Synergistic interactions between Drosophila orthologues of genes spanned by De Novo human CNVs support multiple-hit models of autism

Grice, Stuart J., Liu, Ji-Long and Webber, Caleb ORCID: https://orcid.org/0000-0001-8063-7674 2015. Synergistic interactions between Drosophila orthologues of genes spanned by De Novo human CNVs support multiple-hit models of autism. PLoS Genetics 11 (3) , e1004998. 10.1371/journal.pgen.1004998

PDF - Published Version Available under License Creative Commons Attribution. Download (3MB)

Abstract

Autism spectrum disorders (ASDs) are highly heritable and characterised by deficits in social interaction and communication, as well as restricted and repetitive behaviours. Although a number of highly penetrant ASD gene variants have been identified, there is growing evidence to support a causal role for combinatorial effects arising from the contributions of multiple loci. By examining synaptic and circadian neurological phenotypes resulting from the dosage variants of unique human:fly orthologues in Drosophila, we observe numerous synergistic interactions between pairs of informatically-identified candidate genes whose orthologues are jointly affected by large de novo copy number variants (CNVs). These CNVs were found in the genomes of individuals with autism, including a patient carrying a 22q11.2 deletion. We first demonstrate that dosage alterations of the unique Drosophila orthologues of candidate genes from de novo CNVs that harbour only a single candidate gene display neurological defects similar to those previously reported in Drosophila models of ASD-associated variants. We then considered pairwise dosage changes within the set of orthologues of candidate genes that were affected by the same single human de novo CNV. For three of four CNVs with complete orthologous relationships, we observed significant synergistic effects following the simultaneous dosage change of gene pairs drawn from a single CNV. The phenotypic variation observed at the Drosophila synapse that results from these interacting genetic variants supports a concordant phenotypic outcome across all interacting gene pairs following the direction of human gene copy number change. We observe both specificity and transitivity between interactors, both within and between CNV candidate gene sets, supporting shared and distinct genetic aetiologies. We then show that different interactions affect divergent synaptic processes, demonstrating distinct molecular aetiologies. Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Public Library of Science
ISSN:	1553-7390
Date of First Compliant Deposit:	22 October 2020
Date of Acceptance:	12 January 2015
Last Modified:	07 May 2023 11:28
URI:	https://orca.cardiff.ac.uk/id/eprint/135776

Citation Data

Cited 28 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item