In:
Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6643 ( 2023-04-28)
Abstract:
Mammals, including humans, achieve high levels of organismal complexity largely due to how their proteins are regulated; characterizing the regulatory landscape of the human genome is a longstanding goal of modern biology. Contemporary approaches measure genome-wide biochemical signals, including chromatin accessibility, histone modifications, DNA methylation, and binding of ~1600 transcription factors (TFs) by the human genome. Using these methods, the ENCODE consortium defined almost one million candidate cis-regulatory elements (cCREs). Another approach uses evolutionary conservation to identify potential regulatory regions. We combine these approaches, examining how different functional classes of regulatory elements respond to evolutionary pressures. RATIONALE cCREs tend to be conserved and cCRE classes exhibit varying levels of conservation, suggesting interesting evolutionary dynamics. We examine these dynamics in placental mammals using tools developed by the Zoonomia project: the evolutionary constraint in placental mammals and the reference-free 241-genome alignment. We identify the human cCREs and transcription factor binding sites (TFBSs) conserved in the mammalian lineage, characterize the evolutionary histories of cCREs and TFBSs and identify the driving forces behind their gains and losses and—using biochemical and epigenomic data—assess the likelihood that conserved cCREs and TFBSs are functional in humans and other mammals. RESULTS We explored the ENCODE cCREs derived from epigenomic data and the binding sites of 367 TFs from chromatin immunoprecipitation data. We found a spectrum of mammalian conservation for regulatory elements: on one end lies the highly conserved cCREs and constrained TFBSs, and on the other are primate-specific cCREs and TFBSs overlapping transposable elements (TEs). Conserved elements predominate near genes that function in fundamental cellular processes (metabolism, development) and tend to be functional in other mammalian genomes whereas unconstrained elements lie near genes involved in interaction with the environment. We identified ~439 thousand deeply conserved cCREs (47.5% of cCREs and 4% of the human genome) and 2 million TFBSs (0.8% of the human genome) under mammalian constraint. Using a panel of 69 genome-wide association studies, we found that conserved cCREs and constrained TFBSs achieved high heritability enrichment, demonstrating their utility for functional interpretation of human genetic variants. Meanwhile, more than 85% of primate-specific TFBSs—representing more than 20% of all TFBSs—are derived from TEs. Phylogenetic analysis revealed a staggering number of TFBS clusters sharing patterns of presence and absence across primate genomes and enrichment in specific TE families, suggesting that multiple waves of TE insertion spread these TFBSs during primate evolution. CONCLUSION We charted the evolutionary landscapes of cCREs and TFBSs among placental mammals, identifying a subset of elements under purifying selection in the mammalian lineage. These elements are highly enriched in the human genetic variants associated with a panel of diverse, complex traits, with heritability enrichment contributed by both nucleotides under mammalian and nucleotides under primate constraint. Mammalian evolution of the human regulatory landscape. ( A ) Distribution of human cCREs by the number of genomes they align. ( B ) Projection of cCREs by alignments to the other 240 mammalian genomes. ( C ) Project of HNF4A sites (constrained, red; unconstrained, blue). ( D ) Heritability enrichment for 69 human traits in partitions of TFBSs ordered by evolutionary constraint. ( E ) Heritability enrichment for human traits by subsets of TFBSs.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abn7930
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
