Autism Spectrum Disorder (ASD) is an early onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviors. Family studies demonstrate that ASD has a significant genetic basis with contributions both from inherited and de novo variants. While the majority of variance in liability to ASD is estimated to arise from common genetic variation, 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 family. Tandem repeats (TRs), consisting of approximately 1-20bp motifs repeated in tandem, comprise one of the largest sources of de novo mutations in humans. Yet, largely due to technical challenges they present, de novo TR mutations have not yet been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here, we develop novel bioinformatics tools for identifying and prioritizing de novo TR mutations from whole genome sequencing (WGS) data and use these to perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. Compared to recent work on TRs in ASD, we explicitly infer mutation events and their precise changes in repeat copy number, and primarily focus on more prevalent stepwise copy number changes rather than large or complex expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. TR mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and predicted to be more evolutionarily deleterious compared to mutations observed in unaffected siblings. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.

中文翻译：

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从头序列重复序列突变的全基因组模式及其对自闭症谱系障碍的贡献。

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。家庭研究表明，ASD具有重要的遗传基础，既有遗传变异又有从头变异。虽然估计对ASD的责任的大部分差异是由常见的遗传变异引起的，但据估计，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（TRs）由大约1-20bp的串联基序组成，是人类中从头突变的最大来源之一。但是，由于它们所面临的技术挑战，从头TR突变尚未在全基因组范围内得到鉴定，他们对ASD的贡献尚待探索。在这里，我们开发了新颖的生物信息学工具，用于从全基因组测序（WGS）数据中识别和确定de novo TR突变的优先次序，并使用这些工具在ASD受影响的先证者和未受影响的兄弟姐妹中进行de novo TR突变的全基因组表征。与ASD中TR的最新研究相比，我们明确推断出突变事件及其在重复拷贝数中的精确变化，并且主要集中于更普遍的逐步拷贝数变化，而不是大的或复杂的扩展。我们的结果表明，在ASD先证者中全基因组范围内都存在大量的TR突变。与在未受影响的兄弟姐妹中观察到的突变相比，先证者中的TR突变往往更大，在胎儿的大脑调节区域富集，并且预计在进化上更有害。总体，