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

Document Type

Article

Publication Date

4-28-2023

Keywords

JMG, SS1, Humans, Conserved Sequence, Evolution, Molecular, Genome, Genomics, RNA-Binding Proteins, Sequence Deletion, Brain, Gene Expression Regulation, Developmental

JAX Source

Science. 2023;380(6643):eabn2253.

ISSN

1095-9203

PMID

37104592

DOI

https://doi.org/10.1126/science.abn2253

Grant

This work was supported by the ENCODE Functional Characterization Center (grant UM1 HG009435 to P.C.S., R.T., and S.K.R.); Broad SPARC (P.C.S.); Howard Hughes Medical Institute (P.C.S.); and the National Institutes of Health (grant R00HG010669 to S.K.R., grants R00HG008179 and R35HG011329 to R.T., grant RF1AG065926 to M.F.G. and K.J.B., grant R01MH125246 to M.F.G. and K.J.B., grant R56MH125237 to M.F.G. and K.J.B., grant 5T32MH014276-45 to M.F.G., and grant R01HG008742 to E.K.); the Liweibo PhD scholarship from the University of Massachusetts Chan Medical School (X.L.); and the Distinguished professor award from the Swedish Medical Research Council (K.L.T.)

Abstract

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

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