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

Andrews G, Fan K, Pratt HE, Phalke N, Zoonomia ConsortiumĀ§ , Karlsson EK, Lindblad-Toh K, Gazal S, Moore JE, Weng Z

Science 380 (6643) eabn7930 [2023-04-28; online 2023-04-28]

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.

Bioinformatics Support for Computational Resources

NGI Short read [Service]

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

PubMed 37104580

DOI 10.1126/science.abn7930

Crossref 10.1126/science.abn7930

Publications 9.5.0