Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Science. 2018 Dec 14;362(6420). doi: 10.1126/science.aat6576.
Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
全基因组测序（WGS）促进了对新生非编码突变对复杂疾病的贡献的首次全基因组评估。使用 WGS，我们在 1902 个四联体家族的成员的样本基因组中鉴定了 255,106 个新生突变，其中一个孩子（但不是兄弟姐妹或他们的父母）患有自闭症谱系障碍（ASD）。与编码突变不同，没有任何非编码功能注释类别可以单独分析，与 ASD 显著相关。然而，在多个注释类别中，针对新生风险评分的非编码变异的分析确实表明与突变与启动子区域有关。我们发现，这种启动子信号的最强驱动力源自转录起始位点远端的进化保守转录因子结合位点。这些数据表明，具有进化和功能特征的启动子区域中的新生突变会导致 ASD。
