@article{f9392996c845498e885746ec0f425f83,
title = "Pervasive genetic interactions modulate neurodevelopmental defects of the autism-Associated 16p11.2 deletion in Drosophila melanogaster",
abstract = "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.",
author = "Janani Iyer and Singh, {Mayanglambam Dhruba} and Matthew Jensen and Payal Patel and Lucilla Pizzo and Emily Huber and Haley Koerselman and Weiner, {Alexis T.} and Paola Lepanto and Komal Vadodaria and Alexis Kubina and Qingyu Wang and Abigail Talbert and Sneha Yennawar and Jose Badano and Manak, {J. Robert} and Rolls, {Melissa M.} and Arjun Krishnan and Santhosh Girirajan",
note = "Funding Information: We thank T. Mackay, S. Williams, and J. Moore for helpful discussions on the role of epistasis in our fly interaction studies, and E. Eichler, J. Kumar, F. Hormozdiari, D. Cavener, M. Grotewiel, C. Shashikant, Z-C. Lai, V. Hoxha, and S. Selleck for useful discussions and critical reading of the manuscript. We also thank R. Danjo and R. Pandya for assistance with fly husbandry, I. Albert, A. Sebastian, and Q. Li for assistance with RNA-Sequencing data analysis, A. Castells and A. Schenck for help with NMJ morphometrics, and A. Srivastava for technical help. This work was supported by a Basil O{\textquoteright}Connor Award from the March of Dimes Foundation (#5-FY14-66), NIH R01-GM121907, a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (22535), and resources from the Huck Institutes of the Life Sciences to S.G., and NIH T32-GM102057 to M.J. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-04882-6",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}