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Nat Commun. 2018 Jun 29;9(1):2548. doi: 10.1038/s41467-018-04882-6.

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

Author information

1
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USA.
2
Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
3
Department of Biology, University of Iowa, Iowa City, IA, 52242, USA.
4
Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Montevideo, CP11400, Uruguay.
5
Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA.
6
Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, 48824, USA.
7
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
8
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USA. sxg47@psu.edu.
9
Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. sxg47@psu.edu.
10
Department of Anthropology, The Pennsylvania State University, University Park, PA, 16802, USA. sxg47@psu.edu.

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.

PMID:
29959322
PMCID:
PMC6026208
DOI:
10.1038/s41467-018-04882-6
[Indexed for MEDLINE]
Free PMC Article

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