Loss-of–function mutation in a repressor module of human-specifically activated enhancer HACNS1
Kenta Sumiyama and Naruya Saitou
Molecular Biology and Evolution (2011) first published online September 22, 2011
DOI: 10.1093/molbev/msr231
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 81bp region infers that a GC-biased gene conversion might create these seemingly excessive substitutions. To evaluate the 81bp function, we performed transgenic mouse assay of the HACNS1 construct lacking the 81bp region. The deleted construct showed similar enhancer activity to the intact human HACNS1, suggesting that the function of the human 81bp region is not an activating enhancer, but rather a disrupted repressor. This result infers that loss-of-function in the HACNS1 81bp region, possibly via a GC-biased gene conversion, played an important role in human-specific evolution.
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A. Transgenic mouse analysis of the 81bp deletion construct. No clear difference of expression pattern was observed. B. Putative repressor loss-of-function evolutionary model of HACNS1.
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