Testing implications of the polygenic model for the genetic analysis of loci identified through genome-wide association

Abstract

27The omnigenic model suggests the existence of core networks of genes for quantitative traits, which are influenced 28 by modifiers that may encompass most, if not all expressed genes in the genome. We have studied pupation site 29 choice behaviour in Drosophila to test this model. Based on a GWA analysis of the Drosophila Genetic Reference 30 Panel (DGRP) stocks, we identify candidate genes and show for disrupted versions of the genes that most are indeed 31 involved in the phenotype. These candidate genes also allowed us to identify a core network and we experimentally 32 confirm the involvement of other members of this core network in the trait. Intriguingly, when randomly choosing 20 33 non-network genes we also find an involvement in the trait for most of them. Comparison of phenotypic effect sizes 34 suggest that the core network genes have on average stronger effects. Our data thus confirm the predictions of an 35 omnigenic genetic architecture. 36 37 48 or disease etiology in human disease studies. These are expected to be modified by many, if not all other genes 49 expressed in the same cells. Although the effect sizes of these other genes are expected to be smaller than those of 50 the core genes, in sum they explain more of the genetic variance or heritability than the set of core genes. However, 51an explicit test of this model is still lacking. 52We assess here predictions of the omnigenic model using an ecologically relevant quantitative behavioural trait in 53 Drosophila melanogaster, namely pupation site choice. The pupal stage is a life history stage found in 54 holometabolous insects undergoing transformation between larval and adult stages (Jones and Reiter, 1975; Price, 55 1970). The choice of pupation site is known to directly influence the probability of successful eclosion of adult flies 56 (Joshi and Mueller, 1993; Rodriguez et al., 1992; Sokolowski, 1985), as pupae are exposed to many biotic and 57 abiotic risks while immobilized during the 3-4 days of metamorphosis. Patterns of pupation site choices in a number 58 of Drosophila species have been extensively investigated (Erezyilmaz and Stern, 2013; Markow, 1979; Vandal et al., 59 2012 Vandal et al., 59 , 2008, and substantial variation has been found both within and between species. Several environmental 60 factors, such as temperature (Schnebel and Grossfield, 1992), light (Markow, 1981; Schnebel and Grossfield, 1986), 61 humidity (Casares et al., 1997; Sokal et al., 1960) and food medium (Harini, 2013; Hodge and Caslaw, 1998) have 62 been shown to contribute to the variation. Biotic factors were also identified, including sex (Casares and Carracedo, 63 1987), larval development time (Welbergen and Sokolowski 1994), and larval density in the vial (Joshi and Mueller, 64 1993; Sokolowski and Hansell, 1983). 65Previous genetic association studies to explore the genetic basis of pupation site choice in Drosophila were 66 consistent with it being a complex behavioural trait with a polygenic basis (Erezyilmaz and Stern, 20...

Polygenic adaptation from standing genetic variation allows rapid ecotype formation

“…Genetic manipulation may not be very informative when assessing highly polygenic traits (see e.g. 40 ). But QTL mapping with recently developed refined statistical algorithms for detection of polygenic signals may hold some promise 41 .…”

Genetic basis of offspring number and body weight variation inDrosophila melanogaster

“…The omnigenic model of genetic architecture 35,36 could explain the functionally varied suite of genes associated with offspring number and weight phenotypes. One of the predictions of the omnigenic model is that essentially all genes contribute to a trait through their expression at some appropriate developmental point or in a particular tissue.…”