Leveraging base-pair mammalian constraint to understand genetic variation and human disease
Patrick F. Sullivan, Jennifer R. S. Meadows, Steven Gazal, BaDoi N. Phan, Xue Li, Diane P. Genereux, Michael X. Dong, Matteo Bianchi, Diane P. Genereux, Sharadha Sakthikumar, Jessika Nordin, Ananya Roy, Matthew J. Christmas, Voichita D. Marinescu, Ananya Roy, Ola Wallerman, James R. Xue, Shuyang Yao, Quan Sun, Jin Szatkiewicz, Jia Wen, Laura M. Huckins, Alyssa J. Lawler, Kathleen C. Keough, Zhili Zheng, Jian Zeng, Naomi R. Wray, Yun Li, Jessica Johnson, Jiawen Chen, Benedict Paten, Steven K. Reilly, Graham M. Hughes, Zhiping Weng, Katherine S. Pollard, Graham M. Hughes, Karin Forsberg‐Nilsson, Katherine S. Pollard, Andreas R. Pfenning, Karin Forsberg-Nilsson, Joel Armstrong, Matteo Bianchi, Susan J. Birren, Kevin R. Bredemeyer, Ana M. Breit, Bruce W. Birren, Hiram Clawson, Joana Damas, Federica Di Palma, Mark Diekhans, Michael X. Dong, Eduardo Eizirik, Kaili Fan, Cornelia Fanter, Nicole M. Foley, Karin Forsberg‐Nilsson, Carlos J. Garcia, John Gatesy, Steven Gazal, Carlos J. Garcia, Linda Goodman, Jenna Grimshaw, Michaela K. Halsey, Andrew J. Harris, Glenn Hickey, Michael Hiller, Allyson G. Hindle, Robert Hubley, Graham M. Hughes, Jeremy Johnson, David Juan, Irene M. Kaplow, Graham M. Hughes, Kathleen C. Keough, Bogdan Kirilenko, Klaus‐Peter Koepfli, Jennifer M. Korstian, Amanda Kowalczyk, Sergey V. Kozyrev, Alyssa J. Lawler, Colleen Lawless, Thomas Lehmann, Danielle L. Levesque, Harris A. Lewin, Xue Li, Abigail Lind, Danielle L. Levesque, Ava Mackay-Smith, Voichita D. Marinescu, Tomàs Marquès‐Bonet, Victor C. Mason, Ava Mackay-Smith, Wynn K. Meyer, Jill E. Moore, Lucas R. Moreira, Diana D. Moreno-Santillán, Kathleen M. Morrill, Gerard Muntané, William J. Murphy, Arcadi Navarro
Abstract
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.