Evolutionary constraint and innovation across hundreds of placental mammals
Authors: Christmas Matthew J. , Kaplow Irene M. , Genereux Diane P. , Dong Michael X. , Hughes Graham M. , Li Xue , Sullivan Patrick F. , Hindle Allyson G. , Andrews Gregory , Armstrong Joel C. , Bianchi Matteo , Breit Ana M. , Diekhans Mark , Fanter Cornelia , Foley Nicole M. , Goodman Daniel B. , Goodman Linda , Keough Kathleen C. , Kirilenko Bogdan , Kowalczyk Amanda , Lawless Colleen , Lind Abigail L. , Meadows Jennifer R. S. , Moreira Lucas R. , Redlich Ruby W. , Ryan Louise , Swofford Ross , Valenzuela Alejandro , Wagner Franziska , Wallerman Ola , Brown Ashley R. , Damas Joana , Fan Kaili , Gatesy John , Grimshaw Jenna , Johnson Jeremy , Kozyrev Sergey V. , Lawler Alyssa J. , Marinescu Voichita D. , Morrill Kathleen M. , Osmanski Austin , Paulat Nicole S. , Phan BaDoi N. , Reilly Steven K. , Schäffer Daniel E. , Steiner Cynthia , Supple Megan A. , Wilder Aryn P. , Wirthlin Morgan E. , Xue James R. ,   Zoonomia Consortium§, Birren Bruce W. , Gazal Steven , Hubley Robert M. , Koepfli Klaus-Peter , Marques-Bonet Tomas , Meyer Wynn K. , Nweeia Martin , Sabeti Pardis C. , Shapiro Beth , Smit Arian F. A. , Springer Mark S. , Teeling Emma C. , Weng Zhiping , Hiller Michael , Levesque Danielle L. , Lewin Harris A. , Murphy William J. , Navarro Arcadi , Paten Benedict , Pollard Katherine S. , Ray David A. , Ruf Irina , Ryder Oliver A. , Pfenning Andreas R. , Lindblad-Toh Kerstin , Karlsson Elinor K. , Andrews Gregory , Armstrong Joel C. , Bianchi Matteo , Birren Bruce W. , Bredemeyer Kevin R. , Breit Ana M. , Christmas Matthew J. , Clawson Hiram , Damas Joana , Di Palma Federica , Diekhans Mark , Dong Michael X. , Eizirik Eduardo , Fan Kaili , Fanter Cornelia , Foley Nicole M. , Forsberg-Nilsson Karin , Garcia Carlos J. , Gatesy John , Gazal Steven , Genereux Diane P. , Goodman Linda , Grimshaw Jenna , Halsey Michaela K. , Harris Andrew J. , Hickey Glenn , Hiller Michael , Hindle Allyson G. , Hubley Robert M. , Hughes Graham M. , Johnson Jeremy , Juan David , Kaplow Irene M. , Karlsson Elinor K. , Keough Kathleen C. , Kirilenko Bogdan , Koepfli Klaus-Peter , Korstian Jennifer M. , Kowalczyk Amanda , Kozyrev Sergey V. , Lawler Alyssa J. , Lawless Colleen , Lehmann Thomas , Levesque Danielle L. , Lewin Harris A. , Li Xue , Lind Abigail , Lindblad-Toh Kerstin , Mackay-Smith Ava , Marinescu Voichita D. , Marques-Bonet Tomas , Mason Victor C. , Meadows Jennifer R. S. , Meyer Wynn K. , Moore Jill E. , Moreira Lucas R. , Moreno-Santillan Diana D. , Morrill Kathleen M. , Muntané Gerard , Murphy William J. , Navarro Arcadi , Nweeia Martin , Ortmann Sylvia , Osmanski Austin , Paten Benedict , Paulat Nicole S. , Pfenning Andreas R. , Phan BaDoi N. , Pollard Katherine S. , Pratt Henry E. , Ray David A. , Reilly Steven K. , Rosen Jeb R. , Ruf Irina , Ryan Louise , Ryder Oliver A. , Sabeti Pardis C. , Schäffer Daniel E. , Serres Aitor , Shapiro Beth , Smit Arian F. A. , Springer Mark , Srinivasan Chaitanya , Steiner Cynthia , Storer Jessica M. , Sullivan Kevin A. M. , Sullivan Patrick F. , Sundström Elisabeth , Supple Megan A. , Swofford Ross , Talbot Joy-El , Teeling Emma , Turner-Maier Jason , Valenzuela Alejandro , Wagner Franziska , Wallerman Ola , Wang Chao , Wang Juehan , Weng Zhiping , Wilder Aryn P. , Wirthlin Morgan E. , Xue James R. , Zhang Xiaomeng 
Published: April 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.