title: Loss-of-function mutation in a repressor module of human-specifically activated enhancer HACNS1.
abstract: The cis-regulatory element contributed to gaining humanness is of great interest in human evolutionary studies. A human-accelerated region exceeding neutral evolutionary rates, termed HACNS1, was recently reported as a positively selected sequence acquiring novel TF-binding sites responsible for human-specific gain of limb enhancer function. However, another possibility is loss of function in repressor element in HACNS1. Signature of the human substitutions in the 81-bp region infers that a GC-biased gene conversion (BGC) might create these seemingly excessive substitutions. To evaluate the 81-bp function, we performed transgenic mouse assay of the HACNS1 construct lacking the 81-bp region. The deleted construct showed similar enhancer activity to the intact human HACNS1, suggesting that the function of the human 81-bp region is not an activating enhancer but rather a disrupted repressor. This result infers that loss of function in the HACNS1 81-bp region, possibly via a BGC, played an important role in human-specific evolution.
authors.affiliation: Division of Population Genetics, National Institute of Genetics, Mishima, Japan. ksumiyam@lab.nig.ac.jp
authors.forename: Kenta
authors.initials: K
authors.lastname: Sumiyama
authors.forename: Naruya
authors.initials: N
authors.lastname: Saitou
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D019143:Evolution, Molecular; D005785:Gene Conversion / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
chemical_list: D017931:DNA Primers; C084958:GBX2 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors