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Modern genetic mapping is plagued by the “missing heritability” problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the  Drosophila melanogaster  female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the  Drosophila  Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of  cis -eQTLs and 78% of  trans -eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in  Drosophila  eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies.

Genetic Dissection of the Drosophila melanogaster Female Head Transcriptome Reveals Widespread Allelic Heterogeneity