Journal article
Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster
Nature communications, Vol.9(1), 2548
06/29/2018
DOI: 10.1038/s41467-018-04882-6
PMCID: PMC6026208
PMID: 29959322
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.
Details
- Title: Subtitle
- Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster
- Creators
- Janani Iyer - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAMayanglambam Dhruba Singh - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAMatthew Jensen - Pennsylvania State UniversityPayal Patel - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USALucilla Pizzo - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAEmily Huber - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAHaley Koerselman - Department of Biology, University of Iowa, Iowa City, IA, 52242, USAAlexis T Weiner - Pennsylvania State UniversityPaola Lepanto - Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Montevideo, CP11400, UruguayKomal Vadodaria - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAAlexis Kubina - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAQingyu Wang - Pennsylvania State UniversityAbigail Talbert - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USASneha Yennawar - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAJose Badano - Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Montevideo, CP11400, UruguayJ Robert Manak - Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USAMelissa M Rolls - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USAArjun Krishnan - Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USASanthosh Girirajan - Department of Anthropology, The Pennsylvania State University, University Park, PA, 16802, USA. sxg47@psu.edu
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.9(1), 2548
- DOI
- 10.1038/s41467-018-04882-6
- PMID
- 29959322
- PMCID
- PMC6026208
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- England
- Grant note
- T32 GM102057 / NIGMS NIH HHS 22535 / National Alliance for Research on Schizophrenia and Depression (NARSAD) 5-FY14-66 / March of Dimes Foundation (March of Dimes) T32-GM102057 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01-GM121907 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01 GM121907 / NIGMS NIH HHS
- Language
- English
- Date published
- 06/29/2018
- Academic Unit
- Stead Family Department of Pediatrics; Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9983991999702771
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