The landscape of tolerated genetic variation in humans and primates.
Hong GaoTobias HampJeffrey EdeJoshua G SchraiberJeremy F McRaeMoriel H Singer-BerkYanshen YangAnastasia S D DietrichPetko P FizievLukas F K KudernaLaksshman SundaramYibing WuAashish N AdhikariYair FieldChen ChenSerafim BatzoglouFrançois AguetGabrielle LemireRebecca ReimersDaniel J BalickMareike C JaniakMartin KuhlwilmJoseph D OrkinShivakumara ManuAlejandro ValenzuelaJuraj BergmanMarjolaine RousselleFelipe Ennes SilvaLidia AguedaJulie Marie BlancMarta GutDorien de VriesIan B GoodheadRonald Alan HarrisMuthuswamy RaveendranAxel JensenIdrissa S ChumaJulie E HorvathChristina HvilsomDavid JuanPeter FrandsenFabiano Rodrigues de MeloFabrício BertuolHazel ByrneIracilda SampaioIzeni Pires FariasJoão Valsecchi do AmaralMariluce Rezende MessiasMaria N F da SilvaMihir TrivediRogério Vieira RossiTomas HrbekNicole AndriaholinirinaClément J RabarivolaAlphonse ZaramodyClifford J JollyJane E Phillips-ConroyGregory K WilkersonChristian AbeeJoe H SimmonsEduardo Fernández-DuqueSree KanthaswamyFekadu ShiferawDong-Dong WuLong ZhouYong ShaoGuo-Jie ZhangJulius D KeyyuSascha KnaufQuyen Hanh DoEsther LizanoStefan MerkerArcadi NavarroThomas BataillonTilo NadlerChiea Chuen KhorJessica LeePatrick Boon-Ooi TanWeng Khong LimAndrew C KitchenerDietmar ZinnerIvo Glynne GutAmanda Dawn MelinKaterina GuschanskiMikkel Heide SchierupRobin M D BeckGovindhaswamy UmapathyChristian RoosJean Phillipe BoubliMonkol LekShamil R SunyaevAnne H O'Donnell-LuriaHeidi L RehmJinbo XuJeffrey RogersTomas Marques-BonetKyle Kai-How FarhPublished in: Science (New York, N.Y.) (2023)
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.