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Modifier effects between regulatory and protein-coding variation.

Dimas AS, Stranger BE, Beazley C, Finn RD, Ingle CE, Forrest MS, Ritchie ME, Deloukas P, Tavaré S, Dermitzakis ET - PLoS Genet. (2008)

Bottom Line: Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for.We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis.Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

ABSTRACT
Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis. Furthermore, we show that such interactions in cis can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a cis interaction between regulatory and protein-coding variants has a trans impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.

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Illustration of a hypothetical epistatic interaction between a regulatory and a protein-coding variant.Two double heterozygote individuals may be genotypically identical, but the phasing of alleles can be different and may result in very distinct phenotypes between individuals. In one individual (i) the A allele of the rSNP drives high expression levels of the protein arising from the C allele of the nsSNP. In another individual (ii) the G allele of the rSNP drives low expression levels of the protein arising from the C allele of the nsSNP. If the protein-coding variant is functionally important then this can give rise to different means in the distribution of a complex trait phenotype as shown on the right.
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pgen-1000244-g001: Illustration of a hypothetical epistatic interaction between a regulatory and a protein-coding variant.Two double heterozygote individuals may be genotypically identical, but the phasing of alleles can be different and may result in very distinct phenotypes between individuals. In one individual (i) the A allele of the rSNP drives high expression levels of the protein arising from the C allele of the nsSNP. In another individual (ii) the G allele of the rSNP drives low expression levels of the protein arising from the C allele of the nsSNP. If the protein-coding variant is functionally important then this can give rise to different means in the distribution of a complex trait phenotype as shown on the right.

Mentions: Our model brings together quantitative and qualitative variation. A gene that has an identified cis regulatory variant is differentially expressed among individuals of a population where that variant is segregating [20],[23]. If this gene also contains coding variation, then, assuming that mRNA levels are indicative of mature protein levels, the resulting protein products will not only differ in quantity (expression level) but also in quality or type (amino acid sequence) among individuals. Furthermore, depending on the historical rate of recombination between the regulatory and the coding variants, different allelic combinations (haplotypes) can arise on the two homologous chromosomes in a population. Phasing, the arrangement of the alleles at each variant with respect to one another, can differ between individuals in the population (Figure 1) [25]. If this is the case, the epistasic effect arising from these two variant types can be explored under a specific and testable biological model.


Modifier effects between regulatory and protein-coding variation.

Dimas AS, Stranger BE, Beazley C, Finn RD, Ingle CE, Forrest MS, Ritchie ME, Deloukas P, Tavaré S, Dermitzakis ET - PLoS Genet. (2008)

Illustration of a hypothetical epistatic interaction between a regulatory and a protein-coding variant.Two double heterozygote individuals may be genotypically identical, but the phasing of alleles can be different and may result in very distinct phenotypes between individuals. In one individual (i) the A allele of the rSNP drives high expression levels of the protein arising from the C allele of the nsSNP. In another individual (ii) the G allele of the rSNP drives low expression levels of the protein arising from the C allele of the nsSNP. If the protein-coding variant is functionally important then this can give rise to different means in the distribution of a complex trait phenotype as shown on the right.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570624&req=5

pgen-1000244-g001: Illustration of a hypothetical epistatic interaction between a regulatory and a protein-coding variant.Two double heterozygote individuals may be genotypically identical, but the phasing of alleles can be different and may result in very distinct phenotypes between individuals. In one individual (i) the A allele of the rSNP drives high expression levels of the protein arising from the C allele of the nsSNP. In another individual (ii) the G allele of the rSNP drives low expression levels of the protein arising from the C allele of the nsSNP. If the protein-coding variant is functionally important then this can give rise to different means in the distribution of a complex trait phenotype as shown on the right.
Mentions: Our model brings together quantitative and qualitative variation. A gene that has an identified cis regulatory variant is differentially expressed among individuals of a population where that variant is segregating [20],[23]. If this gene also contains coding variation, then, assuming that mRNA levels are indicative of mature protein levels, the resulting protein products will not only differ in quantity (expression level) but also in quality or type (amino acid sequence) among individuals. Furthermore, depending on the historical rate of recombination between the regulatory and the coding variants, different allelic combinations (haplotypes) can arise on the two homologous chromosomes in a population. Phasing, the arrangement of the alleles at each variant with respect to one another, can differ between individuals in the population (Figure 1) [25]. If this is the case, the epistasic effect arising from these two variant types can be explored under a specific and testable biological model.

Bottom Line: Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for.We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis.Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

ABSTRACT
Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis. Furthermore, we show that such interactions in cis can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a cis interaction between regulatory and protein-coding variants has a trans impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.

Show MeSH