研究揭示從頭串聯重複序列突變的模式及其在自閉症中的作用
作者：
小柯機器人發布時間：2021/1/17 16:05:23
美國加州大學聖地牙哥分校Melissa Gymrek、加州大學洛杉磯分校Kirk E. Lohmueller等研究人員合作揭示從頭串聯重複序列突變的模式及其在自閉症中的作用。該項研究成果發表在2021年1月13日出版的《自然》雜誌上。
研究人員表示，自閉症譜系障礙（ASD）是一種早期發作的發育障礙，其特徵在於溝通和社交互動不足以及限制性或重複性行為。家族研究表明，ASD具有重要的遺傳基礎，既有遺傳變異又有新變異。據估計，從頭突變可能佔所有單純性病例的30％，在這種情況下，每個家庭只有一個孩子受到影響。串聯重複（TR）在這裡被定義為連續重複的1至20個鹼基對的序列，是人類從頭突變的主要來源之一。TR的擴增與數十種神經系統疾病和精神疾病有關。然而，從頭TR突變尚未在全基因組範圍內表徵，其對ASD的貢獻也尚待探索。
研究人員開發了新的生物信息學方法，可從測序數據中識別和確定從頭TR突變的優先次序，並在受ASD影響的先證者和未受影響的兄弟姐妹中進行從頭TR突變的全基因組表徵。研究人員推斷了特定的突變事件及其重複數的精確變化，並且主要集中於更普遍的逐步拷貝數變化，而不是大的擴增。這些結果表明，在ASD先證者中全基因組範圍內都存在大量的TR突變。先證者中的突變往往更大，且在胎兒大腦調節區域富集，並且據預測在進化上更有害。
總的來說，這些結果突出了在未來的從頭突變研究中應當考慮重複變異的重要性。
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