Pervasive genetic interactions modulate neurodevelopmental defects of the autism-Associated 16p11.2 deletion in Drosophila melanogaster

Janani Iyer, Mayanglambam Dhruba Singh, Matthew Jensen, Payal Patel, Lucilla Pizzo, Emily Huber, Haley Koerselman, Alexis T. Weiner, Paola Lepanto, Komal Vadodaria, Alexis Kubina, Qingyu Wang, Abigail Talbert, Sneha Yennawar, Jose Badano, J. Robert Manak, Melissa M. Rolls, Arjun Krishnan, Santhosh Girirajan

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14 Scopus citations

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.

Original languageEnglish (US)
Article number2548
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Iyer, J., Singh, M. D., Jensen, M., Patel, P., Pizzo, L., Huber, E., Koerselman, H., Weiner, A. T., Lepanto, P., Vadodaria, K., Kubina, A., Wang, Q., Talbert, A., Yennawar, S., Badano, J., Manak, J. R., Rolls, M. M., Krishnan, A., & Girirajan, S. (2018). Pervasive genetic interactions modulate neurodevelopmental defects of the autism-Associated 16p11.2 deletion in Drosophila melanogaster. Nature communications, 9(1), [2548]. https://doi.org/10.1038/s41467-018-04882-6