Dataset Information

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.

SUBMITTER: Iyer J

PROVIDER: S-EPMC6026208 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Iyer Janani J Singh Mayanglambam Dhruba MD Jensen Matthew M Patel Payal P Pizzo Lucilla L Huber Emily E Koerselman Haley H Weiner Alexis T AT Lepanto Paola P Vadodaria Komal K Kubina Alexis A Wang Qingyu Q Talbert Abigail A Yennawar Sneha S Badano Jose J Manak J Robert JR Rolls Melissa M MM Krishnan Arjun A Girirajan Santhosh S

Nature communications 20180629 1

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 phenotyp ...[more]

PMID: 29959322

Similar Datasets

Project description:Neurodevelopmental disorders (NDDs) are polygenic in nature and copy number variants (CNVs) are ideal candidates to study the nature of this polygenic risk. The disruption of striatal circuits is considered a central mechanism in NDDs. The 16p11.2 hemi-deletion (16p11.2 del) is one of the most common CNVs associated with NDD, and 16p11.2 del/+ mice show sex-specific striatum-related behavioral phenotypes. However, the critical genes among the 27 genes in the 16p11.2 region that underlie these phenotypes remain unknown. Previously, we applied a novel strategy to identify candidate genes associated with the sex-specific phenotypes of 16p11.2 del/+ mice and identified 3 genes of particular importance within the deleted region: thousand and one amino acid protein kinase 2 (Taok2), seizure-related 6 homolog-like 2 (Sez6l2), and major vault protein (Mvp). Using the CRISPR/Cas9 technique, we generated 3 gene hemi-deletion (3g del/+) mice carrying null mutations in Taok2, Sez6l2, and Mvp. We assessed striatum-dependent phenotypes of these 3g del/+ mice in behavioral, molecular, and imaging studies. Hemi-deletion of Taok2, Sez6l2, and Mvp induces sex-specific behavioral alterations in striatum-dependent behavioral tasks, specifically male-specific hyperactivity and impaired motivation for reward seeking, resembling behavioral phenotypes of 16p11.2 del/+ mice. Moreover, RNAseq analysis revealed that 3g del/+ mice exhibit gene expression changes in the striatum similar to 16p11.2 del/+ mice, but only in males. Pathway analysis identified ribosomal dysfunction and translation dysregulation as molecular mechanisms underlying male-specific, striatum-dependent behavioral alterations. Together, the mutation of 3 genes within the 16p11.2 region phenocopies striatal sex-specific phenotypes of 16p11.2 del/+ mice, unlike single gene mutation studies. These results support the importance of a polygenic approach to study NDDs and our novel strategy to identify genes of interest using gene expression patterns in brain regions, such as the striatum, which are impacted in these disorders.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets