Mammalian evolution of human cis-regulatory elements and transcription factor binding sites

• 成果类型: Article
• 署名作者: Andrews, Gregory; Fan, Kaili; Pratt, Henry E.; Phalke, Nishigandha; Karlsson, Elinor K.; Lindblad-Toh, Kerstin; Gazal, Steven; Moore, Jill E.; Weng, Zhiping
• 署名单位: University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Uppsala University; University of Southern California; University of Southern California; Harvard University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12945
• DOI: 10.1126/science.abn7930
• 发表日期: 2023-04-28
• 关键词: transposable elements; retroelements; association; promoters; landscape; enhancers; genes

摘要

Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.