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.
Highlights
As opposed to syndromic copy-number variants (CNVs) caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation
Rare recurrent copy-number variants (CNVs) with breakpoints typically mapping within segmental duplications are a significant cause of neurodevelopmental disorders, such as intellectual disability/developmental delay (ID/DD), autism, epilepsy, and schizophrenia[1]
Gene discovery within rare syndromic CNVs has traditionally involved mapping the disease-associated region using atypical CNVs, inversions, or translocations to identify a causative gene that explains the distinct phenotypes associated with the CNV, followed by detailed functional evaluation of that gene using animal models
Summary
As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Extensive heterogeneity and incomplete penetrance of the associated phenotypes adds additional challenges to genetic mapping strategies that use atypical variants While this deletion is enriched within various neurodevelopmental disease cohorts, exome sequencing studies of hundreds of individuals have not identified any individual genes within this region as causative for these diseases on their own[9,10,11,12]. Functional studies using cellular[13], mouse[14,15,16,17], and zebrafish models[18] have implicated several different genes within 16p11.2 in neurodevelopmental phenotypes These findings suggest that the observed phenotypes in 16p11.2 deletion are not caused by haploinsufficiency of a single causative gene, but rather are modulated by multiple dosage-sensitive genes in the region, potentially through combinatorial mechanisms within pathways related to neurodevelopment. Our data suggest a complex interaction model for disease pathogenicity, where multiple 16p11.2 genes are sensitive to dosage imbalance and participate in complex interactions that both enhance and suppress the phenotypic effects of each other within cellular proliferation pathways, and in turn are modulated by other genes in the genetic background
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
