"Loss-of-function mutation in a repressor module of human- specifically activated enhancer HACNS1."
"Loss-of-function mutation in a repressor module of human- specifically activated enhancer HACNS1."
复制标题
“人类特异性激活的增强子 HACNS1 的抑制子模块发生功能丧失突变。”
DOI：
10.1093/molbev/msr231
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发表时间：
2011
影响因子：
10.7
通讯作者：
Kenta Sumiyama and Naruya Saitou
中科院分区：
文献类型：
--
作者：
Anbutsu H;Nikoh N;Tanaka K;Fukatsu T;鹿児嶋久美子・津田みどり・山田直隆・Wu L-H・Wang C-P・Wu J-W・Chen Z-Q・Teramoto K・Kumashiro B・Buranapanichpan S;Kenta Sumiyama and Naruya Saitou
顺式调控元件在人类进化研究中具有重要意义。最近报道了一个超过中性进化速率的人类加速区域，称为HACNS 1，作为一个积极选择的序列，获得新的TF结合位点，负责人类特异性获得肢体增强子功能。然而，另一种可能性是HACNS 1中阻遏元件的功能丧失。在81 bp区域中的人类替换的签名推断GC偏向的基因转换（BGC）可能产生这些看似过度的替换。为了评估81-bp的功能，我们对缺失81-bp区域的HACNS 1构建体进行转基因小鼠测定。缺失的构建体显示出与完整的人HACNS 1相似的增强子活性，这表明人81-bp区域的功能不是激活增强子，而是破坏阻遏物。这一结果推断，可能通过BGC，在人类特异性进化中发挥了重要作用的HACNS 1 81-bp区域的功能丧失。
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.