Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression
Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression
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DOI：
10.1093/hmg/ddr283
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发表时间：
2011-09-15
影响因子：
3.5
通讯作者：
Shifman, Sagiv
中科院分区：
文献类型：
--
作者：
Ben-David, Eyal;Granot-Hershkovitz, Einat;Shifman, Sagiv
最近的工作导致了几个自闭症谱系障碍(ASD)易感基因的鉴定，并越来越多地认识到罕见和从头开始突变的重要性。使用目前的策略可能很难检测到一些突变，特别是如果它们位于监管区域。我们提出了一种新的方法来识别功能突变，这些突变利用了这样一个事实，即许多罕见的突变扰乱了来自单个亲代染色体的基因的表达。该方法包括使用单核苷酸多态阵列来测量基因的两个拷贝在整个基因组中的相对表达。等位基因表达已被成功地用于研究常见的调控多态；然而，它尚未被用作罕见突变的筛查工具。我们通过筛选来自一个小的ASD队列的淋巴母细胞系中的单等位基因表达来测试这种方法的潜力。在筛选了多个样本共享的区域后，我们确定了在特定ASD样本中显示单等位基因表达的基因。通过定量测序证实，这些基因(或只有部分)是单等位基因表达的。这些基因既包括先前怀疑的ASD风险因素，也包括新的候选基因。在一个名为自闭症易感候选2(AUTS2)的基因中，我们发现了一种罕见的重复，这可能是单等位基因表达的原因。我们的结果证明了使用全基因组等位基因表达筛查识别罕见调控突变的能力，这一能力可以扩展到其他疾病，特别是那些怀疑涉及罕见显性作用突变的疾病。
Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations.