DNA methylation networks underlying mammalian traits
Authors: Haghani Amin , Li Caesar Z. , Robeck Todd R. , Zhang Joshua , Lu Ake T. , Ablaeva Julia , Acosta-Rodríguez Victoria A. , Adams Danielle M. , Alagaili Abdulaziz N. , Almunia Javier , Aloysius Ajoy , Amor Nabil M.S. , Ardehali Reza , Arneson Adriana , Baker C. Scott , Banks Gareth , Belov Katherine , Bennett Nigel C. , Black Peter , Blumstein Daniel T. , Bors Eleanor K. , Breeze Charles E. , Brooke Robert T. , Brown Janine L. , Carter Gerald , Caulton Alex , Cavin Julie M. , Chakrabarti Lisa , Chatzistamou Ioulia , Chavez Andreas S. , Chen Hao , Cheng Kaiyang , Chiavellini Priscila , Choi Oi-Wa , Clarke Shannon , Cook Joseph A. , Cooper Lisa N. , Cossette Marie-Laurence , Day Joanna , DeYoung Joseph , Dirocco Stacy , Dold Christopher , Dunnum Jonathan L. , Ehmke Erin E. , Emmons Candice K. , Emmrich Stephan , Erbay Ebru , Erlacher-Reid Claire , Faulkes Chris G. , Fei Zhe , Ferguson Steven H. , Finno Carrie J. , Flower Jennifer E. , Gaillard Jean-Michel , Garde Eva , Gerber Livia , Gladyshev Vadim N. , Goya Rodolfo G. , Grant Matthew J , Green Carla B. , Hanson M. Bradley , Hart Daniel W. , Haulena Martin , Herrick Kelsey , Hogan Andrew N. , Hogg Carolyn J. , Hore Timothy A. , Huang Taosheng , Izpisua Belmonte Juan Carlos , Jasinska Anna J. , Jones Gareth , Jourdain Eve , Kashpur Olga , Katcher Harold , Katsumata Etsuko , Kaza Vimala , Kiaris Hippokratis , Kobor Michael S. , Kordowitzki Pawel , Koski William R. , Krützen Michael , Kwon Soo Bin , Larison Brenda , Lee Sang-Goo , Lehmann Marianne , Lemaître Jean-François , Levine Andrew J. , Li Xinmin , Li Cun , Lim Andrea R. , Lin David T. S. , Lindemann Dana M. , Liphardt Schuyler W. , Little Thomas J. , Macoretta Nicholas , Maddox Dewey , Matkin Craig O. , Mattison Julie A. , McClure Matthew , Mergl June , Meudt Jennifer J. , Montano Gisele A. , Mozhui Khyobeni , Munshi-South Jason , Murphy William J. , Naderi Asieh , Nagy Martina , Narayan Pritika , Nathanielsz Peter W. , Nguyen Ngoc B. , Niehrs Christof , Nyamsuren Batsaikhan , O’Brien Justine K. , Ginn Perrie O’Tierney , Odom Duncan T , Ophir Alexander G. , Osborn Steve , Ostrander Elaine A. , Parsons Kim M. , Paul Kimberly C. , Pedersen Amy B. , Pellegrini Matteo , Peters Katharina J. , Petersen Jessica L. , Pietersen Darren W. , Pinho Gabriela M. , Plassais Jocelyn , Poganik Jesse R. , Prado Natalia A. , Reddy Pradeep , Rey Benjamin , Ritz Beate R. , Robbins Jooke , Rodriguez Magdalena , Russell Jennifer , Rydkina Elena , Sailer Lindsay L. , Salmon Adam B. , Sanghavi Akshay , Schachtschneider Kyle M. , Schmitt Dennis , Schmitt Todd , Schomacher Lars , Schook Lawrence B. , Sears Karen E. , Seifert Ashley W. , Shafer Aaron B.A. , Shindyapina Anastasia V. , Simmons Melanie , Singh Kavita , Sinha Ishani , Slone Jesse , Snell Russel G. , Soltanmohammadi Elham , Spangler Matthew L. , Spriggs Maria , Staggs Lydia , Stedman Nancy , Steinman Karen J. , Stewart Donald T , Sugrue Victoria J. , Szladovits Balazs , Takahashi Joseph S. , Takasugi Masaki , Teeling Emma C. , Thompson Michael J. , Van Bonn Bill , Vernes Sonja C. , Villar Diego , Vinters Harry V. , Vu Ha , Wallingford Mary C. , Wang Nan , Wilkinson Gerald S. , Williams Robert W. , Yan Qi , Yao Mingjia , Young Brent G. , Zhang Bohan , Zhang Zhihui , Zhao Yang , Zhao Peng , Zhou Wanding , Zoller Joseph A. , Ernst Jason , Seluanov Andrei , Gorbunova Vera , Yang X. William , Raj Ken , Horvath Steve 
Published: August 2023

Using DNA methylation profiles (
n
= 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
HOXL
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 intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.