Abstract
Organismal phenotypes usually have a quantitative distribution, and their genetic architecture can be studied by genome-wide association (GWA) mapping approaches. In most of such studies, it has become clear that many genes of moderate or small effects contribute to the phenotype.1-4 Hence, the attention has turned toward the loci falling below the GWA cut-off, which may contribute to the phenotype through modifier interactions with a set of core genes, as proposed in the omnigenic model.5 One can thus predict that both moderate effect GWA-derived candidate genes and randomly chosen genes should have a similar likelihood to affect a given phenotype when they are analyzed via gene disruption assays. We have tested this hypothesis by using an automated phenotyping system for Drosophila pupal phenotypes.6,7 We first identified candidate genes for pupal length in a GWA based on the Drosophila Genetic Reference Panel (DGRP)8,9 and showed that most of these candidate genes are indeed involved in the phenotype. We then randomly chose genes below a GWA significance threshold and found that three-quarters of them had also an effect on the trait with comparable effect sizes as the GWA candidate genes. We further tested the effects of these knockout lines on an independent behavioral pupal trait (pupation site choice) and found that a similar fraction had a significant effect as well. Our data thus confirm the implication that a large number of genes can influence independent quantitative traits.
Highlights
The same approach allows to score the independent phenotype of pupation site choice, which represents a behavioral phenotype with a polygenic genetic architecture.[7]
The profiles of pupal case length from 14 wild-type and of 198 Drosophila Genetic Reference Panel (DGRP) inbred lines are shown in Figures S1A and S1B, suggesting that DGRP lines capture the existing variation of pupal case length in Drosophila melanogaster
To identify possible additional candidate genes associated with the variants, we examined the long-range linkage disequilibrium (LD) between pairs of detected candidate variants and with other genetic variants found in the DGRP strains
Summary
We found 50 significant SNPs (p % 1 3 10À5) to be associated with pupal case length in the DGRP strains, corresponding to 67 associating genes that locate within 5 kb up/downstream (default setting in SnpEff)[12] of these genetic variants (Figure 2A; Data S1A). To identify possible additional candidate genes associated with the variants, we examined the long-range linkage disequilibrium (LD) between pairs of detected candidate variants and with other genetic variants found in the DGRP strains. LD blocks were calculated for each significant genetic variant with a commonly used threshold r2 = 0.8,13 and 17 significant LD blocks were found with average block size of 19.3 kb (Data S1B). Combining the additional genes identified in the above LD blocks, we identified in total 90 candidate genes associating with pupal case length variation in Drosophila melanogaster
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