De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10-10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10-13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10-24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10-9; OR=1.84), of which 15.6% (p=4.3×10-3) and 22.5% (p=7.0×10-5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.

中文翻译：

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自闭症中从头突变的全基因组特征。

从头突变（DNM）在自闭症谱系障碍（ASD）中很重要，但到目前为止，分析主要集中在约1.5％的基因组编码基因上。在这里，我们进行了200个ASD亲子三重奏的全基因组测序（WGS），并鉴定了种系和体细胞DNM。我们确认，大多数种系DNMs（75.6％）均来自父亲，并且仅随父系年龄而显着增加（p = 4.2×10-10）。但是，当在ASD中发现簇状DNM（20kb内的簇）时，它们不仅主要起源于母亲（p = 7.7×10-13），而且还可以发现它们与从头拷贝数变异（CNV）相邻。突变率显着升高（p = 2.4×10-24）。通过比较对照中检测到的DNM，我们发现ASD病例中预测的破坏性DNM明显丰富（p = 8.0×10-9； OR = 1.84），其中非编码或基因非编码分别为15.6％（p = 4.3×10-3）和22.5％（p = 7.0×10-5）。DNM最丰富的非编码元件是基因的非翻译区，外显子跳跃和DNase I超敏区所涉及的边界。使用微阵列和新颖的离群值检测测试，我们还发现了2/185（1.1％）的ASD病例中异常的甲基化分布。这些相同的个体在ASD风险基因和表观遗传基因DNMT3A和ADNP中进行了独立鉴定的DNM。我们的数据开始表征不同的全基因组DNM，并突出非编码变异对ASD病因的贡献。跳过外显子和DNase I超敏区域的边界。使用微阵列和新颖的离群值检测测试，我们还发现了2/185（1.1％）的ASD病例中异常的甲基化分布。这些相同的个体在ASD风险基因和表观遗传基因DNMT3A和ADNP中进行了独立鉴定的DNM。我们的数据开始表征不同的全基因组DNM，并突出非编码变异对ASD病因的贡献。跳过外显子和DNase I超敏区域的边界。使用微阵列和新颖的离群值检测测试，我们还发现了2/185（1.1％）的ASD病例中异常的甲基化分布。这些相同的个体在ASD风险基因和表观遗传基因DNMT3A和ADNP中进行了独立鉴定的DNM。我们的数据开始表征不同的全基因组DNM，并突出非编码变异对ASD病因的贡献。