Evolutionary constraint and innovation across hundreds of placental mammals.
Matthew J ChristmasIrene M KaplowDiane P GenereuxMichael X DongGraham M HughesXue LiPatrick F SullivanAllyson G HindleGregory AndrewsJoel C ArmstrongMatteo BianchiAna M BreitMark E DiekhansCornelia FanterNicole M FoleyDaniel B GoodmanLinda GoodmanKathleen C KeoughBogdan M KirilenkoAmanda KowalczykColleen LawlessAbigail L LindJennifer R S MeadowsLucas R MoreiraRuby W RedlichLouise RyanRoss SwoffordAlejandro ValenzuelaFranziska WagnerOla WallermanAshley R BrownJoana DamasKaili FanJohn GatesyJenna R GrimshawJeremy JohnsonSergey V KozyrevAlyssa J LawlerVoichita D MarinescuKathleen M MorrillAustin B OsmanskiNicole S PaulatBaDoi N PhanSteven K ReillyDaniel E SchäfferCynthia C SteinerMegan Ann SuppleAryn P WilderMorgan E WirthlinJames R Xuenull nullBruce W BirrenSteven GazalRobert M HubleyKlaus-Peter KoepfliTomas Marques-BonetWynn K MeyerMartin T NweeiaPardis C SabetiJoshua D KappArian F A SmitMark S SpringerEmma C TeelingNishigandha PhalkeMichael HillerDanielle L LevesqueHarris A LewinWilliam J MurphyArcadi NavarroBenedict PatenKatherine S PollardDavid A RayIrina RufOliver A RyderAndreas R PfenningKerstin Lindblad-TohElinor K KarlssonGregory AndrewsJoel C ArmstrongMatteo BianchiBruce W BirrenKevin R BredemeyerAna M BreitMatthew J ChristmasHiram ClawsonJoana DamasFederica Di PalmaMark DiekhansMichael X DongEduardo EizirikKaili FanCornelia FanterNicole M FoleyKarin Forsberg-NilssonCarlos J GarciaJohn GatesySteven GazalDiane P GenereuxLinda GoodmanJenna GrimshawMichaela K HalseyAndrew J HarrisGlenn HickeyMichael HillerAllyson G HindleRobert M HubleyGraham M HughesJeremy JohnsonDavid JuanIrene M KaplowElinor K KarlssonKathleen C KeoughBogdan KirilenkoKlaus-Peter KoepfliJennifer M KorstianAmanda KowalczykSergey V KozyrevAlyssa J LawlerColleen LawlessThomas LehmannDanielle L LevesqueHarris A LewinXue LiAbigail LindKerstin Lindblad-TohAva Mackay-SmithVoichita D MarinescuTomas Marques-BonetVictor C MasonJennifer R S MeadowsWynn K MeyerJill E MooreLucas R MoreiraDiana D Moreno-SantillanKathleen M MorrillGerard MuntanéWilliam J MurphyArcadi NavarroMartin NweeiaSylvia OrtmannAustin OsmanskiBenedict PatenNicole S PaulatAndreas R PfenningBaDoi N PhanKatherine S PollardHenry E PrattDavid A RaySteven K ReillyJeb R RosenIrina RufLouise RyanOliver A RyderPardis C SabetiDaniel E SchäfferAitor SerresBeth ShapiroArian F A SmitMark SpringerChaitanya SrinivasanCynthia SteinerJessica M StorerKevin A M SullivanPatrick F SullivanElisabeth SundströmMegan A SuppleRoss SwoffordJoy-El TalbotEmma TeelingJason Turner-MaierAlejandro ValenzuelaFranziska WagnerOla WallermanChao WangJuehan WangZhiping WengAryn P WilderMorgan E WirthlinJames R XueXiaomeng ZhangPublished in: Science (New York, N.Y.) (2023)
Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.