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单基因对人类顺式遗传率的贡献约为25%
作者:小柯机器人 发布时间:2019/9/3 14:46:17

近日,美国加州大学旧金山分校人类遗传学研究所教授Noah Zaitlen及其团队发现了超罕见的变异驱动人类基因表达的顺式遗传。该研究2019年9月2号发表于《自然—遗传学》。

课题组人员开发并严格验证了一种联合评估所有等位基因(包括单基因)对表型变异的贡献的方法。将该方法应用于转录调控,这是介于遗传变异和复杂疾病之间的中间环节。科学家利用来自360个欧洲个体的全基因组DNA和淋巴母细胞样细胞系RNA测序数据进行保守估计,单基因对顺式遗传率的贡献约为25%,这使得其他频率的贡献相形见绌。大多数(约76%)的单例遗传力来自于额外的数千个样本中缺失的超细微变异。科学家进一步开发了一个推理程序,以证明结果与普遍的纯化选择一致,从而塑造了大多数人类基因的调控结构。

研究人员表示,绝大多数人类突变的等位基因频率都在1%以下,其中多数只出现过一次(即“单基因突变”)。孟德尔疾病主要由罕见的等位基因引起,但其对复杂表型的累积贡献在很大程度上是未知的。

附:英文原文

Title: Ultrarare variants drive substantial cis heritability of human gene expression

Author: Ryan D. Hernandez, Lawrence H. Uricchio, Kevin Hartman, Chun Ye, Andrew Dahl, Noah Zaitlen

Issue&Volume: Volume 51 Issue 9

Abstract: The vast majority of human mutations have minor allele frequencies under 1%, with the plurality observed only once (that is, ‘singletons’). While Mendelian diseases are predominantly caused by rare alleles, their cumulative contribution to complex phenotypes is largely unknown. We develop and rigorously validate an approach to jointly estimate the contribution of all alleles, including singletons, to phenotypic variation. We apply our approach to transcriptional regulation, an intermediate between genetic variation and complex disease. Using whole-genome DNA and lymphoblastoid cell line RNA sequencing data from 360 European individuals, we conservatively estimate that singletons contribute approximately 25% of cis heritability across genes (dwarfing the contributions of other frequencies). The majority (approximately 76%) of singleton heritability derives from ultrarare variants absent from thousands of additional samples. We develop an inference procedure to demonstrate that our results are consistent with pervasive purifying selection shaping the regulatory architecture of most human genes.

DOI: 10.1038/s41588-019-0487-7

Source:https://www.nature.com/articles/s41588-019-0487-7

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex