The functional and evolutionary impacts of human-specific deletions in conserved elements

• 成果类型: Article
• 署名作者: Xue, James R.; Mackay-Smith, Ava; Mouri, Kousuke; Garcia, Meilin Fernandez; Dong, Michael X.; Akers, Jared F.; Noble, Mark; Li, Xue; Lindblad-Toh, Kerstin; Karlsson, Elinor K.; Noonan, James P.; Capellini, Terence D.; Brennand, Kristen J.; Tewhey, Ryan; Sabeti, Pardis C.; Reilly, Steven K.; Zoonomia Consortium
• 署名单位: Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Yale University; Jackson Laboratory; Yale University; Uppsala University; University of Massachusetts System; University of Massachusetts Worcester; UMass Chan Medical School; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Yale University; Yale University; Harvard University; University of Maine System; University of Maine Orono; Tufts University; Howard Hughes Medical Institute; Harvard University; Harvard T.H. Chan School of Public Health
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9875
• DOI: 10.1126/science.abn2253
• 发表日期: 2023-04-28
• 页码: 369-+
• 关键词: genome; associations; expression; diversity; SEQUENCES; database; update; cells; dna

摘要

Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel reporter assays in six cell types, we discovered 800 hCONDELs conferring significant differences in regulatory activity, half of which enhance rather than disrupt regulatory function. We highlight several hCONDELs with putative human-specific effects on brain development, including HDAC5, CPEB4, and PPP2CA. Reverting an hCONDEL to the ancestral sequence alters the expression of LOXL2 and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.