Mammalian evolution of human cis-regulatory elements and transcription factor binding sites.
Gregory AndrewsKaili FanHenry E PrattNishigandha Phalkenull nullElinor K KarlssonKerstin Lindblad-TohSteven GazalJill E MooreNishigandha PhalkeGregory 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)
Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.