Drosophila study contributes to understanding of autism spectrum disorders-associated gene variants

Grice SJ, Liu JL, Webber C. Synergistic Interactions between Drosophila Orthologues of Genes Spanned by De Novo Human CNVs Support Multiple-Hit Models of Autism. PLoS Genet. 2015 Mar 27;11(3):e1004998. PMID: 25816101.

Fig. 1 from Grice et al. 2015 PLoS Genet.

From the abstract: "Autism spectrum disorders (ASDs) are highly heritable ... 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). ... 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. ... Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease."