Adaptive sequence divergence forged new neurodevelopmental enhancers in humans.
Adaptive sequence divergence forged new neurodevelopmental enhancers in humans.
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DOI：
10.1016/j.cell.2022.10.016
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发表时间：
2022-11-23
期刊：
影响因子：
64.5
通讯作者：
Lowe, Craig B.
中科院分区：
文献类型：
--
作者：
Mangan, Riley J.;Alsina, Fernando C.;Mosti, Federica;Sotelo-Fonseca, Jesus Emiliano;Snellings, Daniel A.;Au, Eric H.;Carvalho, Juliana;Sathyan, Laya;Johnson, Graham D.;Reddy, Timothy E.;Silver, Debra L.;Lowe, Craig B.
对人类独特特征的遗传基础的研究主要集中在保守基因组区域中人类特有的差异，这反映了现有功能元件的适应性修改。然而，对保守区的研究排除了从以前的中性区域衍生出来的功能元件。在这里，我们证明了人类基因组中进化最快的区域，我们称之为人类祖先快速进化区域(HAQERs)，在人类-尼安德特人分裂之前，在人类-尼安德特人分裂之前，在人类内部过渡到限制之前，在定向正选择的间歇性爆发中迅速分化。HAQER富含二价染色质状态，特别是在胃肠道和神经发育组织中，以及与神经发育疾病有关的遗传变异。我们发展了一种体内多重单细胞增强子试验，以发现HAQERs的快速序列分歧在发育中的大脑皮层产生了人型独特的增强子。我们认为，缺乏多效性限制和高突变率使HAQERs具有快速适应和随后的疾病易感性。大多数比较基因组学研究都集中在保守区域。然而，在这项研究中，Mangan等人。确定整个人类基因组中进化最快的区域，并提供关于哪些基因组区域构成人类特有的疾病风险和适应的洞察力。
Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes functional elements that descended from previously neutral regions. Here we demonstrate that the fastest-evolved regions of the human genome, which we term Human Ancestor Quickly Evolved Regions (HAQERs), rapidly diverged in an episodic burst of directional positive selection prior to the human-Neanderthal split before transitioning to constraint within hominins. HAQERs are enriched for bivalent chromatin states, particularly in gastrointestinal and neurodevelopmental tissues, and genetic variants linked to neurodevelopmental disease. We developed a multiplex single-cell in vivo enhancer assay to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex. We propose that a lack of pleiotropic constraints and elevated mutation rates poised HAQERs for rapid adaptation and subsequent susceptibility to disease. Most comparative genomics studies focus on conserved regions. However, in this study, Mangan et al. identify the fastest-evolved regions across the entire human genome and provide insights into which genomic regions underlie human-specific disease risks and adaptations.
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