Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior

Abstract

Human psychiatric disorders such as schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder often include adverse behaviors including increased aggressiveness. Individuals with psychiatric disorders often exhibit social withdrawal, which can further increase the probability of conducting a violent act. Here, we used the inbred, sequenced lines of the Drosophila Genetic Reference Panel (DGRP) to investigate the genetic basis of variation in male aggressive behavior for flies reared in a socialized and socially isolated environment. We identified genetic variation for aggressive behavior, as well as significant genotype-by-social environmental interaction (GSEI); i.e., variation among DGRP genotypes in the degree to which social isolation affected aggression. We performed genome-wide association (GWA) analyses to identify genetic variants associated with aggression within each environment. We used genomic prediction to partition genetic variants into gene ontology (GO) terms and constituent genes, and identified GO terms and genes with high prediction accuracies in both social environments and for GSEI. The top predictive GO terms significantly increased the proportion of variance explained, compared to prediction models based on all segregating variants. We performed genomic prediction across environments, and identified genes in common between the social environments that turned out to be enriched for genome-wide associated variants. A large proportion of the associated genes have previously been associated with aggressive behavior in Drosophila and mice. Further, many of these genes have human orthologs that have been associated with neurological disorders, indicating partially shared genetic mechanisms underlying aggression in animal models and human psychiatric disorders.

Keywords: Drosophila melanogaster; GBLUP; GFBLUP; GenPred; Genomic Selection; Shared data resource; social experience; social isolation.

Figure 1

Assay used to quantify aggressive behavior. (A) Illustration of the Flydiator arena. (B) Top view of the Flydiator arena loaded with pairs of CSB and DGRP flies. CSB, Canton-SB; DGRP, Drosophila Genetic Reference Panel.

Figure 2

Variation in aggression among DGRP lines in two social environments. (A) Mean adjusted phenotypic values of aggressive behavior for flies reared in an isolated environment as a function of the mean adjusted phenotypic values for socially experienced flies. The red dashed line illustrates the expected point with no difference in phenotype from the two social environments. (B) GSEI (${\stackrel{\sim }{\mathit{y}}}_{GSEI}={\stackrel{\sim }{\mathit{y}}}_{\mathrm{soc}}-{\stackrel{\sim }{\mathit{y}}}_{\mathrm{iso}}$) ordered by increasing trait value. The horizontal dashed line indicates the expected value in absence of GSEI. Shaded areas illustrate in which social environment the DGRP lines became more aggressive (orange, flies from the socially isolated environment; purple, flies from the socialized environment). DGRP, Drosophila Genetic Reference Panel; GSEI, genotype-by-social environmental interaction.

Figure 3

Genomic predictions within and across environments using GWA results with bins defined by P-value cutoffs. The data were divided into training and validation sets (10-fold), and GWA analyses were performed on each training set. Each training GWA analysis was then used to predict the genetic values in the validation set [socially experienced flies (red), socially isolated flies (green), or GSEI (blue)] using GFBLUP with feature sets defined by P-value bins. Each panel shows the predictive ability using GWA results from the social environment (A), the socially isolated environment (B), or GSEI (C). Shaded areas indicate the SEM. As comparison, the dashed lines represent the PA (within environment) from sets of randomly selected SNPs of size corresponding to the number of SNPs within environment below the P-value cutoff. GFBLUP, genomic feature best linear unbiased prediction; GSEI, genotype-by-social environmental interaction; GWA, genome-wide association; PA, predictive ability; SNP, single nucleotide polymorphism.