Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USA.
Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
Nat Commun. 2018 Jun 29;9(1):2548. doi: 10.1038/s41467-018-04882-6.
As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes.
与由单个基因引起的综合征相关 CNV 不同，在表现程度不同的 CNV 中广泛存在的表型异质性使疾病基因的发现和功能评估变得复杂。在这里，我们提出了一个与自闭症相关的 16p11.2 缺失相关致病性的复杂相互作用模型，其中 CNV 基因在保守途径中相互作用，以调节表型的表达。使用果蝇 RNAi 系中的多种定量方法，我们确定了在不同组织中敲低单个 16p11.2 同源物的一系列神经发育表型。我们在发育中的眼睛中测试了 565 对两两敲低，并确定了 24 对 16p11.2 同源物之间的相互作用，以及 46 对 16p11.2 同源物和神经发育基因之间的相互作用，与单次敲低相比，这些相互作用抑制或增强了细胞增殖表型。细胞增殖途径内的这些相互作用在人脑特异性网络中也很丰富，为人类提供了转化相关性。我们的研究表明，CNV 内普遍存在的遗传相互作用对细胞和发育表型有一定作用。
