Behavioral individuality reveals genetic control of phenotypic variability

Abstract

Variability is ubiquitous in nature and a fundamental feature of complex systems. Few studies, however, have investigated variance itself as a trait under genetic control. By focusing primarily on trait means and ignoring the effect of alternative alleles on trait variability, we may be missing an important axis of genetic variation contributing to phenotypic differences among individuals 1,2 . To study genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used a panel of Drosophila inbred lines 3 and focused on locomotor handedness 4 , in an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals while others had low levels. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a implicated a neuropil in the central complex 5 of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination 6 . We have validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. This study reveals the constellation of phenotypes that can arise from a single genotype and it shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variability. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.

Neuronal control of locomotor handedness in Drosophila

“…1; CS vs. w 1118 ). The extent of this variation was further confirmed in a companion study of wild-derived inbred lines (22). Another potential source of persistent locomotor handedness is morphological asymmetry.…”

“…cbd KS96 is a missense mutant of Ten-a (25), which encodes a transmembrane protein involved in axon targeting and synapse formation (26,27), and causes severe and widespread defects in the fan-shaped body (FB), ellipsoid body (EB), and noduli (No), leading to high individual-to-individual variation in the gross morphology of the CC (19). Furthermore, a genome-wide association study in a panel of inbred lines implicated SNPs within Ten-a as affecting variability in locomotor handedness (22). This association links natural genetic variation in Ten-a, variability in the function of central complex circuits, and variability in turn bias at the population level.…”

The Multi-allelic Genetic Architecture of a Variance-heterogeneity Locus for Molybdenum Accumulation Acts as a Source of Unexplained Additive Genetic Variance

“…Little is known about the genetic mechanisms contributing to variance-heterogeneity between genotypes in natural populations. Recently, Ayroles et al [24] showed in an unpublished study that allelic plasticity at an individual locus could be a cause, but beyond that other explanations are still hypothetical. Here, we find that the variance-heterogeneity in leaf molybdenum concentration revealed in a collection of wild-collected A.…”

“…epistasis or gene-by-environment interactions) [16,21,25]. The first suggestive empirical evidence for variance-heterogeneity being a property of a single locus was recently presented in an unpublished study by Ayroles et al [24]. In that study, a vGWA association to a behavioral phenotype in the Dropsophila Genome Reference Panel (DGRP) was determined to be driven by a mutation in the Ten-a gene.…”

“…With the advent of GWA analysis, and the later realization that standard additive models leave much of the genetic variance in the analyzed populations uncovered [8], there has been an increased interest in exploring genetic regulation of variance heterogeneity [16,20]. Several recent studies in, for example, humans [21,22], plants [6,19,23], Drosophilia melanogaster [24] and yeast [25] have shown that part of this previously unexplored heritable genetic variation beyond the narrow-sense heritability can be uncovered by reanalyzing existing GWA datasets using methods to detect differences in trait variance (varianceheterogeneity GWA or vGWA for short) between genotypes [20,22,26]. Despite these findings that variancecontrolling loci appear to be relatively common in the genome and can make large contributions to the phenotypic variability [23,25], the molecular basis of variance-controlling loci remain to be uncovered.…”