Comprehensive identification and analysis of human accelerated regulatory DNA.
Comprehensive identification and analysis of human accelerated regulatory DNA.
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DOI：
10.1101/gr.192591.115
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发表时间：
2015-09
期刊：
影响因子：
7
通讯作者：
Akey JM
中科院分区：
文献类型：
--
作者：
Gittelman RM;Hun E;Ay F;Madeoy J;Pennacchio L;Noble WS;Hawkins RD;Akey JM
长期以来，人们一直假设基因调控的变化在人类进化中发挥了重要作用，但与蛋白质编码区相比，调控 DNA 的研究要困难得多。最近的大规模研究创建了基因组规模的 DNase I 超敏感位点 (DHS) 目录，它标记了潜在的功能性调控 DNA。为了更好地定义受人类特异性适应性进化影响的调控 DNA，我们对 130 种细胞类型中发现的超过 1800 万个 DHS 进行了全面的进化和群体遗传学分析。我们鉴定了 524 个在非人类灵长类动物中保守但在人类谱系 (haDHS) 中加速的 DHS，并估计 haDHS 中 70% 的替换可归因于正选择。通过广泛的计算和实验分析，我们证明 haDHS 通常在大脑或神经元细胞类型中活跃；在调节发育重要基因的表达中发挥重要作用，包括许多转录因子，如 SOX6、POU3F2 和 HOX 基因；并找出可能有助于人类特异性表型的适应性调节进化的惊人例子。更一般地说，我们的结果揭示了对人类保守和适应性调节 DNA 的新见解，并完善了将人类与现存灵长类近亲区分开来的一组基因组底物。
It has long been hypothesized that changes in gene regulation have played an important role in human evolution, but regulatory DNA has been much more difficult to study compared with protein-coding regions. Recent large-scale studies have created genome-scale catalogs of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To better define regulatory DNA that has been subject to human-specific adaptive evolution, we performed comprehensive evolutionary and population genetics analyses on over 18 million DHSs discovered in 130 cell types. We identified 524 DHSs that are conserved in nonhuman primates but accelerated in the human lineage (haDHS), and estimate that 70% of substitutions in haDHSs are attributable to positive selection. Through extensive computational and experimental analyses, we demonstrate that haDHSs are often active in brain or neuronal cell types; play an important role in regulating the expression of developmentally important genes, including many transcription factors such as SOX6, POU3F2, and HOX genes; and identify striking examples of adaptive regulatory evolution that may have contributed to human-specific phenotypes. More generally, our results reveal new insights into conserved and adaptive regulatory DNA in humans and refine the set of genomic substrates that distinguish humans from their closest living primate relatives.