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新生罕见遗传变异可能诱导产生自闭症
2021-07-31 21:07

美国华盛顿大学医学院Evan E. Eichler团队在研究中取得进展。他们发现新生异常罕见遗传变异可能是自闭症潜在候选风险基因。该项研究成果发表在2021年7月26日出版的《自然-遗传学》上。

利用来自 3,474 个家族的全基因组测序数据,研究人员发现了另一个具有高影响的风险变异来源,即超罕见变异。研究发现并重现了患者中特异的、可能基因破坏 (LGD) 变体的传递不平衡,并发现95%的高风险变异位于已知的富含从头突变 (DNM)的基因之外。这种变异类别对多重家庭患者具有更大的影响,并与自闭症多重变异模型相吻合。具有个体特异LGD变体患者的候选基因多位于E3泛素-蛋白连接酶复合物、细胞内转运和Erb信号蛋白网络中。

研究人员估计这些变体大约传递了2.5代,并且比兄弟姐妹中类似类型和频率的其他变体出现的晚很多。总体而言,个体特异性LGD变体经历了高频率的纯化选择,并且其似乎作用于一组未知的与自闭症相关的独特基因。

据悉,自闭症是一种高度遗传的复杂疾病,其中DNM对致病性具有显著影响。

附:英文原文

Title: Recent ultra-rare inherited variants implicate new autism candidate risk genes

Author: Amy B. Wilfert, Tychele N. Turner, Shwetha C. Murali, PingHsun Hsieh, Arvis Sulovari, Tianyun Wang, Bradley P. Coe, Hui Guo, Kendra Hoekzema, Trygve E. Bakken, Lara H. Winterkorn, Uday S. Evani, Marta Byrska-Bishop, Rachel K. Earl, Raphael A. Bernier, Michael C. Zody, Evan E. Eichler

Issue&Volume: 2021-07-26

Abstract: Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin–protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.

DOI: 10.1038/s41588-021-00899-8

Source: https://www.nature.com/articles/s41588-021-00899-8

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:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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