There are some other things in [[genetic-modifications.csv]]. 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 discord 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. # Gene candidates for germline genetic modification ## Direct gene candidates ### CD47 suppression 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 * * * 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." ### Myostatin inhibition 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. ### PEPCK-C overexpression In muscle, this allows greatly improved metabolism and endurance (see 'mighty mice'). Synergistic effect with myostatin inhibition is untested, but intriguing. ### 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. ### 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." ### Alpha-galactosidase expression 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. ### CCR5 knockout Provides resistance to HIV and plague. Increases risk from West Nile virus, but who gives a fuck about that. Also see HCP5 (rs2395029), and CCL3L1. See also rs333 for other details. ### LRP5 gene (strong bones) Those with the LRP5 gene have extra strong bones. ### PCSK5 (lower coronary disease) Those with the PCSK5 gene have 88 percent lower coronary disease. Also, PCSK9 (according to George Church) is also capable of lowering susceptibility to coronary disease. ### APP (Alzheimer's) "More than 50 different mutations in the APP gene can cause early-onset Alzheimer disease, which begins before age 65." Amyloid precursor protein ### FUT2 (norovirus / stomach flu resistance) Those with double FUT2 are resistant to stomach flu. rs601338 see also ### Allergy * rs2101521 * rs9266772 * rs7720838 * rs10497813 * rs9860547 * rs6021270 * rs17388568 * rs1998359 * rs17533090 ref ### Lactase persistence (lactose tolerance) 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] ### 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 ### Hyperosmia (increased odor sensitivity) rs1953558 - sensitivity to sweaty odor (isovaleric acid) ### Smell rs6591536 - detection of β-ionone (floral) fragrance ### Pain sensitivity rs6269 "A novel human pain insensitivity disorder caused by a point mutation in ZFHX2" chronic back pain - rs12310519 in SOX5, rs7833174 between CCDC26 and GSDMC, and rs4384683 in DCC ref * "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" * 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) ### 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. ### Malaria resistance DARC - rs2814778 HBB - i3003137 G6PD - rs1050828 ### Taste sweetness - TAS1R2 umami - TAS1R1 sourness - PKD2L1 spiciness - TRPV1 signal - GNAT3, TRPM5, PLCB2 bitterness - TAS2R4, TAS2R5, TAS2R16, TAS2R8, TAS2R38, TAS2R48 see also ref ### Increased metabolism PGC-1alpha Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism ### Sprinting vs. endurance ACTN3 - rs1815739 ### Eye color green eye color - rs7495174 blue eye color - rs12913832 ### Hair color - 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. ### 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" * "Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide" * "ADAM12‐S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation" * "A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation" * "Identification of novel genes significantly affecting growth in catfish through GWAS analysis" ### Hearing SNPs related to hearing loss perfect pitch - rs3057 near 8q24 ### Modulated alcohol cravings rs1799971 ### Baldness rs6152 rs1160312 ### Cognitive

- TKTL1 increases basal radial glial cell abundance, which increases cortical neuron production, [implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals](https://www.science.org/doi/10.1126/science.abl6422) - 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 * 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](http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2805%2901371-5/abstract) "The met-BDNF allele was associated with an 11% reduction in the volume of the hippocampal formation." * CAMTA1 - rs4908449 * CLSTN2 - [rs6439886](https://www.snpedia.com/index.php/Rs6439886) - associated with increased episodic memory performance * COMT - [rs4680](http://snpedia.com/index.php/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](https://www.snpedia.com/index.php/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](http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024588) and [The sorting receptor SorCS1 regulates trafficking of neurexin and AMPA receptors](https://www.ncbi.nlm.nih.gov/pubmed/26291160) * DTNBP1 - not rs2619522 * hippocampus volume - TESC - rs7294919, see [Identification of common variants associated with human hippocampal and intracranial volumes](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635491/) * 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 * 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" Hippocampus stuff: [Some loci](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427729/) 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.) 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. * [rs733722](http://snpedia.com/index.php/Rs733722), near the choline acetyltransferase CHAT gene, -- controls whether galantamine can help fight mental decline in Alzheimer's disease * RIMS1 allele causing blindness but significantly increased verbal intelligence 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

#### 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? #### 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
GABA_AR 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
GABA_AR 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
eIF2α^SS1A 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

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	n_GWS
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 risk factor) * 1q21.1-1q21.2 DUF1220 copy number variations correlated with brain size etc and is very human-specific * 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 * TODO: incorporate results from "A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence" * TODO: incorporate results from "Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function" such as mutations in GATAD2B, SLC39A1, and AUTS2; ATXN1L, ATXN2L, and ATXN7L2; DCDC2 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. * 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 ref: Maintenance of superior learning and memory function in NR2B transgenic mice during ageing) * NR2A overexpression (Hobbie-J mice) ref * "Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor" "... 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) ---- "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]." * 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." ---- * TODO: "A genome-wide association study for extremely high intelligence" (2018) * 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." ## 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. ## 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" ## 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." mutations in: * KLOTHO * FOXO3 and FOXO3A and: * APOB rs1801703, rs12713450, rs12720854 * TOMM40 rs2075650 (see ref) * APOC1 rs4420638 * APOE rs429358 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) * CTEP * ZNF562 ... see "[Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study](http://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=5821&context=open_access_pubs)". 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) 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) ## Other notes 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]. - rs4680 "worrier/warrior" cognitive effects ## Puberty and sexual characteristics erectile dysfunction risk - rs57989773 near 6q16.3 between MCHR2 and SIM1 (ref) MKRN3 H420Q precocious/early puberty puberty timing, check near: MAPK3, PXMP3, VGLL3, ADCY3-POMC, LIN28B height related -- rs4788196 near MAPK3, height-increasing allele correlates to decreased expression of MAPK3 finger length / finger digit ratio SNPs: * rs314277 LIN28B * rs7759968 LIN28B ?? * rs2332175 * rs4902759 upstream of SMOC1 rs193536 - might impact male genitals and TF binding rs246185 near MKL2 on chromosome 16p13.12 might be associated with 2.1 weeks earlier menarche, arrests early puberty, also impacts male genital development 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) # Muscular strength * mutations near FTO, SLC39A8, TFAP2B, TGFA, CELF1, TCF4, BDNF, FOXP1, KIF1B, ANTXR2, etc. ## 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" * RCAN1 "Regulator of Calcineurin 1 helps coordinate whole‐body metabolism and thermogenesis" ref * try over-expression of FST, SIM1, MC4R ## Lungs * GPR126 variation impacts carbon monoxide uptake (DLCO) per alveolar volume (DLCO/VA), ref ## Anti-myopia see "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". ## Anti-acne ## pregnancy ### 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 ## Candidate genes for sports doping This is lifted from [this table](http://diyhpl.us/~bryan/papers2/gene_doping_for_sports_enhancement.png).

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. # Others * 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.") * myostatin and follistatin and muscle hypertrophy * 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 * glucagon-like peptide 1 to increase glucose in liver and reduce lactic acid buildups for athletes * endurance: ACE Alu I/D (rs4646994) (called ACE I); ACTN3 577X; PPARA rs4253778 G; PPARGC1A Gly482; * 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; * human tetrachromacy * 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"". # Sleep 4-5 hours of sleep/night, plus resistance to sleep deprivation -- see "The transcriptional repressor DEC2 regulates sleep length in mammals" (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" * BHLHE41 - [rs121912617](http://snpedia.com/index.php/Rs121912617) NPSR1 - [Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation](https://stm.sciencemag.org/content/11/514/eaax2014.full) [pop article](https://www.frontlinegenomics.com/news/27962/second-gene-mutation-that-lets-people-survive-on-less-sleep/) ADRB1 - [Mutation in Beta1-Adrenergic Receptor Affects Sleep/Wake Behaviors]() [pop article](https://www.cnn.com/2021/06/22/health/short-sleep-gene-wellness-scn/index.html) "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" * sleep duration - PAX8, VRK2 (vaccinia related kinase 2) (rs62158211, rs17190618, rs1380703), rs3768984 * GNB3 - rs1047776 A allele and the rs2238114 C allele * ARNTL - [rs10766071](https://www.snpedia.com/index.php/Rs10766071) "has been associated with shorter sleep duration" * ABCC9 - [rs11046205](https://www.snpedia.com/index.php/Rs11046205) - [A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila](https://www.ncbi.nlm.nih.gov/pubmed/22105623?dopt=Abstract) "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](https://www.snpedia.com/index.php/Rs73598374) (higher quality sleep) * CLOCK - [rs12649507](http://snpedia.com/index.php/Rs12649507) * FTO - [rs9939609](http://snpedia.com/index.php/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 # George Church's wish list * LRP5 G171V/+, extra strong bones * MSTN -/-, lean muscles and low atherosclerosis * SCN9A -/-, insensitivity to pain * ABCC11 -/-, low odor production * CCR5 -/-, HIV resistance * FUT2 -/-, norovirus resistance * PCSK9 -/-, low coronary disease * APP A673T/+, low alzheimers * APOE E2/E2, low alzheimers (E2=R112C, R158C) * GHR,GH, -/-, low cancer * SLC30A8 -/+, low type-2 diabetes * IFIH1 E627X/+, low type-1 diabetes * TERT overproduction, low aging * CDKN2A overproduction, low cancer * TP53 overproduction, low cancer * GRIN2B overproduction, high learning and memory * PDE4B inhibition, low anxiety and high problem solving in mice ### Church: 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. Rare protective alleles: * LRP5 G171V/+, extra strong bones * MSTN -/-, lean muscles and low atherosclerosis * SCN9A -/-, insensitivity to pain * ABCC11 -/-, low odor production * CCR5 -/-, HIV resistance * FUT2 -/-, norovirus resistance * PCSK9 -/-, low coronary disease * APP A673T/+, low alzheimers * APOE E2/E2, low alzheimers (E2=R112C, R158C) * GHR,GH, -/-, low cancer * SLC30A8 -/+, low type-2 diabetes * IFIH1 E627X/+, low type-1 diabetes * TERT overproduction, low aging * CDKN2A overproduction, low cancer * TP53 overproduction, low cancer * GRIN2B overproduction, high learning and memory * PDE4B inhibition, low anxiety and high problem solving in mice 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](https://en.wikipedia.org/wiki/Dsup) from tardigrades for radiation resistance # TODO * KAT7 inactivation in the liver to increase lifespan (a histone acetyltransferase) * ARHGAP11B and human cortex size, see "Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset) * l-gulonolactone oxidase knock-in (re-enable human synthesis of vitamin C) * Retinoid conversion: [BCMO1](https://www.ncbi.nlm.nih.gov/pubmed/19103647) * 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 ) * Engineering into human genome the capability to synthesize essential amino acids, essential fatty acids and essential vitamins * human metabolism and weight loss and insulin stuff and kidney stuff, see * multi-virus resistance * snake vision (infrared stuff) * tetrachromacy * other photoreceptors/rods/stuff for eyesight * organ duplication: multiple kidneys, multiple livers, multiple hearts (Doctor Who syndrome), functional polydactyly * stomach size minimization * kidney/liver size increase, or supernumerary kidneys (extra kidneys) * ~~hippocampus size~~ (done) * sleep: anti-tiredness (might be a form of insomnia?) * sleep: can we combine night owl + morning person? * 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) * copy-paste some of the gene therapies from earonesty's list: * olfactory receptor genes, see and A scalable, multiplexed assay for decoding receptor-ligand interactions * 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. * EPAS1 prevents high-altitude blood-thickening process, and is responsible for the Sherpa people being able to survive in high altitude environments (ref1 ref2) * limb regeneration genetics? * disable menstruation * voluntary 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) * optional or delayed puberty (trigger puberty later or whenever the child wants- wait 5 years? 20 years?) * blood types * blood type antigen knockout (universal blood donor, give blood type O-) (can use CRISPR for this) * hemoglobin from horses? * add sickle cell hemoglobin for anti-malaria reasons * tay-sachs allele and IQ ? * Cas9 immunity, Cas9 tolerance (be permissive or restrictive about future CRISPR dosages) * 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) * 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. * 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." * improved anti-cancer apoptosis stuff * [telomerase stuff](http://gnusha.org/logs/telomerase.log) * "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. * GWAS ADHD loci ref; rs11420276, rs1222063, rs9677504, rs4858241, rs28411770, rs4916723, rs5886709, rs74760947, rs11591402, rs1427829, rs281324, rs212178. * 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). * [disable human wisdom teeth](https://twitter.com/bramcohen/status/1135584368611610624) 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.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458632/) * other mutations in PAX9, and mutations in MSX1, AXIN2, ectodysplasin EDA/EDAR cause oligodontia? * [GWAS third molar agenesis](https://www.nature.com/articles/jhg2013106) THSD7B, GRIN2B, LUZP2, ZBTB24, THYN1 are all probably bad targets * anti-sunburn, sunburn protection- see SOD pathway upregulation * 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. * gwern.net/Embryo-editing * figure out what makes human ARHGAP11B cause mammalian brains to grow so much larger ## Microbiome ### dental caries vaccine [wikipedia](https://en.wikipedia.org/wiki/Caries_vaccine) 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](http://link.springer.com/article/10.1023%2FA%3A1020695902160) # Cellular changes and molecular biology # From "GWAS catalog" * 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) # Authorship Originally authored by yashgaroth on 2012-06-28. See [http://gnusha.org/logs/2012-06-28.log](http://gnusha.org/logs/2012-06-28.log) for more context.