "sleep neuron" stimulation but none so far seem to immediately cause sleep? Compared to systemic anesthesia, a targeted and localized stimulation that causes immediate sleep (or wakefulness) might be valuable. Some neurons trigger SWS but unclear if non-sleep SWS activity has any beneficial biological effect. GABAergic/galanin neurons in the ventrolateral preoptic area (VLPO) is a classic "sleep-promoting" hypothalamus area. Optogenetic or chemogenetic stimulation of GABA/galanin neurons in VLPO can cause rapid NREM sleep induction. (unclear on what timescale that works at)

• TODO: increase the total duration of usable wakefulness, rather than reducing the amount of high-quality sleep.

Social status

in mice:

Pas1 is a regulator of social dominance, ref

certain mutation of Shank2 increases social dominance but impairs other social interactions.

Hedonistic imperative david pearce stuff

David Pearce specifically proposed:

• modify pain sensitivity or insensitivity, see other notes on this page. david pearce is a big fan of SCN9A deletion or modification.
• in Hedonistic Imperative david pearce argues for enlarging mesolimbic dopamine circuitry, selectively boosting mu-opioid and serotonin pathway function, and disabling several countervailing inhibitory feedback processes (e.g., auto-receptors located on the same surface of the same neuron that released the neurotransmitter it responds to, often acting as a built-in inhibitory brake such as by inhibiting further synthesis or release of the neurotransmitter, a form of negative-feedback control over neuronal signaling) to raise hedonic set-points.
• remove dynorphin (aversive/kappa system) from reward circuits
• remove pro-aversive peptides (or peptidergic inputs) such as bradykinin, nociceptin/orphanin FQ, and substance P -- these are related to genes or receptors such as BDKRB1/2, OPRL1/PNOC, and TAC1/NK1R
• polygenic tuning of mood, personality, pro-social tone, hedonic set-point: consider modifications or changes related to COMT, SLC6A4 (SERT), FAAH, ADRA2B (often called the “ADRA2B deletion variant”), and OXTR.

reference table: dynorphin–κ system (PDYN/OPRK1) (stress/ahedonia), bradykinin (BDKRB1/2), nociceptin (PNOC/OPRL1), substance P (TAC1/NK1R)

polygenic hedonic tuning (human alleles): COMT, SLC6A4, FAAH, ADRA2B, OXTR.

mouse and related studies, not necessarily referenced by david pearce hedonistic imperative:

• dynorphin–κ-opioid system modification: reduce dysphoria/anhedonia, produce anti-stress anti-depressant like effects in rodents
• OPRM1 copy number affects social reward
• endogenous enkephalins naturally inhibit anxiety, and preproenkephalin (PENK) knockout increases fear/anxiety. increase mu-opiod receptor targeted signaling, more enkephalin signaling.
• FAAH -/- mice show reduced anxiety and reduced depression-like phenotype
• DAT -/- or DAT knockdown rodents are hyperdopaminergic and hyperactive, hyperlocomotive, more willing to work for rewards
• ΔFosB overexpression in nucleus accumbens heightens sensitivity to rewards (including natural rewards like sucrose/sex); CREB in NAc often shows the opposite (blunting reward; pro-depressant when high).

Reward system tweaks

Reinforcement feedback

Dopamine neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties

or target somatosensory cortex to train nice to fire a single neuron in motor cortex (ref)

"We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor–expressing striatal projection neurons influenced reinforcement learning in mice."

well we could just optogenetically inhibit various mu opioid receptors or neurons in nucleus acumbens.

Various operant conditioning and classical conditioning tasks have been achieved by direct optogenetic activation or inhibition of neurons in the nucleus accumbens or striatum neurons. Encoding these optogenetic receptors into the germline could enable greater real-time control over learning, motivational circuits, etc.

Mania, euphoria, and heightened reward

dopamine transporter (DAT) reduction or knockdown: hyperdopaminergic mice show mania-relevant behavior and high reward sensitivity.

ClockΔ19 mutant (circadian gene): hyperactivity, mania, reduced anxiety, reduced depression, greater reward sensitivity.

Antidepressant effect

TREK-1 (Kcnk2) knockout mice are more resistant to depression across various assays

ΔFosB overexpression in nucleus accumbens increases responsiveness to natural rewards and promotes stress resilience

beta-catenin upregulation in nucleus accumbens (D2-MSNs) - increases resilience after stress; pro-resilient, anxiolytic effects. (ref)

VMAT2 overexpression: more vesicular monoamine storage/release with reduced depressive-like behaviors and improved affective readouts.

more antidepressant-like effects: p11 (S100A10) overexpression, BDNF overexpression (forebrain/CaMKIIα lines), purinergic receptor deletion via P2X7 receptor knockout, FAAH knockout or inhibition, Kv7/KCNQ channel boosting or overexpression in dopamine-producing neurons located in the ventral tegmental area, ...

Positive motivation

D2 receptor overexpression in nucleus accumbens increases willingness to expend effort for goals (ref)

downregulation, blockage or reduction of κ-opioid receptor (Oprk1) reduces negative affect or aversion

don't knock out μ-opioid receptor (Oprm1) because it's necessary for expression of social and food reward

Partner preference

in voles: Vasopressin V1a receptor (Avpr1a) gene transfer via AAV-V1aR overexpression in ventral pallidum converts non-monogamous meadow voles into partner-preferring animals (ref)

in voles: oxytocin receptor upregulation in nucleus accumbens (NAc), part of the ventral (limbic) striatum, enhances alloparental behavior and partner preference formation (ref)

Brain uploading (prepatory)

Full connectome recording via synaptic barcoding and its in vivo reconstruction

Cell lineage tracing and barcoding techniques like brainbow, MAPseq ("Multiplexed Analysis of Projections by Sequencing"), the in situ sequencing variant BARseq, or Connectome-seq use genetic programs to decorate neurons and synapses throughout the brain so that the connectivity (connectome) can be recovered by DNA sequencing instead of electron microscopy brain imaging for brain uploading. To some extent this is often achieved by lentivral or AAV delivery of genetic payload into adult brain to target some of the neurons. intraparenchymal delivery of AAV is undoubtedly helpful for this. However the information is, at this time, only recovered postmortem. (In fact, it is plausible that postmortem AAV or microinjection may (for a short period of time postmortem) be able to do some amount of barcoding). Future versions might be able to emit SYNseq or synaptic barcoding information via exosome export of DNA or something.. but for now it is a postmortem procedure.

Germline compared to AAV synaptic cartography can achieve significantly better distribution and coverage (namely 100% coverage) of cells and neurons in the brain can be achieved via germline genetic engineering of brainbow-style or synaptic barcoding schemes. The effect of this is to grow a human brain that is "extra prepared" for brain uploading via DNA sequencing as opposed to requiring neural anatomy reconstruction via scanning electron microscopy.

In the future it may be possible to deliver genomically encoded full neural network topology information such that a molecular biology program can reconstruct the original neuronal topology or connectome. See also https://gnusha.org/logs/2025-09-30.log for more speculation about what this kind of multi-cellular genetic program would require. It very likely would be in vitro neural circuit reconstruction long before it is ever in vivo human reconstruction... if ever.

Other speculative neuronal enhancements to assist with brain uploading

These are mostly fanciful ideas that should be validated in an animal model first.

Organelle- or compartment-specific tags (e.g. mitochondria, dendritic spines, axon terminals): Improve automated segmentation by giving EM-visible landmarks or fluorescent anchors.

Membrane-tethered reporters: Aid in delineating neuronal boundaries for optical microscopy or electron microscopy.

EM-detectable tags (e.g. APEX2, miniSOG, HRP-fusion proteins): Enable correlative light and electron microscopy, helping bridge genetic labeling with ultrastructural reconstruction.

Add various GFP or fluorescent indicators to neurons. Fluorescent voltage indicators and other fluorescent indicators are available.

Use the oscillatory waves cell identity visualization trick and couple it to barcoding information somehow.

DNA ticker tape memory for calcium spike recording, action potential spike recording, or intracellular protein recorders. Needs to be coupled with cellular export into bloodstream, or maybe only activate it shortly before death. It is unclear what level of information can be recorded or retrieved from this. Similarly with the fluorescent indicators, it may not be wise to express them throughout life and instead wait to activate them until later or maybe during cell death programs.

Various genomically encoded nanobodies can be expressed for antibody-based tagging and staining.

Consider anything that would help with postmortem expansion microscopy for brain imaging.

review PRISM for any other changes that would be beneficial to genomically encode, such as their GFP-fused "protein bits" that space-fill each neuron with a random neural barcode driven by Cre-lox (or polylox barcoding or CRISPR-based barcoding) lineage randomization. It would be interesting if the "protein bits" could be combined with connectome-seq migration of pre-synaptic and post-synaptic RNA barcodes into the synaptic junction for connectome recovery via sequencing. The combination could be achieved, possibly, by having some sort of relationship between the RNA barcode and the abstract bit-vector from the set of "protein bits" expressed by that neuron.

Longevity

• rs2149954 (EBF1 gene?) and rs4420638 (see "Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age" -- which includes other allele recommendations), however note that rs4420638 (near the TOMM40/APOE/APOC1 locus) has been associated with "poorer delayed recall performance". And the rs2149954 alle has been associated with low blood pressure in middle age, and decreased cardiovascular mortality risk, independent of blood pressure.

• Bayesian association scan reveals loci associated with human lifespan and linked biomarkers -- "A recent extreme longevity study[18] found four novel associated protective alleles near CDKN2B/ANRIL (rs4977756-G), SH2B3/ATXN2 (rs3184504-G), ABO (rs514659-A) and HLA (rs3763305-A). Remarkably, the first two variants replicated in our analysis with (one-sided) P values P=4.34 × 10^−6, P=1.08 × 10^−3, P=0.03, P=0.51, respectively."

• Senescent-resistant human mesenchymal progenitor cells counter aging in primates -- "isogenic biallelic FOXO3-engineered human embryonic stem cells (hESCs) with targeted knockin mutations to replace two phosphorylation sites of FOXO3, Ser253 and Ser315, with alanine residues (FOXO32SA/2SA hESCs). When differentiated into MPCs with the FOXO32SA/2SA genetic signature, these cells exhibit enhanced senescence resistance, environmental resilience, and self-renewal capacity, enabling sustained tissue persistence in rodents (and now primates)."

• just load up on lots of senescoprotective or geroprotective alleles

mutations in:

• KLOTHO
• FOXO3 and FOXO3A

and:

• APOB rs1801703, rs12713450, rs12720854

• TOMM40 rs2075650 (see ref)

• APOC1 rs4420638
• APOE rs429358-C is bad for longevity
• ApoE ε2 rs7412 is pro-longevity
• APOE3 Christchurch R136S and RELN-COLBOS: rare protective alleles that delay onset by years to decades even in autosomal-dominant Alzheimer's disease.

ApoE is a lipid-binding apolipoprotein that transports cholesterol and other lipids. In the brain ApoE is the principal cholesterol carrier, moving lipids from astrocytes to neurons via LDL-receptor-family receptors; in peripheral tissues it mediates lipoprotein clearance and cholesterol metabolism.

maybe:

• PPARGC1A rs148144750
• NRG1 rs62497784 (and NRG1 rs35753505 is associated with intelligence)
• RAD52 rs35278212
• NCOR1 rs61753150
• RAD51 rs191297852
• ADCY5 rs61734561

• HLA-DRB5 rs71549220

• PMS2

• GABRR3

• Various frameshift indels in TET2 and DNMT3A, and high levels of granulocytes in blood. "Both TET2 and DNMT3A are factors [28,29] and are thought to silence hematopoietic stem cell self-renewal to permit efficient hematopoietic differentiation [30,31]. Therefore, loss of functionality in these genes is likely to underlie an enhanced self-renewal leading to the observed age-related myeloid lineage bias. This skewing towards the myeloid lineage is assumed to have adverse effects on immune functionality in normal healthy individuals, but in the oldest old the increase of the myeloid compartment might be compensative for the age-related decrease in naive T-cells, known as immuno-senescence. Hence on condition that the enhanced self-renewal, instigated by somatic disruptive mutations in TET2 and DNMT3A, leads to increased levels of competent immune cells, be it of the myeloid lineage though, might partly compensate for the age-related loss of immuno-capacity of the lymphoid compartment." (from "Germ line and somatic characteristics of the long-lived genome")

Maybe also mutations in:

• OBFC1 (telomere maintenance), rs77987791 rs77987791 rs7925084
• GSK3B (healthy aging index)
• NOTCH1 (diastolic blood pressure)
• TP53 (serum HDL)
• CETP (cholesteryl ester transfer protein)
• ZNF562

... see "Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study".

According to ref (table 2), maybe mutations in: AKAP9, ATG7, C1QTNF2, C9orf96/STKLD1, DSC2, EFEMP2, FCGBP, FGA, GP5, HEMK1, IQCK, KIAA1614, KLKB1, MNT, MYO16, MYOF, PLTP, PRL, RAD51AP1, RXFP4, STK31, SUPV3L1, WDR87, ZNF233.

• DCAF4 -- avoid rs2535913; keep G because A is associated with lower leukocyte telomere lengths.

• rs2069837 (IL6) and rs2440012 (ANKRD20A9P) and others from "Novel loci and pathways significantly associated with longevity"

• rs35715456 on chromosome 18 (see "Genome-wide association study of parental life span"); other longevity candidate genes: APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1; EBF1 gene region rs17056207.

• "Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants" -- "In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival ... Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease."

• SNPs near ZNF704 on chromsome 8q21.13 may be a candidate, see ref. See also ZNF562 alleles?

cognitive aging: "Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum" -- MLST8, DHX57 -- see rs6723868 and "surrounding 25 SNPs"; and rs30986 -- "Within 20 kb of rs30986 are six genes: MLST8, PGP, E4F1, ECI1, DNASE1L2, and BRICD5"... and rs26840, rs27709, rs27648.

cognitive aging: TMEM106B and GRN alleles (ref)

skin aging: MC1R alleles have been found to add/subtract 2 years from one's youthful appearance. See rs34265416, rs4785704, rs34714188, rs12924124, rs35026726, rs12931267, rs75570604, MERGED_DEL_2_86235, 16:89913406:D, rs1805007, rs112556696, etc. Also see CALN1 rs10259553 and CORO2A rs35480968. (MC1R V92M is also associated with Alzheimer's disease risk)

skin aging: "Genetic variants associated with skin aging in the Chinese Han population" -- "Our candidate study found a significant association between SNP rs2066853 in exon 10 of the aryl hydrocarbon receptor gene AHR and crow’s feet. In addition, we found a significant association between SNP rs10733310 in intron 5 of BNC2 and pigment spots on the arms, and between SNP rs11979919, 3 kb downstream of COL1A2, and laxity of eyelids. Our results identified genetic risk factors for signs of skin aging (pigmentation, wrinkles or laxity) in Han Chinese."

• Speculative longevity improvements: slow metabolism; and whatever metformin is doing.

• APOE - avoid rs429358-C (0.9 years decrease in lifespan or parental lifespan?)

• gwas longevity results (click associations, sort by p-value)

• longevity - APOE, APOC1, APOC1P1, CHRNA3, IREB2, CDKN2B-AS1, RPS10P26, TLK2, LPA, PLG, TOMM40, MFRP, C1QTNF5, ATXN2, HYKK, CHRNA5, BRAP, MYL2, SLC22A3, LPAL2, ALDH2, TRAFD1, HECTD4, PTPN11, NAA25, ECHS1...

• The Gerontology Research Group has an interest in the following candidate genes, mostly involved in DNA repair and metabolic pathways related to aging and lifespan: RAD54L, LCE3D, AGBL5, BOLA3, VWA3B, C2orf69, OGG1, WDR6, FAM19A1, PLCXD2, SST, SNCA, LARP1B, FBXW7, SUB1, SYCP2L, RNF8, GRIK2, AHR, NEUROD6, ST7, TRIQK, C9orf85, CTNNA3, TCF7L2, LRP5, C11orf1, CAB39L, ASPHD1, DDX19B, VAMP2, ALDOC, HOXB6, TOB1, CCDC102B, CD226, TSHZ1, ADNP2, RAB4B, SALL4, CLIC6, PLP1.

• SERPINE1 null mutation confers 7 year increase in average lifespan among Berne Amish (ref), see also ref

CBP2/TAFI (carboxypeptidase B2) SNP -438A/A (rs2146881) from Reiner 2015 "was found to have extended healthy lifespan by 1.1 years (and overall lifespan by 0.9 years) in men (2224 subjects)." (reddit)

IL6R (rs2228145/Asp358Ala): reduced IL-6 signaling associates with longer parental lifespan (anti-inflammatory angle)

thymus rejuvenation: in old age, or senescent thymus, consider upregulating FOXN1 (thymic epithelial transcription factor).

TODO: incorporate GWAS longevity associations (2019 study)

Mammals (mostly mice)

GH/IGF signaling & nutrient sensing:

• IGF-1 receptor haploinsufficiency (Igf1r+/-), longevity effect especially strong in female PubMed
• consider other insulin/IGF receptor mutations
• growth hormone receptor knockout (GHRKO) ("Laron" model) Wiley Online Library
• IRS1 knockout (Irs1-/-), sex-biased though PubMed
• S6K1 knockout (S6k1-/-; mTOR axis), especially strong effect in females PubMed
• AKT1 haploinsufficiency (Akt1+/-), longer lifespan with metabolic shifts related to mTOR and autophagy PLOS
• FGF21 transgenic overexpression, lifespan extension via GH/IGF modulation PMC, or adipocyte-specific FGF21

sirtuins & stress response:

• SIRT6 overexpression (whole-body), also shown to reduce frailty in B6 mice. Nature; Also consider using SIRT6 from whale instead.
• use a human centenarian SIRT6 variant with increased double-strand break repair and LINE-1 suppression
• brain-specific SIRT1 overexpression (BRASTO mice), increase median and max lifespans, via hypothalamic mechanism PubMed
• LINE1 repression (i don't understand this?)

oxidative stress & mitochondria:

• mitochondrial catalase transgenic (MCAT), increase of median and max lifespan, downregulates oxidative damage. PubMed
• selegiline (L-deprenyl) is an irreversible, selective MAO-B inhibitor whose longevity-relevant biology is mostly about lowering mitochondria-derived oxidative stress and switching on pro-survival gene programs (antioxidant, anti-apoptotic, and neurotrophic. Knoll rat experiments reported lifespan extension with chronic low-dose deprenyl (ref). reddit.
• MAOB expression rises with age, but is this a cause or an effect or both?
• selegiline expression where, everywhere? or certain localized tissues?
• reminder that phenylethylamine+selegiline is essentially meth (combo TAAR1 agonist plus MOA-B antagonist) and should be approached with extreme caution

KLOTHO:

• KLOTHO overexpression (KlTg): improved lifespan, endocrine effects on insulin/IGF signaling. PubMed
• possibly you want KLOTHO heterozygosit?

Myc & growth control:

• reduced Myc expression (haploinsufficiency): longer healthy lifespan with broad protection PMC

p66Shc (ROS signaling adaptor) knockout: unclear whether this has a positive effect or not PMC

senescent-cell clearance (genetic "senolysis"):

• INK-ATTAC transgene (drug-inducible ablation of p16Ink4a+ cells) PMC

telomeres:

• Telomerase (TERT) overexpression: delayed aging and increased longevity without extra cancer in treated cohorts (AAV gene therapy of wildtype mice in this study) PubMed
• TODO: here is a ref for telomerase/telomere GWAS.

Brain / hypothalamus (neuron-focused)

• brain-specific SIRT1 overexpression (already mentioned)
• inhibiting hypothalamic IKKβ/NF-κB slows whole-body aging and extended lifespan, via central neuro-immune axis PMC
• some sort of role played by hypothalamic neural stem/progenitor cells, where ablation accelerates aging, and transplantation or stem-cell exosomes slows aging and extends lifespan PMC

Adipose / endocrine adipokines

• fat-specific insulin receptor knockout (FIRKO) produces a lean phenotype with increased lifespan via different adipose insulin signaling. PubMed
• adiponectin overexpression (ΔGly Tg): healthier aging with a median lifespan increase, knockout shortens lifespan. eLife

Liver-driven endocrine signals

• FGF21 transgenic (liver-secreted "starvation" hormone) PMC

Vasculature / endothelium

• endothelium-targeted Sirt7 gene therapy (ICAM2 promoter) PMC
• counteracting age-related VEGF insufficiency (vascular rejuvenation) PubMed

Skeletal muscle (myokine/autophagy axis)

• muscle-specific TFEB overexpression, causing improved muscle proteostasis and reduced brain neuroinflammation PMC

Heart (cardiomyocytes)

• cardiac-specific catalase overexpression PubMed

Mitochondria

• mitochondria-targeted catalase overexpression increases mouse lifespan (15-20% median increase) and reduces age-associated oxidative damage.
• Mclk1/Coq7 haploinsufficiency (Mclk1 +/-): decreasing ubiquinone-biosynthesis enzyme activity produces long-lived mice across backgrounds; mechanisms include altered mitochondrial ROS/signaling with preserved respiration.
• SURF1 knockout
• hMTH1/NUDT1 overexpression clears 8-oxo-dGTP from the nucleotide pool, lowers oxidative nucleic-acid damage, and extends lifespan.
• OPA1 overexpression (inner-membrane fusion/cristae integrity) preserves cristae architecture, improves respiratory-chain efficiency.
• ATG5 overexpression to increase mitophagy increases mouse lifespan.
• Parkin (PARK2) overexpression for more mitophagy.
• mtOGG1 (mitochondria-targeted 8-oxoguanine DNA glycosylase) overexpression to improve mtDNA base-excision repair.
• PRDX3 (mitochondrial peroxiredoxin) overexpression to lower mitochonrial H2O2 (? unclear if this is effective)

mitochondrion membrane "peroxidizability" is lower in long-lived species. Across mammals (incl. humans) and birds, mitochondrial phospholipids have fewer highly polyunsaturated fatty acids (esp. DHA) → membranes are harder to oxidize, lipid peroxidation is lower, and mitochondria age more slowly. Humans fall on the "low peroxidizability" end vs mice. Naked mole-rats and many birds are extreme examples

mtDNA mutations scale with lifespan. get good at mtDNA repair or mitophagy.

antioxidant/repair capacity or location may track longevity better than raw ROS production. (ref)

bats have enhanced mitophagy/DNA-damage responses and a dampened NLRP3 inflammasome, reducing mito-inflammation during stress (flight). (ref)

human mitochondria have lower PUFA content and a lower peroxidation index than mice.

naked mole rats mitochondrial membranes are unusually resistant to peroxidation (very low DHA in phospholipids).

human oocyte mitochondria seem to be uniquely protected. (ref)

TODO: look for human mitochondrial longevity mutations in the literature.

mtDNA copy number (mtDNA-CN) should be increased (ref)

MitoSENS: mitochondria DNA mutations need to be bypassed (MitoSENS) by moving mtDNA genes to the nucleus (allotopic expression) and import the proteins back into mitochondria to maintain cellular respiration. Allotopic expression of mitochondrial genes into the nucleus will require recoding for cytosolic translation and also mitochondrial targeting sequences. Mitochondrial-targeted nucleases could be used to eliminate mutant genomes. Therapeutic mitochondrial transplantation or progenitor cell transfer. Engineer enhanced mitochondrial import machinery. Add mitochondrial-targeted DNA repair systems. Overexpress mitochondrial biogenesis factors (PGC-1α, NRF1/2).

See also mitochondria.

Strategies for engineered negligible senescence

Aubrey de Grey proposed "Strategies for Engineered Negligible Senescence" which includes the following:

https://sens.org/

Strategies for Engineered Negligible Senescence is a repair-based approach to aging. It consists of seven categories of molecular and cellular damage that accumulate with age and proposes targeted adult interventions to keep their levels below the threshold that causes pathology. While SENS is primarily focused on adult aging, many of the concepts can be used to inform human germline genetic engineering for anti-aging.

• cell loss (like from non-dividing cells) and atrophy requires replacement (RepleniSens) via tissue engineering and stem cell therapies to restore cell numbers and function. Stimulation or proliferation of resident progenitors to replace lost cells.
• death-resistant (senescent) cells must be removed (ApoptoSens) via targeted ablation such as through senolytic drugs or via immune/CAR-T approaches. p16-activated caspase, senolytic small molecule therapy (dasatinib, quercetin, navitoclax), immune-mediated clearance of senescent cells (CAR-NK cells, vaccination against senescent antigens).
• extracellular aggregates require immunoclearance (AmyloSENS): use vaccination/antibody therapies to tag and remove amyloids such as Aβ or transthyretin in tissue spaces. Active or passive immunization to tag aggregates for microglia/macrophage uptake. Use catalytic monoclonal antibodies or nanobodies that enhance proteolysis. Use engineered proteases like neprilysin or MMP variants. See neprilysin overexpression. Enhance endogenous clearance pathways. alagebrium (ALT-711) analogue expression during thymic negative selection.
• intracellular aggregates should be digested by better lysosomes (LysoSENS) by introducing novel lysosomal enzymes (like those sourced from microbes) to digest stubborn junk like oxidized cholesterol adducts and lipofuscin that materially clog lysosomes. Genomically encode modified enzymes with better trafficking and activity, like bacterial or fungal hydrolases. Transcriptional upregulation of TFEB (master lysosomal biogenesis factor) or TFEB overexpression. Engineer pH-optimized variants of existing lysosomal enzymes. Overexpress other autophagy/lysosomal biogenesis factors. ATG5 overexpression. Beclin-1(Becn1) F121A knock-in to boost autophagy. reverse proteotoxic pathology and lipofuscin via upregulation of lysosome and TFEB programs.
• extracellular crosslinks require the matrix to be replaced or broken (GlycoSENS) via development of crosslink-brakers (such as glucosepane) or refresh extracellular matrix to restore tissue elasticity, especially in arteries. Glyoxalase-1 (Glo1) overexpression.
• mitochondria DNA mutations need to be bypassed (MitoSENS) by moving mtDNA genes to the nucleus (allotopic expression) and import the proteins back into mitochondria to maintain cellular respiration. Allotopic expression of mitochondrial genes into the nucleus will require recoding for cytosolic translation and also mitochondrial targeting sequences. Mitochondrial-targeted nucleases could be used to eliminate mutant genomes. Therapeutic mitochondrial transplantation or progenitor cell transfer. Engineer enhanced mitochondrial import machinery. Add mitochondrial-targeted DNA repair systems. Overexpress mitochondrial biogenesis factors (PGC-1α, NRF1/2).
• oncogenic nuclear (epi)mutations to pre-empt cancer (OncoSENS) by the "widespread interruption of lengthening of telomeres" to prevent lethal tumor overgrowth, in addition to periodic stem cell reseeding throughout the body; CRISPR/dCas9-based targeted demethylation or histone acetylation to restore youthful gene expression; possibly some epigenetic rejuvenation via transient yamanaka-factor expression for partial reprogramming but i am skeptical. tumor-suppressor genes must not be silenced, in fact they must be unsilenced, and chromatin remodeling errors must be fixed or be made to trigger apoptosis. Immune surveillance to kill pre-cancerous cells. Engineer more robust tumor suppressor networks. Add novel DNA damage sensors and response pathways. Super p53 with added extra Ink4/Arf (s-Arf/p53 mice) produced significantly longer lifespan and delayed aging.

Some of the SENS opportunities can be met via germline engineering:

• design redundant metabolic pathways to prevent single points of failure
• create "damage-proof" protein variants less prone to aggregation/oxidation
• dramatically upregulate proteostasis networks
• engineer enhanced DNA proofreading and repair machinery, like double-strand break sensor, detection, and repair, or go into apoptosis
• look for better bacterial/archaeal DNA repair systems from other organisms
• metabolic optimization: engineer more efficient electron transport chains with less ROS production
• add alternative respiratory pathways (like those in long-lived animals)
• optimize NAD+ synthesis and utilization pathways
• engineer telomerase regulation for optimal telomere maintenance
• create enhanced stem cell reserves and regenerative capacity
• import longevity genes from extremely long-lived species (bowhead whales, Greenland sharks, naked mole rats)
• add extremophile stress resistance genes
• integrate plant/bacterial antioxidant systems
• damage-resistant proteins? metabolically optimized protein encodings?
• place "stemness" genes (PAX7, LGR5, SOX2, MYC, TERT) under endogenous or synthetic stress-inducible promoters
• maintain larger stem cell pools and create a "progenitor bias" in every tissue, possibly with FOXO3 modifications or upregulation
• probably significantly more opportunities that have long been overlooked.

Other aging intervention

This is based on a "how aging works" outline from.. many years ago.

mitochondria-targeted catalase overexpression increases mouse lifespan and reduces age-associated oxidative damage.

MnSOD (Sod2) modest overexpression to buffer superoxide without fully flattening redox signals.

GPx4 or Prdx3 mitochondrial-targeted overexpression for lipid peroxides/H2O2 control. GPx4 overexpression reduces age-related pathology; Prdx3 guards mitochondrial redox.

Nox2 (Cybb) loss-of-function or p47phox (Ncf1) hypomorph, curbs AngII/PKC-driven ROS amplification and vascular remodeling.

p47phox phosphorylation-site mutants that reduce PKC-to-NOX docking. preserve baseline NOX but lower "gain" to H2O2 bursts. (ref)

Agtr1a (AT1A) heterozygous knockout or hypomorph: AT1A loss extends lifespan, lowers oxidative damage, increases mitochondria and Sirt3 and Nampt.

klotho knock-in

something for the mTOR axis like S6k1 -/-??

preserve nuclear FOXO stress-resilience without chronic overactivation?

SIRT6 overexpression, previously mentioned.

fix inflammatory aging feedback loops: 1) Ager (RAGE) loss-of-function or sRAGE-favored knock-in, 2) TLR4 hypomorph rather than TLR4 null, to attenuate inflammaging, get less adipose inflammation, and better glucose tolerance.

p38α (Mapk14) activity-dampening allele in stem-cell compartments (HSC/MuSC-biased regulatory elements), or Dusp/Mkp-1 enhancer knock-in. p38 drives HSC/MuSC aging; partial inhibition rejuvenates engraftment. complete p38 loss is deleterious.

mitochondrial biogenesis: moderate Pgc-1α enhancer knock-in, or modest overexpression of Parkin/Pink1. Restore biogenesis/mitophagy where it declines with age; avoid cardiac overexpression toxicity.

Many redox/antioxidant overexpressions fail to extend lifespan unless mitochondria-targeted (mCAT is the exception).

Longevity in other animals

• C. elegans: daf-2 (insulin/IGF receptor) mutants PMC
• C. elegans: age-1 (PI3K); upstream of DAF-16/FOXO PubMed
• C. elegans: intestine-specific degradation of insulin/IGF receptor DAF-2 nearly doubled lifespan; neuronal/hypodermal knockdown gave smaller gains. Nature
• Drosophila FOXO/dFOXO activation shows improved lifespan with adipose-like tissue-specific expression. Fight Aging!, Science

Elephants have many extra copies of p53 (TP53) + hyper-responsive DNA-damage signaling. Elephants carry ~20 TP53 retrogenes. Elephant cells trigger apoptosis at lower damage thresholds. (ref). "Zombie" pro-apoptotic gene LIF6. A re-functionalized LIF pseudogene (LIF6) is directly upregulated by TP53 after DNA damage and triggers mitochondrial apoptosis, as a second independent tumor-suppression layer (ref).

bowhead whales: DNA repair & replication factors under selection/duplication. Comparative genomics found bowhead-specific changes in ERCC1 and duplication/lineage-specific changes in PCNA, plus shifts in pathways tied to DNA repair/cell cycle and cancer resistance. (ref) However, whale does not seem to have more p53.

whales and dolphins: upgrades in tumor suppression. tumor-suppressor genes show positive selection and faster turnover. higher cancer resistance. (ref)

naked mole rats: cancer resistance via extracellular matrix and secretion of very high-molecular-mass hyaluronan (HMM-HA). Mechanism ties to p16^INK4a–mediated early contact inhibition. better proteostasis, proteim homeostasis, and stress resistance. Make a ultra-high-activity hyaluronic acid synthase (HAS2) or take it from naked mole rat. Should the HA-degrading enzyme HYAL2 be deleted? This super-sized hyaluronic acid binds CD44 receptors, suppresses the senescence-associated secretory phenotype, keeps the extracellular matrix densely hydrated and elastic, sequesters reactive oxygen species, and antagonizes NF-κB–driven inflammation, thereby maintaining tissue integrity, delaying cellular senescence, and contributes to the naked mole rat's long lifespan. Generally this page needs more hyaluronic acid content.

bats: reduced growth signaling via GHR/IGF14. telomere maintenance without age-related shortening. Inflammation braking as a longevity strategy: bats have dampened cytosolic DNA sensing (loss of PYHIN genes; STING S358 change), curbing chronic inflammation that drives aging.

rockfishes: positive selection in DNA-repair pathways. (ref)

galapagos tortoise: DNA repair, mitochondrial homeostasis, enhanced immune pathways. XRC6 variant.

TODO

• mitochondrial target of rapamycin (mTOR), mTOR inhibitors, etc...
• endocrine niches broadcast longevity or aging signals; you don't need every cell to change, instead targeting key "broadcast" cell types can move systemic aging (fat, endothelium, hypothalamus, skeletal muscle).
• KAT7 inactivation in the liver to increase lifespan (a histone acetyltransferase). KAT7 is a driver of cellular senescence.
• TODO: chemical activators of telomerase
• TODO: TERT, telomeres and telomerase stuff

Big mice die young but large animals live longer

human eunuchs live 14-19 years longer especially when castrated young. castration delays epigenetic aging and feminizes DNA methylation patterns.

Crazy longevity ideas

• senscent cell killswitch by designer drugs, "INK-ATTAC and p16::3MR, to allow for drug-inducible suicide genes to selectively eliminate p16ink4a-positive senescence at any time" ref (anti-aging/longevity)

Reproductive systems

Fertility

the following is mostly mouse science:

• BAX knockout (-/-) causes a greater follicular endowmnet and oocyte endowment
• BCL-2 overexpression in oocytes increases the primordial follicular endowment by birth; transgenic bcl-2 mice were generated that overexpress human bcl-2 in an effort to reduce prenatal oocyte loss. The later stage follicular pruning still occurs, of course.
• PUMA (BBC3) knockout: increases germ cell and primordial follicle numbers in embryonic and early postnatal ovaries.
• caspase-2 knockout or inhibition: reduces oocyte apoptosis; knockout mice show increased oocyte survival and larger ovarian reserves in experimental settings.
• increase primordial germ cells (PGCs) founder cell count via time-tuned BMP/WNT priming of the posterior epiblast. BMP4 from extraembryonic ectoderm and WNT3 give epiblast cells competence to become PGCs and induce the core specifiers PRDM1/BLIMP1, PRDM14, TFAP2C. Note that biphasic BMP4 or conditional BMP4 happloinsufficiency or Noggin expression may be necessary to preserve PGC pool size.
• epiblast-restricted overexpression (Sox2-CreERT2) of Prdm1/Prdm14/Tfap2c during the competence window should increase the fraction of cells choosing the PGC fate.
• strengthen chemoattraction, chemotaxis and survival cues during the migration and colonization phase via KITL-KIT upregulation in gonadal ridge or along the migration path, for motility and survival; gonad- or mesentery-restricted CXCL12 overexpression or boosted CXCR4 in PGCs might increase capture efficiency; improve beta1-integrin-ECM engagement via PGC-specific ITGB1 gain-of-function or gonadal fibronectin/laminin overexpression. Note that migration cues and integrins are pleiotropic, so it's important to use cell-type-restricted enhancers or drivers to gate these genetic programs.
• oogonia expansion and meiotic entry timing - extend the mitotic window before meiosis during fetal development: delay STRA8 induction via transient Cyp26b1 expression in the fetal ovary or oocyte-restricted dampening of RA/STRA8 signaling, which could allow for extra mitoses to occur, then there are more oogonia available to be enclosed into primordial follicles.
• oogonia expansion and meiotic entry timing - cell-cyle acceleration in oogonia: drive CDK4/6–Cyclin D activity or lower p21/p27 in germ cells to increase symmetric divisions before meiotic S-phase, ideally paired with enhanced DNA repair.
• follicle assembly and perinatal survival - expand the somatic niche (pregranulosa supply) - cortical Lgr5+ pregranulosa cells (stimulated by RSPO1–WNT4–β-catenin) proliferate (upregulate?) to provide the granulosa pool. RSPO1 overexpression or stabilized beta-catenin in ovarian surface epithelium/Lgr5+ lineages could enlarge the scaffold that encloses more oocytes into follicles.
• follicle assembly and perinatal survival - nudge Notch to improve cyst resolution and produce more one-oocyte follicles - oocyte JAG1 upregulation or granulosa Notch sensitization might increase efficient enclosure and reduce multi-oocyte follicles or follicular atresia.
• follicle assembly and perinatal survival - brief prepubertal YAP1 activation in pregranulosa could enlarge early follicle support without prematurely activating the pool.
• Review: primordial pool of follicles and nest breakdown in mammalian ovaries (2009)
• oocyte apoptosis occurs around fetal/perinatal life when the germline cyst breaks down and only a subset of germ cells become oocytes.
• some oocyte apoptosis is related to DNA damage such as double-strand breaks (oocyte DNA damage checkpoint), and this should probably not be blocked, except to the extent that we can upregulate DNA damage repair (although in pools of millions of oocytes it is unclear if DNA damage repair is an important component to maintaining a large supply). Trp63 (TAp63) loss or Chek2 loss protects primordial oocytes from elimination after irradiation/chemo, if you want to preserve oocytes even with damaged DNA. There might be good reasons to want to preserve mature oocytes with damaged DNA, such as for ooplasm donation or oocyte enucleaton.
• oogonia expansion and meiotic entry timing - raise DNA repair capacity to prevent checkpoint-mediated culling: BRCA1 deficiency shrinks the oocyte reserve, while RAD51 activity promotes survival. transgenic RAD51 or BRCA1 up-tuning (oocyte-restricted, perinatal) could reduce DNA damage response (DDR)-triggered losses during/leaving meiotic prophase.
• during cyst breakdown, many nurse-like germ cells die via a non-apoptotic PCD program (acidification). acidification can be blocked pharmacologically (bafilomycin/concanamycin). In mouse perinatal ovaries, many cyst sister cells behave as nurse cells and die via a non-apoptotic, lysosome/acidification-driven PCD aided by pre-granulosa cells (V-ATPase/cathepsin–dependent).
• autophagy supports oocyte survival: germ cell–specific ATG7 knockout causes major primordial-follicle loss (primary ovarian insufficiency phenotype).
• in growing follicles, granulosa-cell apoptosis is central to atresia. Consider altering granulosa cell apoptosis programs (Fas/FasL system, caspase-3).
• evidence for non-apoptotic RCD (autophagy, pyroptosis, ferroptosis) in the ovary in somatic (granulosa) cells.
• CHK1-dependent elimination (checkpoint-1): CHK1 works semi-redundantly with CHK2 to cull oocytes that carry unrepaired meiotic DNA double-strand breaks (DSBs). In Chk2-/- neonatal ovaries, CHK1 turns on after birth and continues the culling. Inhibiting CHK1 in vitro (see LY2603618) rescues oocyte number in Chk2-/- ovaries but also slows cyst breakdown and slows primordial follicle formation.
• Hippo-YAP/TAZ controls ovarian somatic proliferation and ovary organ scaling; granulosa YAP activity promotes growth, while LATS1/2 restrain it.
• larger ovaries and follicles via growth hormone

• upregulate IGF-1 for size, also IGF-1 increases ovulated oocyte number

• protect the ovary during adolescence and pre-puberty ("anti-burnout") via AMH and mTOR inhibitors and AS101 reduces "burnout" (ref); consider low dose persistent AMH or mTOR inhibition (perhaps targeted to the ovary)

• physiologic fetal pruning needs to be aborted or mitigated somehow, possibly via S1P pathway agonism (ref) or S1P pathway protection

Artificial twinning or genetic predisposition to twinning

• (genomically encoded) AMH antibody to reduce circulating AMH such that FSH can recruit more follicles but potentially accelerating ovarian aging and accelerating menopause.
• increased ovarian sensitivity to FSH (via SMAD3 (TGF-β signaling mediator which tunes the ovary's sensitivity to gonadotropin and biasing towards hyperovulation) and oocyte factors).
• dosage of GDF9 (oocyte-derived growth factor) and BMP15 profoundly controls ovulation rate.
• FSHB) (FSH β–subunit promoter/nearby region) variants are repeatedly associated with having dizygotic twins. Mechanistically, FSHB variants modulate circulating FSH and menstrual-cycle dynamics, plausibly increasing the chance of multiple dominant follicles and therefore two ovulations in one cycle.

Monozygotic twinning rates are increased when the zona pellucida is thinned/breached or with specific culture conditions (such as blastocyst culture, other conditions), pointing to abnormal hatching or delayed splitting as triggers. This ties the mechanism to blastocyst dynamics and zona integrity, not to known maternal alleles. There is also a mechanical method for splitting the human embryo into two separate monozygotic embryos from a published study in the the 1990s that a research society censored and demanded that all research data be deleted. oh also he resigned :(.

Fertility goals

• increase fertility
• ovarian hypertrophy, larger ovaries
• more oocytes, more eggs, more primordial follicles, enhanced ovarian reserves, more activated follicles
• more oocyte survival during gestation and pre-pubertal culling
• better DNA DSB repair inside oocytes
• extra ovaries, supernumerary ovaries, access ovaries
• more mature oocytes even with some amount of DNA DSBs or other problems, to use the mature eggs for oocyte donation, ooplasm donation, or oocyte enucleation
• enable further germline genetic engineering
• deliver young mitochondria to aging oocytes, or otherwise optimize mitochondria for 50+ years of support in a cell-cycle-arrested oocyte.
• minimize follicular atrophy, hypoxia, or oxidative stress

TODO

• somehow cause a pool of mitotically-active oogonial stem cells to survive and persist throughout life (prevent meiotic entry, maintain pluripotency, suppress further differentiation cues, interfere with basement-membrane assembly to keep germ cell nests open and not compartmentalized by follicles, engineer somatic ovarian stroma to express GDNF (glial-cell-line-derived neurotrophic factor) and CXCL12 (two niche factors that maintain spermatogonial stem cells in mammalian testes and are absent in the fetal ovary), impose epigenetic breaks on differentiation, inhibit histone-demethylase KDM4B, and then suppression of TAp63 isoforms or up-regulation of anti-apoptotic BCL2 in the OSC sub-lineage would let extra oogonia survive.)
• for very long lived oocytes, consider amphibian or xenopus oocyte DNA DSB or DDR detection and repair genes and mutations
• could we convert spermatogonial sperm cells into mitotically-active oogonial stem cells to produce oocytes instead of sperm? what about the female imprint pattern?
• oocyte-specific deletion of Petn to cause premature follicular activation
• disable Hippo to allow for multiple oocyte activation
• look closer at Hippo in the context of ovarian fragmentation techniques
• FSH overexpression to increase fertility
• disable AMH to increase fertility
• FOXO3 overexpression for enhanced ovarian reserves
• enable or increase human postnatal oogenesis (a controversial subject in fertility science)
• speculation that PCOS (polycystic ovary syndrome) may be related to a larger ovarian follicle pool?
• TODO: consider antibody targets for any of the above, including folliculogenesis, oocyte differentiation, maturation, AMH, follicular atresia, etc.
• TODO: what causes the pre-pubertal drop in follice count or oocyte pool?
• consider GFP expression in oocytes to assist with finding oocytes during future medical procedures
• cortical stroma is largely avascular and has no direct blood supply: arteries penetrate the hilus, branch in the medulla, and then form a fine network that stops at the cortico-medullal border. from there, oxygen, nutrients and drugs must diffuse through the cortical stroma to reach primordial follicles. large animals (sow, cow, ewe) have a thick cortex; the inner third is therefore the most hypoxic and most dependent on follicle-derived VEGF for local neovascularization. cortical stroma itself remains virtually capillary-free until follicles are recruited and secrete angiogenic factors.
• dolphin ovary cortical stroma is very thick. significant hypoxia adaptation. Lactate dehydrogenase isoforms are shifted to the anaerobic LDH-5 form, indicating metabolic reliance on glycolysis rather than oxidative phosphorylation. Antioxidant enzyme activities (SOD, catalase, GPx) in dolphin cortical stroma are low and comparable to values measured in cow, and they decline with age, so the same ROS vulnerability exists.
• PCOS may alter stromal vascularity or vascularization.

• programmed or permanent infertility (you'd be making a bet on the development of assisted reproduction technologies in the future, such as creating sperm or eggs from skin cells) (many infertility-causing mutations are known); there are various longevity benefits from certain kinds of eunuch.

• in mice: Hdac6 overexpression causes older mice to continue to produce larger litters.

• PEPCK-Cmus mice (overexpression of cytosolic PEPCK in skeletal muscle) show a longer window of remaining reproductively active

• ventromedial hypothalamus circuits are essential for female mating behavior

• inhibition of hypothalamic AgRP neurons rescues fertility of diet induced obesity female mice (ref)

Certain genetic changes could be beneficial for the production of human oocytes that are usable for human cloning, ooplasm donation, somatic cell nuclear transfer, in vitro fertilization, etc: more mitochondria, larger oocytes, more ooplasm, various cell cycle intervention "hooks", ..

Crazy ideas for more fertility

• fetal ovarian donation either from clones or fetal ovarian/oocyte donation from an aborted fetus
• extra ovaries, this is genetically difficult to implement.

Pregnancy

TODO: increase predisposition to twinning or maternal-utero compatibility with pregnancies of multiples. see also fertility upregulation in the TODO section below. see also in vitro fertilization (WIP).

Reduced morning sickness during pregnancy

• heightened morning sickness and vomiting: rs1891246, rs790899 -- see Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2)
• "Genetic variants influencing the human chorionic gonadotrophin hormone, serotonin and autoimmune functioning have been proposed as candidates for nausea and vomiting during pregnancy (NVP). It has also been proposed that there is a higher frequency of severe NVP in patients with disorders in taste sensation, in the glycoprotein hormone receptor or in fatty acid transport." from ref

Puberty and sexual characteristics

• age at first sexual intercourse: mutations near or related to ESR1, CADM2

• number of sexual partners: mutations near or related to CADM2

• risk taking behavior (MDFIC)

• gay gene? low p value found via GWAS, but they put it into mice anyway..

Puberty

MKRN3 H420Q precocious/early puberty

puberty timing, check near: MAPK3, PXMP3, VGLL3, ADCY3-POMC, LIN28B

rs246185 near MKL2 on chromosome 16p13.12 might be associated with 2.1 weeks earlier menarche, arrests early puberty, also impacts male genital development

puberty block: global kisspeptin (kiss1) knockout, global GPR54 (Kiss1R) knockout, conditional (targeted to ARC or APV neuron) Kiss1 deletion or suppression (ref), dicer ablation in Kiss1 neurons

delayed puberty via suppression of GnRH neurons before puberty

for each year of delayed puberty there is a +9 month longevity boost

turn off GnRH neurons (or have them dedifferentiate or change identity) via dominant negative FGFR expression? (ref); or beta1-integrin ablation in GnRH neurons? targeted ablation of GnRH neurons via cell-type-specific expression of diphtheria toxin receptor (DTR) or caspase?

block pituitary response to GnRH via GnRH receptor (GnRHR) knockout

GnRH1 knockout - direct elimination of the primary GnRH peptide.

other possibilities:

• Neurokinin B (NKB/TAC3) knockout: remove the upstream signal for GnRH expression.

• pituitary hormone disruption: eliminate and knockout LH beta subunit (LHB), or FSH beta subunit (FSHB); common glycoprotein alpha subunit (CGA) knockout (to affect both LH and FSH); or pituitary-specific transcription factor knockouts (SF1, PROP1, POU1F1).

• gonadal steroidgenesis blocking (testosterone, estradiol, steroidogenesis regulators, etc..), not entirely recommended.. was the goal eunuch? see separate eunuch section.

• anti-mullerian hormone (AMH) overexpression can suppress gonadal function

• gonadal development: gonadotropin receptor knockouts (LHCGR (LH/hCG receptor), FSHR (FSH receptor))

• germline-specific ablation or apoptosis etc.

• synthetic transcriptional repressors or designer proteins to silence pubertal gene networks

Puberty blockers can also be used to make "perma puppies" that don't go through puberty or mature into adulthood.

TODO: make puberty optional or subject to a master control switch via inducible expression techniques. Let the child trigger puberty whenever they want: wait 5 more years? wait 20 years?

Delay puberty by a substantial amount: look at mutations in/around ZNF483, GPR83 (a G protein‐coupled receptor) related to GnRH neurons (GPR83 seems to modulate signaling of MC3R, which is known to sense nutritional signals). Also LIN28B, MKRN3, KISS1, rs364663 at the LIN28B locus (effect ≈ 0.089 years per allele). Delayed puberty has been found in families with mutations in or around FGFR1, GNRHR. Mutant HS6ST1. Familial delayed puberty via disruption of GnRH neuronal migration during embryonic development and IGSF10 from a Finnish family.

Menstruation and menstruation pain (dysmenorrhea)

reduce pain in the uterus (dysmenorrhea) via NaV1.7 (SCN9A) congenital pain insensitivity modifications targeted to the uterus? conditional expression based on systemic drug to activate it? It would be interesting to be able to re-activate the SCN9A nociceptors in the uterus during pregnancy.

TRPV1-lineage primary afferents drive pelvic tactile allodynia in endometriosis and VEGF-driven uterine pain models; maybe TRPV1 antagonism or neuron-specific manipulation could blunt uterine pain?

maybe an oxytocin-linked contractility pathway is responsible for some of the pain? (ref) Consider uterus-targeted COX-2 inhibition, knockout, or reduction.

reduce or disable dysmenorrhea (primary locus might be NGF, IL1A, and IL1B). pain severity seems to be associated with nerve growth factor (NGF) mutations (ref).

Another way to reduce mensturation pain is to surgical (but could possibly be replicated by genetics): ovarian denervation for dysmenorrhoea, presacral neurectomy but high risk of complications including constipation and urinary dysfunction, laproscopic uterine nerve ablation is another option but has not been found to eliminate the pain suggesting that the source of menstrual pain may have multiple origins. Also the laproscopic uterine nerve ablation apparently only offers short-term pain relief (12 months) (ref)??

TODO: disable menstruation by switching human biology to estrus instead of menstruation. This will be difficult. Separately, menstruation can be disabled by exogenous systemic oral contraceptives (Lybrel, Seasonique), progestin-only methods (hormonal IUD, depot medroxyprogesterone acetate (Depo-Provera), etonogestrel implant, and we could express the hormone endogenously if we want to add that. Direct physical endometrial ablation or hysterectomy is an alternative option.

Menopause

delayed age of menopause: rs13196892 located between genes TXNDC5 and MUTED is associated with delayed age of menopause, and rs6467223 in TNPO3 is also associated with delayed age of menopause.

maybe: optional or delayed menopause, such as through ovarian time travel where you cryopreserve one of the ovaries early in life and then implant it 50 years later to use your younger ovary later. This is not a genetic change.

See also puberty blocking genetics.

Sexual characteristics

mammary and breast size: http://www.snpedia.com/index.php/Breast_size and ref - see rs7816345, rs4849887, rs17625845, rs12173570, rs7089814, rs12371778, rs62314947, rs7089814(C;C), rs4665972(C;C), rs4849887(C;C), rs2819348(T;T), rs17356907(A;A), rs34479159(T;T), rs10488023(A;A), rs61159171(C;C), rs61280460(A;T), rs4820792(C;C), rs7837045(A;C), rs17625845(T;T), rs1529102(C;T), rs7102705(A;G), rs7104745(A;A), rs12585963(A;A), rs62314947(C;T)

erectile dysfunction risk - rs57989773 near 6q16.3 between MCHR2 and SIM1 (ref)

rs193536 - might impact male genitals and TF binding

The embryonic genital tubercle is the shared primordium of penis/clitoris. Sonic hedgehog SHH from urethral epithelium maintains a proliferative mesenchymal progenitor pool; loss shrinks the organ by ~75% via lengthened cell cycle. WNT5A also drives outgrowth and urethral tubulogenesis. HOXA13/HOXD13 dosage is essential for genital tubercle formation. Androgen signaling (androgen receptor signaling via SRD5A2-mediated DHT) masculinizes the genital tubercle. Androgen receptor loss (Tfm) (such as AR knockout) yields female-typical external genitalia. In mouse, SRD5A2 loss can be partly buffered by testosterone. Androgen biosynthesis plays some role in addition to androgen receptors.

in mice: (1) genital tubercle outgrowth via SHH, beta-catenin, WNT signaling, (2) masculinization.

Regulation of external genitalia development (2019)

mouse - Delineating a conserved genetic casette promoting outgrowth of body appendages. Note that the genital tubercle is larger in the AER-R26Fgf8-GOF (gain of function) embryos which also show excessive limb development. There is also in one figure a postaxial extra digit in the forelimb. "To compare the function of FGF8 in the limb and GT, we mated the R26Fgf8 allele with a transgenic Msx2-Cre line [35], which confers Cre expression in the forming and mature AER and the ventral limb ectoderm. As expected, the AER-R26Fgf8-GOF mutants exhibited excessive limb growth and developed extra digits (asterisk in Figure 3J), an enlarged calcaneus bone (arrowhead in Figure 3K), and ectopic skeletal elements (arrows in Figure 3J–3K, and Figure S4G) in both forelimbs and hindlimbs. These overgrowth phenotypes are similar but more severe than what has been observed in the AER-Fgf4-GOF embryos, and further support the concept that FGF8 plays a pivotal role in promoting the outgrowth of both appendages."

prostate volume - rs11736129 (ref), SYN3 locus.

in mice, prostate size is determined by prolactin and the MYC/miR-32 axis. ejaculate volume possibly driven by FGF3 overexpression (enlarged seminal vesicles and other accessory glands). See this review of mouse male reproductive phenotypes of genetically altered mice.

finger length / finger digit ratio SNPs:

• rs314277 LIN28B
• rs7759968 LIN28B ??
• rs2332175
• rs4902759 upstream of SMOC1

Muscle

Muscle hypertrophy

Muscle hypertrophy can be achieved through myostatin inhibition or knockout of myostatin.

There are a number of options here, but with germline modification, a muscle-specific knockout of ACVR2B or myostatin are good choices.

Also follistatin overexpression in muscle.

myostatin and follistatin and muscle hypertrophy, downregulation of activin type II receptor (ActRIIA/B) (targeted by bimagrumab).

Muscle hyperplasia

As an alternative to muscle hypertrophy, you could instead increase muscle cell progenitors and increase the number of myocytes in the limbs or certain muscle groups (muscular hyperplasia).

TEAD1 (Hippo pathway effector complex partner): myofiber-specific TEAD1 overexpression drives a dramatic satellite-cell hyperplasia (many more Pax7+ cells) without increasing muscle size at baseline. This primes tissue for larger regenerative output because there are more myoblasts available to form new fibers.

Fn14 Tnfrsf12a (TWEAK receptor) in satellite cells increases satellite cell proliferation/self-renewal during injury.

beta-catenin activity is critical for determining myofiber number during myogenesis in embryogenesis.

Tcf4+ fibroblasts / PDGFRα+ FAPs regulate myogenesis and can bias fiber formation during development and regeneration. (ref)

A missense mutant myostatin causes hyperplasia without hypertrophy in the mouse muscle (2002) (myostatin C313Y)

Note: in both muscular hypertrophy and muscular hyperplasia, it is important to check what happens to the heart, or to specifically exclude the heart from targeting.

Muscle strength

muscle-targeted IGF-1 overexpression (various promoters: mIGF-1, α-actin, MCK) increases postnatal muscle mass and strength; multiple lines report larger fibers and higher tetanic force, and protection from age-related weakness. Mechanistically linked to AKT/mTOR.

FOXO family (muscle catabolism gatekeepers): FoxO1/3/4 triple knockout mice maintain or increase strength into aging by suppressing atrophy programs (UPS/autophagy genes). Earlier work shows FoxO loss protects from muscle loss.

inducible/conditional muscle AKT1 activation causes fiber hypertrophy and higher strength, especially in fast glycolytic fibers. myr-AKT1 models show increased grip/peak force and IIb fiber growth.

enhancing ACTN3 (α-actinin-3 "power gene") function or maintaining fast-fiber identity is pro-strength.

conditional Ctnnb1 (beta-catenin) studies show it's critical for fetal myogenic progenitor number and eventual myofiber output, which will secondarily set attainable strength.

in human:

• power/strength markers: ACE Alu I/D (rs4646994) (called ACE D); ACTN3 Arg577; AMPD1 Gln12; HIF1A 582Ser; MTHFR rs1801131 C; NOS3 rs2070744 T; PPARG 12Ala;
• muscular strength - https://www.biorxiv.org/content/early/2017/10/10/201020 - mutations near FTO, SLC39A8, TFAP2B, TGFA, CELF1, TCF4, BDNF, FOXP1, KIF1B, ANTXR2, etc.

Muscle (hyper)innervation

Note that muscles naturally pull in more innervation on its own when growing, although only to a point. Myostatin null mice show more total axons and more motor axon innervation. By comparison, muscle IGF-1 increases muscle mass but not innervation.

• hyperinnervation via muscle GDNF overexpression but no behavior changes reported.
• LRP4 overexpression in muscle improves neuromuscular junction (NMJ) structure/innervation. increased grip strength, hanging time, and running distance.
• DOK7 overexpression enlarges neuromuscular junctions, increases innervation, improves motor function. improved rotarod performance and plantarflexion torque. enhanced motor activity and extended lifespan.
• PGC-1α remodels NMJ morphology to look more "training-like" phenotype
• high MuSK overexpression in muscle (HSA::MuSK transgene): leads to ectopic AChR clusters and synapses throughout the muscle; motor axons branch to contact these sites, and synapses form even without agrin, rescuing lethality in agrin mutants (i.e., more synapses than normal patterning would allow
• more neuromuscular junction formation via muscle-wide secretion of transgenic "mini-agrin"
• excessive phrenic nerve branching and innervation of ectopic diaphragm muscle via motor neuron Neuropilin-1 (Npn-1) loss
• Pten deletion in motor neurons: hypertrophic axons/nerve and accelerated recovery of axon numbers after facial nerve injury; baseline terminals enlarged (a sprouting-prone phenotype).

Early in development, each endplate is initially polyneuronal but undergoes synapse elimination to end up mono-innervated. Is this necessary? Can it be eliminated?

Muscle metabolism

PEPCK-C overexpression: In muscle, this allows greatly improved metabolism and endurance (see "mighty mice"). Synergistic effect with myostatin inhibition is untested.

Sprinting vs endurance

• alpha-actin-3 (actinin) for endurance and increased power in sprinters (Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation) ("The results showed that the skeletal muscle of people lacking α-aktinin-3 had a greater proportion of slow-twitch fibers. When they were in the process of cooling, these people were able to maintain their body temperature in a more energy-efficient way. People who lack α-aktinin-3 rarely succeed in sports requiring strength and explosiveness, while a tendency towards greater capacity has been observed in these people in endurance sports.")
• ACTN3 - sprinting vs endurance - rs1815739
• ACTN3 - could we make sprinting vs endurance changes in ACTN3 something that could be genetically switchable in adult if delivered as a germline alteration?
• endurance: ACE Alu I/D (rs4646994) (called ACE I); ACTN3 577X; PPARA rs4253778 G; PPARGC1A Gly482;

Muscle TODO

• hormone targeting
• muscle injury repair and satellite cells
• creatine metabolism?
• muscle recruitment stuff
• genomically encoded exercise mimetics

Sports-related enhancements

Candidate genes for sports doping

This is lifted from this table.

Gene/product	System/organ targets	Gene product properties	Physiologic response
ACE	skeletal muscles	peptidyl dipeptidase	ACE-D is involved in fast twitch muscles.
ACTN3	skeletal muscles	actin-binding proteins related to dystrophin	Involved in fast-twitch muscles.
endorphins	central and peripheral nervous system	widely active peptides	pain modulation
EPO	hematopoietic system	glycoprotein hormone	Increases RBC mass and oxygen delivery.
HGH	endocrine system	191-amino acid protein	Increases muscle size, power, and recovery.
HIF	hematologic and immune systems	multisubunit protein	Regulates transcription at hypoxia response elements.
IGF-1	endocrine/metabolic/skeletal muscle	70-amino acid protein	Increases muscle size, power, and recovery by increasing regulator cells.
myostatin (MSTN)	skeletal muscle	2-subunit protein	Regulates skeletal muscle. Inhibition increases muscle size, power, and recovery.
PPAR-delta	skeletal muscle and adipose tissue	nuclear hormone receptor protein	Promotes fat metabolism and increases number of slow twitch fibers.
VEGF	vascular endothelium	glyosylated disulfide-bonded homodimers	Induces development of new blood vessels.

Abbreviations: ACE, angiotensin-converting enzyme; ACTN3, actinin binding protein 3; EPO, erythropoetin; HGH, human growth factor; HIF, hypoxia inducible factor; IGF-1, insulin-like growth factor; PPAR-delta, peroxisome proliferators-activated receptor (delta); VEGF, vascular endothelial growth factor.

Other genetic changes for sports

• glucagon-like peptide 1 to increase glucose in liver and reduce lactic acid buildups for athletes
• erythropoietin for red blood cell production
• insulin-like growth factor 1
• "an increase in synthesis of monoamines could improve the mood of athletes"
• preproenkephalin for pain reduction
• rs17822931 - dry earwax, sweat production, body odor. "rs17822931(T;T) individuals were at least 5-fold less likely to use deodorant, consistent with them being "genotypically nonodorous"".
• see muscle sections above.

Theoretical "heterozygote advantages" genes

The principle here is that diseases such as sickle cell or Tay-Sachs, among many others, persist in a population because having one 'good' and one 'bad' copy of the gene offers a significant advantage - in disease resistance, intelligence, etc.

While it would be nice to find a point mutation that would mimic the benefits of heterozygosity, the most straightforward option would be to give someone both variants of the gene, with ~50% expression of each.

Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9 -- there is at least one other technique for doing this, perhaps the other one wasn't co-authored by the ex-president of stanford (an independent panel found "manipulation and/or grossly inadequate data handling"? in other research).

Using heterozygous alleles is useful because we know several exact effects of +/- gene dosage, whereas it would take possibly substantial trial-and-error to figure out the exact expression profile to replicate via synthetic gene circuit for expression of that same gene. It's not necessarily "50% expression" merely because the effect is caused by heterozygosity..

It could be possible to program germline genomic programs that cause heterozygotic allele dosage depending on cell type or cell-specific expression throughout development or post-birth gene expression, instead of whole-body heterozygotic allele. So some cells or tissues or organs in the body can be homozygous for the allele while other cells can have different gene dosage and therefore different expression. In general it is probably better to have whole-body heterozyous programming for an allele because you can do upfront sequencing and quality control on the genome before making a fetus, whereas chromosome editing during development (or later in life) will have more moving parts that need to be more carefully quality controlled upfront.

While this document is mainly about germline genetic engineering for whole-body genetic modification, it would also be interesting to consider any beneficial impact from heterozygotic allele gene editing in different cell populations in the adult via adult gene therapy or cell therapy.

TODO: vitamin D linked heterozygotic advantage mutation that allows for escape from accelerated clearance. Causes lower risk of severe respiratory infections and better pregnancy outcomes at high latitude. GC1F/GC1S.

George Church's human genetic engineering wish list

George Church's human genetic engineering wish list

Multigenic traits can have single gene variants -- often rare in populations, (or synthetic alleles absent in nature) with large impacts. Synthetic gene circuits can also provide a monogenic effect.

Genotype: -/- means double-null for the gene (from both mother and father). +/- means one copy ok (+) and one broken (-) is sufficient to have a positive impact. The rest require very specific sequences to see the positive effect. For example E6V means that at position 6 an "E" (Glutamate amino acid codon GAG) is mutated into a "V" (Valine codon GTG).

Gene	Genotype	Protective, resilient or extreme effects	Potential Negatives:
LRP5	G171V/+	Extra-strong bones	Low Buoyancy
MSTN	-/-	Large, lean muscles, low atherosclerosis
FBXO32	-/-	Reduced muscle atrophy	-
MC1R	overprod.	UV radiation resistance	-
TRIM63	-/-	Reduced muscle atrophy	Hypertrophic cardiomyopathy
SCN9A	-/-	Pain insensitive	Unnoticed harm
FAAH-OUT	del/del	Pain insensitive	Unnoticed harm
NTRK1	del/del	Pain insensitive, no sweat	Unnoticed harm, hyperthermia
HSD17B13	+/TA(lof)	Low Chronic Liver Disease
HOXA11	unstated	Augmented manipulation ability with six-fingered hands
ABCC11	-/-	Low odor production
PRNP	G127V	Prion resistance
IFNL4	dG/TT	High Hepatitis C virus clearance
CCR5	-/-	HIV resistance	W.Nile Virus & flu; bone
FUT2	-/-	Norovirus resistance	Crohn's disease
IL23R	R381Q/+	IBD: Crohn's disease, Ulcerative colitis
HBB	E6V/+	Malaria resistance	Exertional rhabdomyolysis
PKU	+/-	Ochratoxin resistance?	Cognitive disability in -/-
CFTR	+/-	TB or other?	GI,Lung issues in -/-
HEXA	+/-	Mycobacteria resistance?	lethal by 4yo -/-
APOL1	+/-	Trypanosoma brucei	Kidney disease risk
APOA1	R173C/+	Low HDL & CVD
PCSK9	-/-	Low coronary disease	Diabetes, Low cognition
GHR,GH	-/-	Low cancer, stature
SLC30A8	-/+	Low T2 Diabetes
IFIH1 = MDA5	E627X/+	Low T1 Diabetes
ANGPTL3	-/+	Lipid and cardiac health
BDKRB2	a/g expression	Deep Diving
PDE10A	c/t incr thyroxine	Breath-hold diving
EGLN1	a/g	High altitude
EPAS1	3.4kb del	High altitude
MTHFR	A222V	High altitude
EPOR	W439X	High oxygen transport
BHLHE41 = DEC2	P385R/+	Less sleep
GRM1	R889W/+ or S458A/+	Less sleep
NPSR1	Y206H/+	Less sleep
ADRB1	A187V	Less sleep
APOE	E2/E2	Low Alzheimer's (E2=R112C, R158C)
APOE	R136S/R136S	Resilience to dominant Alzheimer's PSEN1-E280A
RELN	H3447R/+	Resilience to dominant Alzheimer's PSEN1-E280A
APP	A673T/+	Low Alzheimer's
GLUK4	del/+	Low bipolar, high cognitive
RIMS1	R844H/+	High cognitive	Late onset visual loss
BPIFB4	LAV:I229V/+	Healthspan, low CVD
CETP	I405V/I405V	exceptional longevity & cognitive
SIRT6	A313S or N308K	exceptional longevity
TPH2	g703t	Low aggressiveness / anxiety.
DRD4	exon3 VNTR	Low anxiety, high risk tolerance.
COMT	V158M	Low anxiety, high risk tolerance.	ADHD, headaches, etc
SLC6A4	43bp indel	Low stress, ADHD.	?
BDNF	M66V	Learning.
NR3C1	a>g	Low PTSD risk.
KO, Knock-in, gene therapy	Mice & other mammals
nmrHas2	overprod.	Low aging
CISD2	overprod.	Low aging
BUB1B	overprod.	Low aging
PAWR	overprod.	Low aging
PPARG	overprod.	Low aging
PTEN	overprod.	Low aging
SIRT1	overprod.	Low aging
SIRT6	overprod.	Low aging
SOST	-/-	Bone loss resistance
NPC1	+/-	Ebola resistance
CTNNB1	overprod.	Radiation resistance
TERT	overprod.	Low aging
CDKN2A	overprod.	Low cancer
TP53	overprod.	Low cancer
GRIN2B	overprod.	High learning & memory
NR2B	overprod.	Learning & memory enhancement
ARHGAP11B	human transgene in marmosets	Increased neocortex size & folding
MCPH1	human transgene in rhesus	Human-like brain neoteny
PDE4B	inhib.	Low anxiety, high problem solving
FOXP2	humanized	Learn stimulus-response associations faster
CCR5	-/- & +/-	Enhanced learning, low atherosclerosis, low hepatotox	Flavi- & Orthomyxo- viruses
NLGN3	R451C/Y	Enhanced spatial learning abilities	Impaired social (ASD)
KCNH3	-/- & +/-	Enhanced cognitive function
SP0535	transgenic	improved cognitive ability and working memory
SERPINE1	null/+	Median survival increase from 75 to 85 yr
KL=KLOTHO	gene therapy	Age-related diseases (review-2016)(cognitive-2023)
FGF21	gene therapy	Age-related
sTGFβR2	gene therapy	Age-related
OCT4+SOX2+KLF4	gene therapy	Optic nerve damage recovery
Cognition-related gene therapies
NGF	overprod.	(human) Low Alzheimer's
NEU1	overprod.	(mice) Low Alzheimer's
NGFR	overprod.	(mice) Low Alzheimer's
miR-29b	overprod.	(human cells) Low Alzheimer's
BACE1 siRNAs	overprod.	(mice) Low Alzheimer's
anti-amyloid antibodies	overprod.	(mice) Low Alzheimer's
APPsα	overprod.	(mice) Low Alzheimer's
Based on genome comparisons
Various	Alleles	Parrot longevity & cognition
CHRNA1	W187R	alpha-neurotoxin resistance in Mellivora, Erinaceus, Herpestes, Sus, Naja
NOTCH2NL	Overprod.	Human-specific modifiers of cortical size

Note: Some of the above studies need independent reproduction.

legend: Lower case a,c,g,t are nucleotide variants (typically regulatory), while uppercase indicated amino acid variants.

If you know of additional published or unpublished examples, or anyone who is exceptionally resistance to any disease, or strong familial hereditary traits, please let us know.

Resilience Project, HMS Fairbairn Family Lyme Research Initiative.

geochurch see also list

Longevity: GenAge Database of Ageing-Related Genes

LAV: 30 rare, protective, non-synon mitonuclear Longevity Associated Variants in 18 genes: ITPR1, LRPPRC, ALDOA, MFN2, SPTLC2, ACACB, SAMM50, FAR1, HARS2, ISCU, PMPCB, ATXN3, NDUFS2, ACADM, KIF1B, PRR5L, CYBB, DEPTOR

Height: ~9,500 SNPs explain ~29% of phenotypic variance

Pathogens: CFTR, NPC1, HEXA: Resistance to typhoid, cholera, mycotoxin abortions, enveloped viruses via MOGS, filoviruses, rabies via myasthenia gravis

Space: radiation, low gravity, etc.

geochurch thanklog

Thanks (in chronological order): Joao Pedro de Magalhaes (HAGR), Jason Bobe, Cory Smith, Luke Dabin, Mark Handle, David Thompson, Noah Davidsohn(6), Dimitrie Leustean, Sergiy Velychko, Christopher Schön(3), Chris Mason(3), Michael Shadpour for suggested additions. --GMC

geochurch changelog

26-Oct-2011 4 genes: MSTN, LRP5, PCSK9, CCR5

04-Apr-2012 5 genes: + FUT2

23-Oct-2013 6 genes: + APP

05-Feb-2014 11 genes.

10-Sep-2015 19 genes.

06-Sep-2017 28 genes.

24-Oct-2018 44 genes.

14-Aug-2019 51 genes.

09-Oct-2019 52 genes: + ADRB1

18-Oct-2019 54 genes: + NPSR1 + NTRK1

08-Nov-2019 55 genes: + APOA1

05-Jan-2022 59 genes: + MCPH1 + NOTCH2NL + ARHGAP11B + NR2B

23-Aug-2022 60 genes: + KCNH3

21-Nov-2022 67 genes: + Klotho + CHRNA1 + FGF21 + sTGFβR2 + OCT4 + SOX2 + KLF4

22-Nov-2022 74 genes: + CISD2 + BUB1B + PAWR + PPARG + PTEN + SIRT1 + SIRT6

03-Apr-2023 75 genes: + SP0535

24-Oct-2023 76 genes: + SERPINE1

22-Dec-2023 79 genes: + MC1R, FBXO32, TRIM63

12-Nov-2024 80 genes: + GRM1

07-Sep-2025 86 genes: + TPH2 + DRD4 + COMT + SLC6A4 + BDNF + NR3C1

geochurch space genetics

Space genetics: What if we cure aging and eliminate poverty and diseases of developing nations? We're going to have overpopulation, or at least some people say that. I don't think it's a great solution to say well we're not going to cure diseases of poverty or aging of the industrialized nation. One possibility is going to space. I don't mean this frivolously. It's a good idea for our species because we're at risk from supervolcanoes and asteroids. In space, we have a new set of problems including radiation and low gravity even on Mars. And then there's space genetics issues. We have a consortium on this and space colony challenges.

We have challenges like gravity, osteoporosis, neuro-behavioral issues, microbiome issues.

Kind of a quirky list here. These are rare protective alleles. They are things that make your bones extra strong which could result in something that could help in space, or on earth. Some that reduce pain sensitivity, which you might want to turn on and off, because if you have it off all the time then maybe you end up hurting yourself like kids chewing on their tongues. ABCC11 will give you low odor which might be helpful in space travel contexts. The good version is common in Asian populations.

There are some things that have been tested in animals, like low cancer and high cognitive ability.

What about radiation resistance? Here's a case in the literature where radiation resistance was improved 100,000-fold. 10-fold using e14-deletion. 50-fold using recA. 20-fold using yfjK. And 10-fold using dnaB. See Ecoli, Byrne et al, eLife 2014 ("Evolution of extreme resistance to ionizing radiation via genetic adaptation of DNA repair"). This only requires 4 mutations. There is a wide variation in natural organisms, but the only difference here is those 4 mutations.

• Dsup from tardigrades for radiation resistance

Regeneration

Make a general embryological platform for regeneration. Salamanders achieve this through dedifferentiation but perhaps for human we can achieve this via in vivo maintenance of primordial pluripotent stem cells throughout adult life. There might be other ways to achieve this goal around healing.

Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle

Lack of p21 expression links cell cycle control and appendage regeneration in mice

TODO: maintain primordial pluripotent stem cell pools throughout adult life.

TODO: look at salamander cell dedifferentiation capabilities, can we import that into human cells as a switchable capability?

Just saying "regeneration" is kind of ridiculous, it's like saying "let's add hiberation" -- okay good luck...

TODO

• Tetracycline response elements, i.e. tet-on and tet-off, can be used for transgenes where constant expression is undesirable. While a number of options for such inducible expression exist, the tet system is the most studied. It is left as an exercise to the reader to determine which genes would be suitable candidates [I will add some when I get around to it (editor's note: 13 years later.... Also DREADDs might allow for higher multiplexing or bandwidth?)].

• l-gulonolactone oxidase knock-in (re-enable human synthesis of vitamin C) http://www.anti-agingfirewalls.com/2018/03/11/double-gene-knockout-behind-obesity-epidemic/, or via GULO

• retinoid conversion: BCMO1

• Engineering into human genome the capability to synthesize essential amino acids, essential fatty acids and essential vitamins ("synthesizing a prototrophic human genome")

• for digestion, consider: add desaturase enzyme to convert from n-6 polyunsaturated fatty acid (PUFA) to n-3 PUFA (like DHA or other omega 3 fatty acid) (fat-1 pigs, fat-1 cattle, pigs with both fat1 and fat2 to handle more precursors, ...); keratinase, chitinase, uricase, better lysozymes, oxalate oxidase, ligninase, better proteases. Not all of these should be encoded into human germline due to inefficiency. Also, adding this to our food supply or gut microbiome is easier than adding it to human germline. Are there other digestion and metabolism modifications we should consider?

• optimize metabolism and nutrition for modern dietary demands (see here)

• human metabolism and weight loss and insulin stuff and kidney stuff, see http://gnusha.org/logs/2018-02-18.log

• hemoglobin from horses? can we just slap in a better myoglobin?

• add sickle cell hemoglobin for anti-malaria reasons

• for metabolism, consider ATP synthase re-engineering to remove more c-rings, or add more c-rings; differential expression of this ATP synthase based on which cell or tissue.

• reduce oxidative stress: enhance antioxidant defense, reduce ROS production, improve ROS detoxification, support redox homeostasis. Consider increasing expression of mitochondrial superoxide dismutase, glutathione peroxidases, catalase (target to peroxisomes or mitochondria), mitochondrial peroxiredoxins; for redox regulators: NRF2/NFE2L2 gain of function, FOXO3 overexpression to upregulate MnSOD/catalase/sestrin, PGC-1α to induce mitochondrial biogenesis and antioxidant enzymes (SOD2, GPX1); ROS producers - knockdown NADPH oxidases as a major source of ROS in many tissues, monoamine oxidase B, SDHA complex II, .... increase GCLC/GCLM to ratelimit glutathione synthesis; SLC7A11 overexpression to support GSH synthesis; thoredoxin reductase overexpression to regenerate reduced thioredoxin which is a key redox buffer. Careful about where these changes are expressed, in what cells or which tissues. This might be slop, consider systemic effects and oxidative homeostasis/respiration/etc.

• multi-virus resistance through recoding the genome to use an alternate codon mapping code so that virus genomes that use natty codon-AA mappings are unable to replicate inside cells that have their whole genome codon recoded. (belongs in immune section?)

• TODO: review human accelerated regions (segments of the human genome that are conserved throughout vertebrate evolution but are strikingly different in humans, especially compared to chimpanzees); and long non-coding RNAs (lncRNAs). See also "A high-resolution map of human evolutionary constraint using 29 mammals. Note also that thee are human-specific deletions compared to chimpanzees in otherwise conserved sequences. "A study examining intragenic clustering of human accelerated elements found that the transcription factor neuronal PAS domain-containing protein 3 (NPAS3) has the largest population of noncoding-accelerated regions. NPAS3 is active during mammalian brain development and the human accelerated elements within this locus predominantly appear to act as transcriptional enhancers."

• find areas of "accelerated evolution" in recent human genome; look at common mutations in the population; most mutations are probably detrimental or neutral. It's possible to figure out which genes (and alleles in particular) have been spreading rapidly throughout the population, so we should look at that information. Compare against neanderthal genome and other ancient human genomes that have been sequenced. Compare also to great ape genomes, chimpanzee, orangutan, macquee, etc. See also recent human adaptation (2024).

• "Partitioning heritability by functional annotation using genome-wide association summary statistics table 1 shows regions correlated with different conditions such as height (chondrogenic dif, H3K27ac), age at menarche (fetal brain tissue, H3K4me3), etc. Modifications in H3K4me3 in the angular gyrus correlate with years of education.

• in human vs apes, humans have 5 more copies of DRD5 than any other primate ref; and an increase in variable number of tandem repeats within the coding region of the third exon of the DRD4 gene (different gene).

• stomach size minimization or control

• organ duplication: multiple kidneys, multiple livers, multiple hearts (Doctor Who syndrome), functional polydactyly

• kidney/liver size increase, or supernumerary kidneys (extra kidneys), possibly through genetic modification but also possibly through cloning and etal surgery to add cloned liver (as an alternative to liver organoid transplant or liver organ donor transplant)

• sleep: reduced or zero perception of sleep pressure, anti-tiredness (might be a form of insomnia? might be adenosine metabolism related in brain neurons?) Stronger chemical or molecular control over sleep-related neurons.

• copy-paste some of the gene therapies from earonesty's list: https://web.archive.org/web/20150907230432/http://www.documentroot.com/2014/08/gene-therapies-i-want-to-see-developed.html

• gallstone disease - variants in ABCG8 and TRAF3 ref

• diving; large spleen - PDE10A mutations, thyroid hormone modulation; BDKRB2 - affects constriction of blood vessels in the extremities; FAM178B - related to carbon dioxide blood levels.

• alcohol stuff: ADH1B2 and ADH1B3 contribute to faster conversion of alcohol to acetaldehyde. ALDH1B1 contributes to faster clearance of acetaldehyde. ALDH22 common in asians is the alcohol flush reaction and is unable to break down acetaldehyde, a toxic byproduct of alcohol, so it's much easier to get alcohol poisoning.

• tay-sachs allele and IQ ? was this debunked or no?

• personality - see ref (?) This system is conserved across various mammalian species. SNORD copy number variations. "Particularly significant are SNORD115 and SNORD116_2. The latter is the variant that is predicted to bind to Ankrd11 exon X, while the possible target genes for the other two SNORD116 variants are not yet clear. These latter ones show generally only little copy number variation (Table 1). However, we note that the direction of the correlation is different between rodents and humans. In humans, the relatively higher anxiety group has the smaller number of copies, while it is the other way around in the three tested rodent species (see above)." -- regulation of behavioral variance using snoRNAs.

• disable human wisdom teeth aka third molar agenesis or M3 agenesis

  • PAX9 Ala240Pro Is Not Associated with Hypodondotia/Oligodontia or Cleft Lip/Palate but May Cause Congenitally Missing Third Molars.

    • other mutations in PAX9, and mutations in MSX1, AXIN2, ectodysplasin EDA/EDAR cause oligodontia?

  • GWAS third molar agenesis THSD7B, GRIN2B, LUZP2, ZBTB24, THYN1 are all probably bad targets

• gwern.net/Embryo-editing

• encode CRISPR-Cas9 or even dCas9 fusion proteins into the germline genome such that future payloads can rely on Cas9 or dCas9 availability for future genetic upgrade delivery into adults.

• disable germline transmission of certain modifications (germline editing is primarily required for zero mosaicism by modifying pre-conception or post-conception a single cell embryo, but this is only a delivery detail not something specifically related to desiring inheritance; long-term inheritance is a secondary goal that could be toggled on and off)

• if you can cause ancephalic (or anencephalic?) human fetal development via embryo engineering (such as for human cloning), then i wonder if you could introduce an engineered non-ancephalic neural cell line into the embryo (hybrid, mosaic or chimeric embryo) and have it develop the cortical neural tissues instead of the ancephalic cell line. this reduces concerns of non-brain pleitropy. The metabolic and other biological requirements in neurons is likely to be vastly different from the demands of the other cell types in the body; an increase in separation of concerns can reduce undesirable or unintended side effects including non-genomic other-tissue/other-organ "off-target effects".

• anti-sunburn, sunburn protection- see SOD pathway upregulation. additional radiation damage resistance, radiation damage repair, DNA damage repair pathway upregulate, ...

• reduce human skin attractiveness to mosquitos, possibly related to carboxylic acid secretions. Why can't we secrete nicer smelling odors or perfumes anyway.

• TODO: incorporate things about neochromosomes and human artificial chromosomes (HACs) from the IRC logs. sc2.0 had a neochromosome to store all their tRNA synthetases. you can knock out an essential gene on a natural chromosome and put it on the artificial one so the neochromosome doesn't get lost over time.

• TODO: make a generic embryological platform for cell-specific expression and cell life cycle control during embryological development to target specific progenitor cell types or proliferators to increase their abundance, or otherwise regulate their proliferation or upregulate/downregulate, such that we can modularly plugin or swap out which cells we are targeting, based on cell lifecycle, rather than having to focus on unique genes related to those specific tissues or organs. Or will we have to edit specific to each tissue type due to quorum sensing and other growth limiting factors? Loss of CDK inhibitor p27Kip1 globally increases organ size and causes multiorgan hyperplasia. Consider CDK4/Cyclin-D1 overexpression. Generic proliferation effectors shown to scale progenitor pools during development.

• improved gyrification, sulcri, encephalization things, better brain anatomy, better white fiber tracts

• appearance, face genetics, symmetry, which parent does the child look like, etc

• resistance to cryoprotectant toxicity for cryonics, cryovitrification, glutaraldehyde cross-linking, etc.

• TODO: make a document or system for GWAS variants, or alleles, or other mutations, indels, chromosomal microdeletions, etc, for which variants to avoid when making a germline genetically engineered human. Simply eliminating non-consensus genome mutations will substantially improve health and longevity, as Bram Cohen likes to point out. Did he not publish on this? there's no reference for this concept? There is also some additional value in intentionally avoiding known-harmful mutations or alterations.

• acromegaly-like targeted GH/IGF-1 receptor improvement in hands to increase hand size?

• supernumerary or extra cranial nerve roots or other spinal nerve fibers, with the expectation that they might be repurposed in the future for brain-computer interfaces or for reinnervation of muscles. Could be convenient to have some spare nerve fibers around that are already correctly wired into the brain. Might also help with surgical repair of brachial plexus injuries or other nerve fiber dissection injuries. With spare nerve fibers, the surgeon would have sufficient material to patch you back together. Are there any nerve fiber targeted genetic changes that could assist with PEG+chitin nerve fiber repair and healing?

• codon recoding: other than for multi-virus anti-virus resistance, check for poorly coded proteins in the human genome and recode for codon efficiency. Should we migrate proteins that use "rare codons" to use less rare codons (figure out how to achieve equivalent function with a non-rare codon)?

• whole body cell lineage tracing could be scientifically interesting, except that other than for brain uploading not sure if it has a practical use?

• TODO: figure out how to add electroreceptors to human biology. See https://gnusha.org/logs/2025-10-01.log for some ideas about converting primary sensory neurons in epidermis for the detection of microvolt electric field potentials on contact with (for example) someone else's head as a sort of EEG electrode and sensing strategy. With an adequate antennae or microvoltage sensor in the cortex, it may also be possible to do remote (steerable? steered?) sensing of distant entrainment without a direct axon inside of the brain.

• TODO: magnetoreception from birds? This should already be somewhere on this page. Don't know if it would work or if it has been added to mice yet.

• think hard about other outcomes that could be achieved with "immediate early genes" neural behavior cell-tagging techniques.

• TODO: pick good cell expansion, neuronal morphology modifications, electrophysiology tweaks, or optogenetic targets in the prefrontal cortex. These are classic sites for abstraction, rule representation, reasoning, and cognitive control. In primates, the caudate, nucleus accumbens, and dorsal striatum are heavily implicated in controlling rule switching and updating. More generally there are many other circuits in the brain worthy of consideration for either (1) germline cell growth control, (2) overexpression or other regulation of protein expression, and (3) encoding of optogenetic receptors, such as in regions such as thalamocortical, perceptual, direct somatosensory neuron activation, hippocampus, amygdala, basal ganglia, etc. Is it possible to pick certain neurons for optogenetic activation and use an out-of-band computer algorithm for the enhancement of learning rates, reasoning, abstraction, or other tasks? Does adding cells help? Does adding NMDA receptors help? more/less NMDA receptors? NR2B receptors? Direct control over cell-targeted synaptic plasticity under computer control via biofeedback and optogenetics? Consider targeting of association cortex or temporal cortex. What about online real-time stimulation changes for language/grammar learning?

Neuronal enhancements for brain-computer interface

TODO: larger neurons on surface of brain for interface with brain-computer interfaces? are there any other genetic changes to facilitate interfacing with long-term electrode implants? or the vascular electrode (stentrode?) scheme? optogenetic control of neurons proximal to the surface of the neocortex or other brain cortex surfaces? what about inside grooves, gyri or sulcri? Optogenetics seems like one area to consider for brain-computer interfacing at least in the "write" direction. There are many optogenetics systems available for germline and in vivo stimulaton of freely moving/behaving animals with implants. Minimize astrocyte reactivity via reduction of glial fibrillary acidic protein expression for long term electrode compatibility. Coat brain implant electrodes with AAV for localized delivery and expression of anti-inflammatory factors, modulation of inflammatory response or pro-inflammatory cytokines, reduce microglial activation around implants. Integrin overexpression to enhance cell adhesion to electrode surfaces. ECM modifiers like fibronectin expression. Red-shifted opsins like ChrimsonR or Jaws for deeper tissue penetration in optogenetics, or two-photon responsive opsins. Are there any free-range animal BCI research projects using genetically encoded voltage indicators to transmit information to the BCI? Or fluorescent calcium indicators? or is it only via chronic window imaging? Ion channel overexpression and other electrophysiology shaping. Would larger dendiritc arbors be helpful? For stentrodes or vascular interface is there anything available to improve interfacing? Upconversion nanoparticles for even more distant neural stimulation via optogenetics. For long-term chronic implants consider LOX (lysyl oxidase) knockdown to reduce collagen crosslinking. BCI could deliver AAV with gene therapy for anti-apoptotic factors, neurotrophic support. Sonogenetic interfacial improvement via mechanosensitive ion channels. Check out magnetogenetics to see if magnetic field responsive ion channels are working or not (maybe something from birds). Neurons can report on their own activity via activity-dependent fluorophores or the oscillatory waves system.

Multiplex DREADDs for cell-type-specific retargeting of transient optogenetic receptor expression

With 46 unique DREADDs with zero cross-talk, you can systemically target every different cell type in the human body. With 92 bits you could get unique cell addressability (uh depending on diffusion and stuff), which seems less useful because you won't know which exact cell got which address? This scheme uses combinatorial ligand-AND addressing: each cell type is prewired with a unique subset of orthogonal DREADDs, and it is "armed" only when the correct delivery of ligands (a k-of-n code) is present over a sliding window period, triggering a synthetic transcriptional circuit that transiently expresses an optogenetic receptor equipped with self-limiting kinetics (e.g., degrons) so the receptor eventually gets recycled while transcriptional activity also decays with time. The opto-receptor can be tuned to cell-type-specific behavior for neurons or other cell types for GPCR style circuit triggering. The optogenetic element can be a receptor or it can be an azobenzene-controlled transcription factor inside the cell nucleus. GPCR per cell type can be hooked up to specific cell-type-specific genetic programming instead of universally expressing a single optogenetic receptor type. Further complicating matters there are also "optogenetic GPCRs" in the literature. Sonoporation mechanosensitive receptor types are available. Various chemogenetic receptors are available. Lots of options here.

Anyway, the result of this scheme is that you can reuse optogenetic receptor wavelengths over the lifetime of the human and use the same wavelengths (at different times) to trigger different kinds of neurons at different times (or other cell behaviors that were pre-engineered). You might also be able to scale via different optogenetic wavelength receptors for simultaneous stimulation or activation of different neuron types through this scheme.

For optogenetic receptors I think we only have a handful right now, maybe four or five? Double check.

And unfortunately the current record for DREADD multiplexing seems to be three or four ligands/receptors?? That's not very multiplexicative so far...

This technique could be combined with "immediate early genes" to specifically "tag" neurons for later re-activation. Maybe even in a "reusable" or "refreshable" way so that "immediate early gene" techniques can be used multiple times throughout the animal's life to target different neurons or different neural circuits.

This could also be used to facilitate better brain-computer interfaces, especially stimulation. Read-out could also be enhanced via fluorescence, optical oscillatory wave generation, luciferase, or other cell signal generation.

See also https://gnusha.org/logs/2025-10-02.log which is where the multiplex DREADD technique for optogenetic re-binding scheme was originally conceived or speculated.

TODO: Also think more about what could be done if we instead use 92 bits to uniquely address every cell in the body. The problem is that you don't know which cells correspond to which addresses. You might be able to localize it by randomly triggering different bits and then looking for some sort of fluorescent event throughout the body to identify the mapping between different bit-vectors and different cells. On second thought, you will need more than 92 bits because you cannot enforce that every cell has a unique address except by making it statistically improbable through the provision of more bits. How many more would you need?

And how would you learn which cells respond to which combinations of bits? How would you solve the search problem where you need to figure out the mapping between a bit-vector and a specific cell? You would want a way to query all the cells in the body and ask them to please fluoresce if they respond to bit n in the bit-vector and then you record that information. You sweep through all the bits and then you combine into a giant bitmask table to get the address of each cell that you were visually tracking.

possibly the cells could self-report via protein recording device that they make internally and export, or it's on a cilia on the external surface of the cell membrane and then detaches and is recoverable in the bloodstream. You could use connectome-seq style mapseq techniques to get a rough approximation of their location in the global graph of cell-cell adjoinancy matrix if not their exact location at least. You could then cartographically pinpoint some of the more popular or easily-identifiable nodes in the graph to track them to their exact location in the mammalian body, and use that to approximate the physical targeting of nearby adjacent cells.

More DNA damage repair via DNA error correction codes etc

TODO: DNA damage repair: improve mismatch repair; improve homologous recombination; upregulate DNA repair enzymes; improve DNA damage radiation resistance; re-engineer the whole human genome and central dogma of molecular biology to use checksums and error correction codes so that DNA mutation errors can be correctly fixed. There are many kinds of error correction codes with interesting properties, such as being able to fix a certain number of errors but at a certain cost of redundancy or encoding size. This would require substantial theoretical molecular biology and protein engineering, and it would likely have a substantial energy cost.

Even more advanced would be a cell network consensus-based DNA error detection and DNA error correction system. This consensus-based DNA validation system would use engineered intercellular communication networks where individual cells randomly sample genomic fragments and query neighboring cells through engineered quorum sensing molecules, DNA fragment querying to neighboring cells, large natural competence pores (or other kinds of transmembrane pores), exosomes, and synthetic G-protein coupled receptor signaling pathways to establish distributed consensus about sequence fidelity. The approach exploits the statistical improbability that identical mutations occur independently across multiple adjacent cells, using Byzantine fault-tolerant algorithms implemented through genetic circuits to distinguish between inherited damage (present across lineages) and spontaneous mutations (isolated to individual cells), ultimately triggering targeted DNA repair mechanisms via fragment import, controlled apoptosis, or lineage replacement when consensus indicates genomic corruption has occurred.

To some extent, the immune system already performs rudimentary versions of this through MHC presentation surveillance and the elimination of cells displaying aberrant peptide signatures, but this proposed system would extend beyond protein-level monitoring to direct nucleotide sequence validation, creating a tissue-wide distributed computing network for genomic integrity maintenance that could dramatically reduce cancer incidence and age-related genetic drift across multicellular organisms. Is there a way to present mRNA transcripts via a MHC-like strategy so that the immune system can monitor random genomic fragments? MHC presentation would be expanded to include objects beyond proteins.

Stretching even farther into the realm of fantasy, another alternative is to design a mechanism of delivering and replacing chromosomes to cells throughout the body via a very large natural competence pore or some sort of exosome technique. Instead of relying on the cellular machinery to maintain the genome over decades or centuries, instead here the idea is to directly deliver genomic material through the bloodstream to distribute to cells throughout the body and re-program them with a known-good copy of the original genome. This would apply also to mtDNA, or maybe all the mitochondrial DNA gets internalized into the nuclear genome anyway for other reasons. Synthetic horizontal gene transfer is another option: cells could communicate with each other and decide which cell has the superior genomic integrity, and then copies are sent over to the other cells (probably easier to just have the other cells die and use cellular division to replace them instead).

Other simple interventions may be appropriate, such as a radiation counter or something that detects a higher incidence of mutational damage, and does consensus or quorum sensing based off of localized high mutational damage or load to decide for apoptosis or whether some other ongoing incident is occurring. A single incident of a DNA base flipping is one thing, but multiple mutations occurring in short succession should be treated as another issue entirely.

ref: Enzymatic elimination of errors from DNA using error correction codes which also mentions an idea for "ECDSA encryption enzymes" (yeah good luck with that buddy).

IRC logs: https://gnusha.org/logs/2017-05-12.log and https://gnusha.org/logs/2017-05-16.log and https://gnusha.org/logs/2025-09-29.log

Microbiome

• TODO: intracellular protein recorders inside gut microbiome to report on metabolism?
• TODO: something about endogenous K2 production

dental caries vaccine

wikipedia

a genetically modified strain of Streptococcus mutans called BCS3-L1, is incapable of producing lactic acid, which dissolves tooth enamel, and aggressively replaces native flora. In laboratory tests, rats who were given BCS3-L1 were conferred with a lifetime of protection against S. mutans. Dr. Jeffrey D. Hillman suggests that treatment with BCS3-L1 in humans could also provide a lifetime of protection, or, at worst, require occasional re-applications. He figures the treatment would be available in dentists' offices and "will probably cost less than $100.

paper: Genetically modified Streptococcus mutans for the prevention of dental caries

Cellular changes and molecular biology

https://twitter.com/AdamMarblestone/status/792803428774866944

From "GWAS catalog"

https://www.ebi.ac.uk/gwas

• self-employment: rs10776614-T, rs17166082-A
• skin youthfulness
• amphetamine response
• response to metformin: rs11212617-A, rs11212617-C, etc.
• verbal-numerical reasoning
• puberty onset
• high number of children: rs13161115-C, rs10908474-A, rs2415984-A, rs10009124
• human facial variation: nose, lip morphology
• eyebrow thickness: rs112458845 (FOXL2), etc.
• reading ability: rs2192161-A, rs7187223-A, or rs349045-T and rs133885 in dyslexia
• narcolepsy: rs1154155-G, rs1154155-C, rs10995245-A, etc.
• musical aptitude
• monobrow
• manic episodes
• loneliness
• longevity and lifespan such as rs12949468 (TLK2), rs4639950 (C1QTNF5), rs7894051 (ECHS1), rs4904670 (NRED2), rs2292664 (RIMBP2)
• insomnia
• length of menstrual cycle: rs564036233-GA (FSHB), rs3124592-G (NOTCH1)
• hoarding: rs3747767-A (LCA5), rs1844437-C, rs2388436-G
• handedness: rs7182874-T (VIMP, PCSK6, CHSY1, SNRPA1), rs11855415-A (PCSK6)
• age-related hearing impairment: rs4932196-T (ISG20, ACAN)
• freckles: rs1805007-T (MC1R), rs12203592-T (IRF4), rs12931267-G (FANCA), rs1015362-G (ASIP), rs4911414-T (ASIP)
• extraversion (personality): rs644148-G (ZNF180)

(insert rant here about how GWAS has rotted everyone's brain and everyone hyperfocuses on GWAS to the detriment of human life...)

there's also OMIM "Online mendelian inheritance in man".

Authorship

This document is old and still updated as of 2025. It is the largest document on the Internet pertaining to human germline genetic engineeirng enhancements. Originally authored by yashgaroth on 2012-06-28. See http://gnusha.org/logs/2012-06-28.log for more context about the original authorship. It has since been updated by multiple different authors and editors.

There are some other modification items remaining in genetic-modifications.csv.