Genomic Patterns of De Novo Mutation in Simplex Autism.
Genomic Patterns of De Novo Mutation in Simplex Autism.
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DOI：
10.1016/j.cell.2017.08.047
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发表时间：
2017-10-19
期刊：
影响因子：
64.5
通讯作者：
Eichler EE
中科院分区：
文献类型：
--
作者：
Turner TN;Coe BP;Dickel DE;Hoekzema K;Nelson BJ;Zody MC;Kronenberg ZN;Hormozdiari F;Raja A;Pennacchio LA;Darnell RB;Eichler EE
为了进一步了解自闭症的遗传病因，我们生成并分析了来自516个特发性自闭症家族（2,064名个体）的基因组序列数据。该资源包括> 5900万个单核苷酸变异（SNV）和9，212个私人拷贝数变异（CNV），其中分别有133，992个和88个是从头突变（DNM）。我们估计每代每个位点的突变率约为1.5×10−8个SNV，重复DNA的突变率明显更高。比较先证者和未受影响的同胞，我们观察到几个DNM趋势。先证者携带更多的基因破坏性CNV和SNV，导致严重的错义突变，并映射到预测的胎儿脑启动子和胚胎干细胞增强子。这些差异在自闭症基因中变得更加明显（p=1.8×10−3，OR=2.2）。患者更有可能在不同的基因中携带多个编码和非编码DNM，这些基因在纹状体神经元中表达丰富（p=3×10−3），这表明了一条表征遗传学上更复杂的自闭症病例的途径。对516个有一个自闭症儿童和一个未受影响的兄弟姐妹的家庭的基因组分析表明，单纯型自闭症是由从头突变引起的，是寡基因的。
To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ~1.5×10−8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p=1.8×10−3, OR=2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p=3×10−3), suggesting a path forward for characterizing genetically more complex cases of autism. Genomic analysis of 516 families with an autistic child and an unaffected sibling suggests that simplex autism results from de novo mutation and is oligogenic.