Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown1. Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes2,3,4,5. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species6,7,8. Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor (AR) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage9,10. Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G)11,12, a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations6,7,8 and inactivation events13 long proposed to have an important role in human evolutionary divergence.
We thank D. DeGusta for providing chimpanzee DNA, S. McConnell and P. Buckmaster for discussions, and M. Hiller and C. Barr for ontology analysis support. This work was supported in part by a Bio-X graduate fellowship (C.Y.M.), a Ruth L. Kirschstein NRSA post-doctoral fellowship (1 F32 HD062137-01, P.L.R.), a National Defense Science and Engineering Graduate fellowship (A.A.P.), a National Science Scholarship of the Agency of Science, Technology, and Research, Singapore (X.L.), a Stanford Graduate Fellowship (A.M.W.), an Edward Mallinckrodt, Jr. Foundation grant (G.B.), and National Institute of Health grants R01 HD059862 (G.B.), R01 HG005058 (G.B.) and P50 HG002568 (D.M.K.). G.B. is a Packard Fellow, Searle Scholar, Microsoft Faculty Fellow and an Alfred P. Sloan Fellow. D.M.K. is an investigator of the Howard Hughes Medical Institute.
This file is an annotated spreadsheet providing access to all 583 hCONDELs, 344 cCONDELs, and 350 mCONDELs.