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

• 成果类型: Article
• 署名作者: 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; 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
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill; Karolinska Institutet; Uppsala University; University of Southern California; University of Southern California; Carnegie Mellon University; University of Massachusetts System; University of Massachusetts Worcester; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Uppsala University; Harvard University; Icahn School of Medicine at Mount Sinai; Carnegie Mellon University; Carnegie Mellon University; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; University of Queensland; University of North Carolina; University of North Carolina Chapel Hill; Yale University; University College Dublin; Chan Zuckerberg Initiative (CZI); University of Nottingham; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9055
• DOI: 10.1126/science.abn2937
• 发表日期: 2023-04-28
• 页码: 367-+
• 关键词: fto obesity variant; causal variants; association; EVOLUTION; gata3; map

摘要

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.