小柯机器人

美国加州大学圣地亚哥分校Melissa Gymrek、加州大学洛杉矶分校Kirk E. Lohmueller等研究人员合作揭示从头串联重复序列突变的模式及其在自闭症中的作用。该项研究成果发表在2021年1月13日出版的《自然》杂志上。

研究人员表示，自闭症谱系障碍（ASD）是一种早期发作的发育障碍，其特征在于沟通和社交互动不足以及限制性或重复性行为。家族研究表明，ASD具有重要的遗传基础，既有遗传变异又有新变异。据估计，从头突变可能占所有单纯性病例的30％，在这种情况下，每个家庭只有一个孩子受到影响。串联重复（TR）在这里被定义为连续重复的1至20个碱基对的序列，是人类从头突变的主要来源之一。TR的扩增与数十种神经系统疾病和精神疾病有关。然而，从头TR突变尚未在全基因组范围内表征，其对ASD的贡献也尚待探索。

研究人员开发了新的生物信息学方法，可从测序数据中识别和确定从头TR突变的优先次序，并在受ASD影响的先证者和未受影响的兄弟姐妹中进行从头TR突变的全基因组表征。研究人员推断了特定的突变事件及其重复数的精确变化，并且主要集中于更普遍的逐步拷贝数变化，而不是大的扩增。这些结果表明，在ASD先证者中全基因组范围内都存在大量的TR突变。先证者中的突变往往更大，且在胎儿大脑调节区域富集，并且据预测在进化上更有害。

总的来说，这些结果突出了在未来的从头突变研究中应当考虑重复变异的重要性。

附：英文原文

Title: Patterns of de novo tandem repeat mutations and their role in autism

Author: Ileena Mitra, Bonnie Huang, Nima Mousavi, Nichole Ma, Michael Lamkin, Richard Yanicky, Sharona Shleizer-Burko, Kirk E. Lohmueller, Melissa Gymrek

Issue&Volume: 2021-01-13

Abstract: Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants3,4. It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), defined here as sequences of 1 to 20 base pairs in size repeated consecutively, comprise one of the major sources of de novo mutations in humans6. TR expansions are implicated in dozens of neurological and psychiatric disorders7. Yet, de novo TR mutations have not been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here we develop new bioinformatics methods for identifying and prioritizing de novo TR mutations from sequencing data and perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. We infer specific mutation events and their precise changes in repeat number, and primarily focus on more prevalent stepwise copy number changes rather than large expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. Mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and are predicted to be more evolutionarily deleterious. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.

DOI: 10.1038/s41586-020-03078-7

Source: https://www.nature.com/articles/s41586-020-03078-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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