The Drosophila Gene Sulfateless Modulates Autism-Like Behaviors.

Kevin A Hope,Ben May,Lawrence T Reiter,Janis O’Donnell,James S Sutcliffe,Daniel Flatten,Peter Cavitch

doi:10.3389/fgene.2019.00574

Abstract

Major challenges to identifying genes that contribute to autism spectrum disorder (ASD) risk include the availability of large ASD cohorts, the contribution of many genes overall, and small effect sizes attributable to common gene variants. An alternative approach is to use a model organism to detect alleles that impact ASD-relevant behaviors and ask whether homologous human genes infer ASD risk. Here we utilized the Drosophila genetic reference panel (DGRP) as a tool to probe for perturbation in naturally occurring behaviors in Drosophila melanogaster that are analogous to three behavior domains: impaired social communication, social reciprocity and repetitive behaviors or restricted interests. Using 40 of the available DGRP lines, we identified single nucleotide polymorphisms (SNPs) in or near genes controlling these behavior domains, including ASD gene orthologs (neurexin 4 and neuroligin 2), an intellectual disability (ID) gene homolog (kirre), and a gene encoding a heparan sulfate (HS) modifying enzyme called sulfateless (sfl). SNPs in sfl were associated with all three ASD-like behaviors. Using RNAi knock-down of neuronal sfl expression, we observed significant changes in expressive and receptive communication during mating, decreased grooming behavior, and increased social spacing. These results suggest a role for HS proteoglycan synthesis and/or modification in normal social communication, repetitive behavior, and social interaction in flies. Finally, using the DGRP to directly identify genetic effects relevant to a neuropsychiatric disorder further demonstrates the utility of the Drosophila system in the discovery of genes relevant to human disease.

Highlights

Major hurdles to understanding the pathophysiology of autism spectrum disorder (ASD) include extreme genetic heterogeneity combined with small effect sizes for most risk genes, and the inherent difficulty in identifying non-genetic factors that may increase autism risk
Genome wide association studies (GWAS) use genotype arrays to capture common genetic variation across the genome and test for association with disease using family-based or case-control designs. This approach has been remarkably successful in schizophrenia for which combined samples in the psychiatric genomics consortium (PGC) have surpassed 50,000 and have identified well over 150 genomewide significant loci (Li et al, 2017; Pardinas et al, 2018)
We sought to identify measurable fly behaviors that map to the three core ASD phenotypic domains: communication, social interaction and repetitive behaviors, and restricted interests

Summary

Introduction

Major hurdles to understanding the pathophysiology of autism spectrum disorder (ASD) include extreme genetic heterogeneity combined with small effect sizes for most risk genes, and the inherent difficulty in identifying non-genetic factors (e.g., environmental and epigenetic) that may increase autism risk. 20–30% of cases of non-syndromic ASD correspond to individually sfl Modulates ASD Behaviors rare, highly penetrant, often de novo, variants These variants range from “pathogenic” to significant risk variants of large effect and can show incomplete penetrance, pleiotropy or both (De Rubeis et al, 2014; Sanders et al, 2015). Genome wide association studies (GWAS) use genotype arrays to capture common genetic variation across the genome and test for association with disease using family-based or case-control designs This approach has been remarkably successful in schizophrenia for which combined samples in the psychiatric genomics consortium (PGC) have surpassed 50,000 and have identified well over 150 genomewide significant loci (Li et al, 2017; Pardinas et al, 2018). The most recent ASD GWAS from the PGC identified only a few genome-wide significant loci (Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium, 2017), but amalgamated ASD cohorts are not yet of the size to reach the critical “inflection point” previously observed for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014)

Methods

Results

Conclusion