Leveraging base-pair mammalian constraint to understand genetic variation and human disease

作者：Patrick F. Sullivan, Patrick F. Sullivan, Jennifer R. S. Meadows, Jennifer R. S. Meadows, Steven Gazal, Steven Gazal, BaDoi N. Phan, Xue Li, Diane P. Genereux, Michael X. Dong, Matteo Bianchi, Gregory Andrews, Sharadha Sakthikumar, Jessika Nordin, Ananya Roy, Matthew J. Christmas, Voichita D. Marinescu, Chao Wang, Ola Wallerman, James R. Xue, Shuyang Yao, Quan Sun, Jin Szatkiewicz, Jia Wen, Laura M. Huckins, Alyssa 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, Andreas R. Pfenning, Karin Forsberg-Nilsson, Elinor K. Karlsson, Kerstin Lindblad-Toh, Gregory Andrews, Joel C. Armstrong, Matteo Bianchi, Bruce W. Birren, Kevin R. Bredemeyer, Ana M. Breit, Matthew J. Christmas, Hiram Clawson, Joana Damas, Federica Di Palma, Mark E. Diekhans, Michael X. Dong, Eduardo Eizirik, Kaili Fan, Cornelia E. Fanter, Nicole M. Foley, Karin Forsberg‐Nilsson, Carlos J. Garcia, John Gatesy, Steven Gazal, Steven Gazal, Diane P. Genereux, Linda Goodman, Jenna Grimshaw, Michaela K. Halsey, Andrew J. Harris, Glenn Hickey, Michael Hiller, Allyson G. Hindle, Robert M. Hubley, Graham M. Hughes, Jeremy Johnson, David Juan, Irene M. Kaplow, Elinor K. Karlsson, Kathleen C. Keough, Bogdan Kirilenko, Klaus‐Peter Koepfli, Jennifer M. Korstian, Amanda M. Kowalczyk, Sergey V. Kozyrev, Alyssa J. Lawler, Colleen Lawless, Thomas Lehmann, Danielle L. Levesque, Harris A. Lewin, Xue Li, Abigail Lind, Kerstin Lindblad-Toh, Ava Mackay-Smith, Voichita D. Marinescu, Tomàs Marquès‐Bonet, Victor C. Mason, Jennifer R. S. Meadows, Jennifer R. S. Meadows, Wynn K. Meyer, Jill E. Moore, Lucas R. Moreira, Diana D. Moreno-Santillán, Kathleen M. Morrill, Gerard Muntané, William J. Murphy, Arcadi Navarro, Martin Nweeia, Sylvia Ortmann, Austin B. Osmanski, Benedict Paten, Nicole S. Paulat, Andreas R. Pfenning, BaDoi N. Phan, Katherine S. Pollard, Henry Pratt, David A. Ray, Steven K. Reilly, Jeb R. Rosen, Irina Ruf, Louise Ryan, Oliver A. Ryder, Pardis Christine Sabeti, Daniel E. Schäffer, Aitor Serres, Beth Shapiro, Arian F. A. Smit, Mark S. Springer, Chaitanya Srinivasan, Cynthia Steiner, Jessica M. Storer, Kevin A. M. Sullivan, Patrick F. Sullivan, Patrick F. Sullivan, Elisabeth Sundström, Megan A. Supple, Ross Swofford, Joy-El Talbot, Emma C. Teeling, Jason Turner-Maier, Alejandro Valenzuela, Franziska Wagner, Ola Wallerman, Chao Wang, Juehan Wang, Zhiping Weng, Aryn P. Wilder, Morgan E. Wirthlin, James R. Xue, Xiaomeng Zhang · 发表于：Science · 年份：2023 · DOI：10.1126/science.abn2937 · 被引用次数：125 · 研究领域：Genetic Associations and Epidemiology、Genomics and Phylogenetic Studies、Genomics and Rare Diseases

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.