De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types.
De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types.
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DOI：
10.1186/s13229-020-00386-7
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发表时间：
2020-10-08
期刊：
影响因子：
6.2
通讯作者：
Devlin B
中科院分区：
文献类型：
--
作者：
Chen S;Wang J;Cicek E;Roeder K;Yu H;Devlin B
全外显子组测序研究对于鉴定基因突变时影响自闭症谱系障碍（ASD）风险的基因是有用的。尽管如此，关联信号主要来自从头蛋白质截短变体，而不是更常见的错义变体。尽管它们在人类中很常见，但确定哪些错义变体影响表型以及如何影响表型仍然是一个挑战。我们研究了从头错义变异的功能相关性，特别是它们是否可能破坏蛋白质相互作用，并通过综合基因组学，转录组学和蛋白质组学分析提名ASD风险的新基因。利用我们之前的相互作用组扰动预测器，我们确定了一组可能破坏蛋白质-蛋白质相互作用的错义变体。对于编码中断的相互作用的基因，我们使用批量和推断的细胞类型特异性脑转录组来评估它们在发育中的大脑和特定细胞类型内的表达模式。连接所有被破坏的蛋白质对，我们构建了一个“ASD破坏网络”。最后，我们将蛋白质相互作用和细胞类型特异性共表达网络与已发表的关联数据整合在一起，以细胞类型特异性方式揭示ASD风险中的新基因。 扩展早期的工作，我们表明，破坏蛋白质相互作用的从头错义变体在ASD患者中富集，通常会影响枢纽蛋白质并破坏枢纽相互作用。编码被破坏的互补相互作用物的基因往往是风险基因，并且从这些蛋白质构建的相互作用网络富含ASD蛋白质。与其他研究一致，通过破坏蛋白质相互作用鉴定的基因在发育早期以及兴奋性和抑制性神经元谱系中表达。使用三种神经元细胞类型-兴奋性，抑制性和神经祖细胞-的推断基因共表达，我们暗示了数百个风险基因（FDR 0.05），约60%是新的，具有真正ASD基因的特征。在不同的细胞类型中，这些基因影响神经元的形态发生和神经元的通讯，而神经祖细胞显示出对边缘系统发育的强烈富集。一些分析使用了不完善的关联犯罪原则;结果是统计性的，而不是功能性的。破坏的蛋白质相互作用识别参与ASD风险的基因集。它们在大脑发育过程中和细胞类型内的基因表达突出了它们与ASD的关系。
Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses. Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein–protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an “ASD disrupted network.” Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner. Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types—excitatory, inhibitory, and neural progenitor—we implicate several hundred genes in risk (FDR 0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system. Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional. Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD.
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影响因子：
5
作者：
COHEN, S;KAMARCK, T;MERMELSTEIN, R
通讯作者：
MERMELSTEIN, R
DOI：
10.1016/j.obhdp.2006.05.003
发表时间：
2007-09-01
影响因子：
4.6
作者：
Devoe, Sanford E.;Pfeffer, Jeffrey
通讯作者：
Pfeffer, Jeffrey
影响因子：
7.6
作者：
Leary, Mark R.;Tate, Eleanor B.;Hancock, Jessica
通讯作者：
Hancock, Jessica
影响因子：
1.8
作者：
Bogels, Susan;Hoogstad, Bert;Restifo, Kathleen
通讯作者：
Restifo, Kathleen
影响因子：
8.2
作者：
Condon, Paul;Desbordes, Gaelle;DeSteno, David
通讯作者：
DeSteno, David