Strong epistatic and additive effects of linked candidate SNPs for Drosophila pigmentation have implications for analysis of genome-wide association studies results
Résumé
Background: 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. 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.
Results: We 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.
Conclusions: Our 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.
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