Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster.
Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster.
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DOI：
10.1038/s41467-018-04882-6
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发表时间：
2018-06-29
影响因子：
16.6
通讯作者：
Girirajan S
中科院分区：
文献类型：
--
作者：
Iyer J;Singh MD;Jensen M;Patel P;Pizzo L;Huber E;Koerselman H;Weiner AT;Lepanto P;Vadodaria K;Kubina A;Wang Q;Talbert A;Yennawar S;Badano J;Manak JR;Rolls MM;Krishnan A;Girirajan S
与单基因引起的综合征型CNVs相反，可变表达CNVs中广泛的表型异质性使疾病基因的发现和功能评估复杂化。在这里，我们提出了自闭症相关16p11.2缺失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。在果蝇RNAi细胞系中使用多种定量方法，我们鉴定了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个配对敲低，并鉴定了24对16p11.2同源物之间的相互作用，以及46对16p11.2同源物与神经发育基因之间的相互作用，与一次敲低相比，抑制或增强细胞增殖表型。细胞增殖途径中的这些相互作用也在人脑特异性网络中丰富，为人类提供翻译相关性。我们的研究表明，CNVs中普遍存在的遗传相互作用对细胞和发育表型的影响。16p11.2缺失会导致一系列神经发育表型，但到目前为止，测序研究还不能确定单个基因本身是导致这种疾病的原因。在这里，作者利用14个16p11.2基因的果蝇同源物，采用组合方法来表明基因相互作用有助于神经表型。
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. The 16p11.2 deletion leads to a range of neurodevelopmental phenotypes, but to date, sequencing studies have not been able to pinpoint individual genes that are causative for the disease on their own. Here, using Drosophila homologs of 14 16p11.2 genes, the authors take a combinatorial approach to show that gene interactions contribute to a neurological phenotype.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
5.3
作者：
Ehaideb, Salleh N.;Wignall, Elizabeth A.;Kasuya, Junko;Evans, William H.;Iyengar, Atulya;Koerselman, Haley L.;Lilienthal, Anthony J.;Bassuk, Alexander G.;Kitamoto, Toshihiro;Manak, J. Robert
通讯作者：
Manak, J. Robert
影响因子：
4.5
作者：
Grice SJ;Liu JL;Webber C
通讯作者：
Webber C
影响因子：
7
作者：
Andrews T;Honti F;Pfundt R;de Leeuw N;Hehir-Kwa J;Vulto-van Silfhout A;de Vries B;Webber C
通讯作者：
Webber C