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PLoS Genet. Jan 2011; 7(1): e1001275.
Published online Jan 13, 2011. doi:  10.1371/journal.pgen.1001275
PMCID: PMC3020931

Composite Effects of Polymorphisms near Multiple Regulatory Elements Create a Major-Effect QTL

Gregory S. Barsh, Editor


Many agriculturally, evolutionarily, and medically important characters vary in a quantitative fashion. Unfortunately, the genes and sequence variants accounting for this variation remain largely unknown due to a variety of biological and technical challenges. Drosophila melanogaster contains high levels of sequence variation and low linkage disequilibrium, allowing us to dissect the effects of many causative variants within a single locus. Here, we take advantage of these features to identify and characterize the sequence polymorphisms that comprise major effect QTL alleles segregating at the bric-a-brac locus. We show that natural bric-a-brac alleles with large effects on cuticular pigmentation reflect a cumulative impact of polymorphisms that affect three functional regions: a promoter, a tissue-specific enhancer, and a Polycomb response element. Analysis of allele-specific expression at the bric-a-brac locus confirms that these polymorphisms modulate transcription at the cis-regulatory level. Our results establish that a single QTL can act through a confluence of multiple molecular mechanisms and that sequence variation in regions flanking experimentally validated functional elements can have significant quantitative effects on transcriptional activity and phenotype. These findings have important design and conceptual implications for basic and medical genomics.

Author Summary

Genes responsible for quantitative variation have been identified for a diverse range of phenotypes. However, much remains to be learned about the distribution of causative genetic variation within a locus. In this study, we investigated a locus that contributes to natural variation in abdominal pigmentation in Drosophila melanogaster. We found that the large phenotypic effect of this locus results from the cumulative action of many small-effect polymorphisms that are concentrated in three distinct functional regions: a promoter, a tissue-specific enhancer, and a Polycomb response element (a region involved in chromatin remodeling). The same regions influence the adult phenotype and transcript abundance, indicating that the causative sequence variants act by modulating transcription. Interestingly, these polymorphisms cluster near, but not within, the functionally validated regulatory regions, suggesting that DNA sequences surrounding core functional elements may play a key role in quantitative variation.

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