Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion

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.

doi:10.1101/185355

bioRxiv · 10.1101/185355

Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion

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.

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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 identified a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We tested 565 pairwise knockdowns in the developing eye, and identified 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppressed or enhanced cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways were also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for genetic interactions within CNVs and identifies potential therapeutic targets for neurodevelopmental disorders.

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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.. 2017-09-20. Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion. https://doi.org/10.1101/185355

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