Human-specific loss of regulatory DNA and the evolution of human-specific traits

Humans differ from other animals in many aspects of anatomy, physiology, and behavior; 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 changes2-5. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species6-8. 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 signaling 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 tumor 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 alterations6-8 and inactivation events13 long proposed to play an important role in human evolutionary divergence.