Protective and Enhancing Alleles. [See also sortable spreadsheet format]
Multigenic traits can have single gene variants -- often rare in populations, (or synthetic alleles absent in nature) with large impacts.
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.
For example: "Ten genes reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing, including familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1) are often not highly penetrant when ascertained incidentally from the general population." [Such penetrance can lead to work on modifier genes].
Lower case a,c,g,t are nucleotide variants (typically regulatory), while uppercase indicated amino acid variants.
See also:
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.
If you know of additional published or unpublished examples, or anyone who is exceptionally resistance to any disease, please let us know.
Resilience Project, HMS Fairbairn Family Lyme Research Initiative.
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, Siddharth Iyer for suggested additions. --GMC
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