title: Comprehensive identification and analysis of human accelerated regulatory DNA.
abstract: It has long been hypothesized that changes in gene regulation have played an important role in human evolution, but regulatory DNA has been much more difficult to study compared with protein-coding regions. Recent large-scale studies have created genome-scale catalogs of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To better define regulatory DNA that has been subject to human-specific adaptive evolution, we performed comprehensive evolutionary and population genetics analyses on over 18 million DHSs discovered in 130 cell types. We identified 524 DHSs that are conserved in nonhuman primates but accelerated in the human lineage (haDHS), and estimate that 70% of substitutions in haDHSs are attributable to positive selection. Through extensive computational and experimental analyses, we demonstrate that haDHSs are often active in brain or neuronal cell types; play an important role in regulating the expression of developmentally important genes, including many transcription factors such as SOX6, POU3F2, and HOX genes; and identify striking examples of adaptive regulatory evolution that may have contributed to human-specific phenotypes. More generally, our results reveal new insights into conserved and adaptive regulatory DNA in humans and refine the set of genomic substrates that distinguish humans from their closest living primate relatives.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Gittelman
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Enna
authors.initials: E
authors.lastname: Hun
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Ferhat
authors.initials: F
authors.lastname: Ay
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Madeoy
authors.affiliation: Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, California 94701, USA.
authors.forename: Len
authors.initials: L
authors.lastname: Pennacchio
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors.forename: William S
authors.initials: WS
authors.lastname: Noble
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors.forename: R David
authors.initials: RD
authors.lastname: Hawkins
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics; D000818:Animals; D019070:Cell Lineage; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D023281:Genomics / Q000379:methods; D006801:Humans; D010802:Phylogeny; D011323:Primates; D050436:Regulatory Elements, Transcriptional; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D002843:Chromatin