美国杜克大学Craig B. Lowe课题组发现，适应性序列分化在人类中形成新的神经发育增强子。2022年11月23日出版的《细胞》杂志发表了这项成果。

研究人员证明了人类基因组中演化最快的区域，被称为“人类祖先快速演化区域”（HAQER）。这个区域在人类-尼安德特人分裂之前，在定向正向选择的偶发性爆发中迅速分化，然后过渡到人类内部的约束。HAQER富集了二价染色质状态，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。研究人员开发了一个多重的单细胞体内增强子检测，发现HAQER的快速序列分化在发育中的大脑皮层产生了人类特有的增强子。研究人员提出，由于缺乏多态性约束和突变率的提高，使HAQER具备了快速适应和随后对疾病的易感性。

据了解，对人类独特性状的遗传基础的研究集中在人类特有的保守基因组区域的分化上，这反映了对现有功能元件的适应性修改。然而，对保守区域的研究排除了从以前的中性区域降生的功能元件。

附：英文原文

Title: Adaptive sequence divergence forged new neurodevelopmental enhancers in humans

Author: Riley J. Mangan, Fernando C. Alsina, Federica Mosti, Jesús Emiliano Sotelo-Fonseca, Daniel A. Snellings, Eric H. Au, Juliana Carvalho, Laya Sathyan, Graham D. Johnson, Timothy E. Reddy, Debra L. Silver, Craig B. Lowe

Issue&Volume: 2022/11/23

Abstract: 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.

DOI: 10.1016/j.cell.2022.10.016

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01358-7