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Composite effects of polymorphisms near multiple regulatory elements create a major-effect QTL.

Bickel RD, Kopp A, Nuzhdin SV - PLoS Genet. (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America. rbickel2@unl.edu

ABSTRACT
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.

Show MeSH
Pigmentation and the haplotype of associated polymorphisms.The haplotype represents the relative number of dark and light alleles at the associated polymorphisms within the region. Individuals with negative scores have more light alleles than dark alleles and positive scores have more dark alleles than light alleles (see Materials and Methods for details). The line represents the best fit of the pigmentation as a function of haplotype score. Each of the three regions is displayed individually and all three together.
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pgen-1001275-g004: Pigmentation and the haplotype of associated polymorphisms.The haplotype represents the relative number of dark and light alleles at the associated polymorphisms within the region. Individuals with negative scores have more light alleles than dark alleles and positive scores have more dark alleles than light alleles (see Materials and Methods for details). The line represents the best fit of the pigmentation as a function of haplotype score. Each of the three regions is displayed individually and all three together.

Mentions: The effect size of each of these associated polymorphisms is small, but within each region, these polymorphisms form haplotypes that have a large effect on pigmentation. To examine these effects, we assigned each individual a haplotype score, which indicates the relative number of dark and light alleles they contain at the significant polymorphisms (see Material and Methods for details). A negative haplotype score indicates more light alleles than dark alleles, a positive score more dark than light and a score of zero indicates an equal number of dark and light alleles. There is a strong correlation between the haplotype score and pigmentation for all three regions (Figure 4) (p<.001).


Composite effects of polymorphisms near multiple regulatory elements create a major-effect QTL.

Bickel RD, Kopp A, Nuzhdin SV - PLoS Genet. (2011)

Pigmentation and the haplotype of associated polymorphisms.The haplotype represents the relative number of dark and light alleles at the associated polymorphisms within the region. Individuals with negative scores have more light alleles than dark alleles and positive scores have more dark alleles than light alleles (see Materials and Methods for details). The line represents the best fit of the pigmentation as a function of haplotype score. Each of the three regions is displayed individually and all three together.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020931&req=5

pgen-1001275-g004: Pigmentation and the haplotype of associated polymorphisms.The haplotype represents the relative number of dark and light alleles at the associated polymorphisms within the region. Individuals with negative scores have more light alleles than dark alleles and positive scores have more dark alleles than light alleles (see Materials and Methods for details). The line represents the best fit of the pigmentation as a function of haplotype score. Each of the three regions is displayed individually and all three together.
Mentions: The effect size of each of these associated polymorphisms is small, but within each region, these polymorphisms form haplotypes that have a large effect on pigmentation. To examine these effects, we assigned each individual a haplotype score, which indicates the relative number of dark and light alleles they contain at the significant polymorphisms (see Material and Methods for details). A negative haplotype score indicates more light alleles than dark alleles, a positive score more dark than light and a score of zero indicates an equal number of dark and light alleles. There is a strong correlation between the haplotype score and pigmentation for all three regions (Figure 4) (p<.001).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Science, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America. rbickel2@unl.edu

ABSTRACT
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.

Show MeSH