Strong epistatic and additive effects of linked candidate SNPs for Drosophila pigmentation have implications for analysis of genome-wide association studies results

Jean-Michel Gibert,Viola Nolte,Frédérique Peronnet,Jorge Blanco,Christian Schlötterer,Marlies Dolezal

doi:10.1186/s13059-017-1262-7

Abstract

BackgroundThe mapping resolution of genome-wide association studies (GWAS) is limited by historic recombination events and effects are often assigned to haplotype blocks rather than individual SNPs. It is not clear how many of the SNPs in the block, and which ones, are causative. Drosophila pigmentation is a powerful model to dissect the genetic basis of intra-specific and inter-specific phenotypic variation. Three tightly linked SNPs in the t-MSE enhancer have been identified in three D. melanogaster populations as major contributors to female abdominal pigmentation. This enhancer controls the expression of the pigmentation gene tan (t) in the abdominal epidermis. Two of the three SNPs were confirmed in an independent study using the D. melanogaster Genetic Reference Panel established from a North American population.ResultsWe determined the functional impact of SNP1, SNP2, and SNP3 using transgenic lines to test all possible haplotypes in vivo. We show that all three candidate SNPs contribute to female Drosophila abdominal pigmentation. Interestingly, only two SNPs agree with the effect predicted by GWAS; the third one goes in the opposite direction because of linkage disequilibrium between multiple functional SNPs. Our experimental design uncovered strong additive effects for the three SNPs, but we also found significant epistatic effects explaining up to 11% of the total variation.ConclusionsOur results suggest that linked causal variants are important for the interpretation of GWAS and functional validation is needed to understand the genetic architecture of traits.

Highlights

The mapping resolution of genome-wide association studies (GWAS) is limited by historic recombination events and effects are often assigned to haplotype blocks rather than individual SNPs
Pool-GWAS in three natural D. melanogaster populations identified three closely linked SNPs as major contributors to female abdominal pigmentation [8, 9]. These three SNPs are located within a 208-bp window of the t-MSE enhancer, which controls the expression of the pigmentation gene tan (t) in the abdominal epidermis [10]: X-9121129 (SNP1), X9121094 (SNP2), and X-9120922 (SNP3) (Additional files 1 and 2: Table S1 and Figure S1)
Using the D. melanogaster Genetic Reference Panel, which was established from a North American population, two of the SNPs identified by Pool-GWAS (SNP1, SNP2) were detected [12]

Summary

Introduction

The mapping resolution of genome-wide association studies (GWAS) is limited by historic recombination events and effects are often assigned to haplotype blocks rather than individual SNPs. Three tightly linked SNPs in the t-MSE enhancer have been identified in three D. melanogaster populations as major contributors to female abdominal pigmentation This enhancer controls the expression of the pigmentation gene tan (t) in the abdominal epidermis. Pool-GWAS in three natural D. melanogaster populations identified three closely linked SNPs as major contributors to female abdominal pigmentation [8, 9]. These three SNPs are located within a 208-bp window of the t-MSE enhancer, which controls the expression of the pigmentation gene tan (t) in the abdominal epidermis [10]: X-9121129 (SNP1), X9121094 (SNP2), and X-9120922 (SNP3) (Additional files 1 and 2: Table S1 and Figure S1). Using the D. melanogaster Genetic Reference Panel, which was established from a North American population, two of the SNPs identified by Pool-GWAS (SNP1, SNP2) were detected [12]

Methods

Results

Conclusion