Leveraging base-pair mammalian constraint to understand genetic variation and human disease
Authors: Sullivan Patrick F. , Meadows Jennifer R. S. , Gazal Steven , Phan BaDoi N. , Li Xue , Genereux Diane P. , Dong Michael X. , Bianchi Matteo , Andrews Gregory , Sakthikumar Sharadha , Nordin Jessika , Roy Ananya , Christmas Matthew J. , Marinescu Voichita D. , Wang Chao , Wallerman Ola , Xue James , Yao Shuyang , Sun Quan , Szatkiewicz Jin , Wen Jia , Huckins Laura M. , Lawler Alyssa , Keough Kathleen C. , Zheng Zhili , Zeng Jian , Wray Naomi R. , Li Yun , Johnson Jessica , Chen Jiawen ,   Zoonomia Consortium§, Paten Benedict , Reilly Steven K. , Hughes Graham M. , Weng Zhiping , Pollard Katherine S. , Pfenning Andreas R. , Forsberg-Nilsson Karin , Karlsson Elinor K. , Lindblad-Toh Kerstin , 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

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.