biostudies-literatureHaghani ABritish Heart FoundationCancer Research UKNIDCR NIH HHSEuropean Research CouncilNIA NIH HHSNIEHS NIH HHSNatural Environment Research CouncilWellcome TrustNIH HHSeabq5693https://www.ebi.ac.uk/biostudies/studies/S-EPMC11180965biostudies-literatureUnknown381(6658)Using DNA methylation profiles (<i>n</i> = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in <i>HOXL</i> subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an inteScience (New York, N.Y.)DNA methylation networks underlying mammalian traits.PMC1118096520412NE/R011397/1P30 AG013319R01 AG050797R21 AG078784R21 DE028271U34 AG068482788937FS/18/39/33684R01 AG072736R01 AG043930P01 AG047200R01 AG067782R21 ES024356R56 AG076607R01 AG027237R56 AG072736R21 AG055841R01 AG065403R37 AG046320R21 OD022988U01 AG060908P30 AG044271R01 AG045795Salmon ABCossette MLZhang JWilkinson GSSchomacher LLehmann MPaul KCOstrander EAKrutzen MAlmunia JArdehali RSears KELevine AJCook JAEhmke EENyamsuren BAcosta-Rodriguez VASchachtschneider KMNarayan PThompson MJZhang BArneson ASoltanmohammadi EGerber LEmmrich SSpangler MLPinho GMSimmons MHore TARussell JFei ZLin DTSBrown JLGaillard JMKatcher HKobor MSKashpur OMatkin COOsborn SSzladovits BDirocco SErbay EBrooke RTJasinska AJKatsumata EAblaeva JVernes SCLim ARRydkina EStaggs LDay JJones GHaulena MSpriggs MZhao YWallingford MCYang XWMaddox DAdams DMNagy MVillar DPrado NAZhao PCheng KLemaitre JFErlacher-Reid CFlower JEGoya RGNathanielsz PWParsons KMTakahashi JSBlack PHerrick KDunnum JLLee SGCaulton AWilliams RWZhou WTakasugi MNaderi AYoung BGLu ATVu HSteinman KJHuang TMacoretta NSlone JRobeck TRPeters KJHart DWDeYoung JAloysius AMontano GAShafer ABAChatzistamou IEmmons CKBlumstein DTChavez ASGrant MJMozhui KSchmitt TLiphardt SWLi CZNguyen NBVinters HVClarke SSinha IChoi OWStewart DTCarter GWang NHanson MBHogan ANSingh KSugrue VJChakrabarti LShindyapina AVBreeze CEKaza VMergl JLindemann DMRey BSailer LLDold CVan Bonn BSchook LBSnell RGLi CPlassais JYao MAlagaili ANChiavellini PGreen CBChen HIzpisua Belmonte JCNiehrs CLi XRitz BRHaghani ABennett NCPetersen JLRobbins JReddy POdom DTPellegrini MRodriguez MMunshi-South JGladyshev VNPedersen ABStedman NCooper LNJourdain EGarde EKordowitzki PLittle TJSanghavi AKoski WRFaulkes CGErnst JRaj KBors EKMattison JAGinn POFerguson SHMeudt JJBanks GBelov KYan QHogg CJKiaris HPietersen DWSeifert AWCavin JMMurphy WJMcClure MGorbunova VHorvath SFinno CJO'Brien JKTeeling ECAmor NMSSchmitt DBaker CSPoganik JRZoller JAZhang ZKwon SBLarison BOphir AGSeluanov AfalseDNA methylation networks underlying mammalian traits.Using DNA methylation profiles (<i>n</i> = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in <i>HOXL</i> subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an inte2023-01-01T00:00:00Z2023 Aug2026-05-29T09:52:45.263Z2026-04-08T04:09:17.478ZS-EPMC111809653756187510.1126/science.abq5693