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Genotype-based test in mapping cis-regulatory variants from allele-specific expression data.

Lefebvre JF, Vello E, Ge B, Montgomery SB, Dermitzakis ET, Pastinen T, Labuda D - PLoS ONE (2012)

Bottom Line: In this study, we introduce a genotype-based mapping test that does not require haplotype-phase inference to locate regulatory regions.The genotype-based test performed equally well with the experimental AI datasets, either from genome-wide cDNA hybridization arrays or from RNA sequencing.By avoiding the need of haplotype inference, the genotype-based test will suit AI analyses in population samples of unknown haplotype structure and will additionally facilitate the identification of cis-regulatory variants that are located far away from the regulated transcript.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche du CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

ABSTRACT
Identifying and understanding the impact of gene regulatory variation is of considerable importance in evolutionary and medical genetics; such variants are thought to be responsible for human-specific adaptation and to have an important role in genetic disease. Regulatory variation in cis is readily detected in individuals showing uneven expression of a transcript from its two allelic copies, an observation referred to as allelic imbalance (AI). Identifying individuals exhibiting AI allows mapping of regulatory DNA regions and the potential to identify the underlying causal genetic variant(s). However, existing mapping methods require knowledge of the haplotypes, which make them sensitive to phasing errors. In this study, we introduce a genotype-based mapping test that does not require haplotype-phase inference to locate regulatory regions. The test relies on partitioning genotypes of individuals exhibiting AI and those not expressing AI in a 2×3 contingency table. The performance of this test to detect linkage disequilibrium (LD) between a potential regulatory site and a SNP located in this region was examined by analyzing the simulated and the empirical AI datasets. In simulation experiments, the genotype-based test outperforms the haplotype-based tests with the increasing distance separating the regulatory region from its regulated transcript. The genotype-based test performed equally well with the experimental AI datasets, either from genome-wide cDNA hybridization arrays or from RNA sequencing. By avoiding the need of haplotype inference, the genotype-based test will suit AI analyses in population samples of unknown haplotype structure and will additionally facilitate the identification of cis-regulatory variants that are located far away from the regulated transcript.

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Related in: MedlinePlus

Ideograms of linear regression and binomial haplotype-based tests, and of contingency genotype-based test.How AI results are used in the three tests with hypothetical SNPs, SNP1 and SNP2, chosen such that SNP1 is not linked to the R-site whereas SNP2 is.
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pone-0038667-g001: Ideograms of linear regression and binomial haplotype-based tests, and of contingency genotype-based test.How AI results are used in the three tests with hypothetical SNPs, SNP1 and SNP2, chosen such that SNP1 is not linked to the R-site whereas SNP2 is.

Mentions: Consider a regulatory site R that affects expression of a gene X (Figure 1A). Of its two alleles R (ancestral) and r (derived), one causes up-regulation and the other down-regulation of the regulated transcript. As a consequence, RNAs transcribed from two parental copies of this gene are unequally expressed in Rr heterozygotes, causing AI that can be revealed by measuring relative levels of the corresponding allelic transcripts. On the chromosome expressing gene X, there are SNPs (referred to as sites A) that can be tested for association with AI caused by the R site. In Figure 1A, some of these sites (SNP1 and SNP2) are found within the regulatory region, in the vicinity and in linkage with the R site. Polymorphic sites that are found within the transcript itself are used as informative markers, which allow distinguishing between allelic transcripts from the two copies of the chromosome and their expression levels. In this example, there is no linkage between the regulatory region and the transcribed region polymorphisms. Informative markers instrumental in revealing AI and those that are informative in locating the R site are physically separated. This emphasizes the difference between the AI detection and the mapping of the corresponding regulatory region. In practice the majority of cis-regulatory elements are very close to the transcript they control, and tightly linked to the informative markers.


Genotype-based test in mapping cis-regulatory variants from allele-specific expression data.

Lefebvre JF, Vello E, Ge B, Montgomery SB, Dermitzakis ET, Pastinen T, Labuda D - PLoS ONE (2012)

Ideograms of linear regression and binomial haplotype-based tests, and of contingency genotype-based test.How AI results are used in the three tests with hypothetical SNPs, SNP1 and SNP2, chosen such that SNP1 is not linked to the R-site whereas SNP2 is.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369843&req=5

pone-0038667-g001: Ideograms of linear regression and binomial haplotype-based tests, and of contingency genotype-based test.How AI results are used in the three tests with hypothetical SNPs, SNP1 and SNP2, chosen such that SNP1 is not linked to the R-site whereas SNP2 is.
Mentions: Consider a regulatory site R that affects expression of a gene X (Figure 1A). Of its two alleles R (ancestral) and r (derived), one causes up-regulation and the other down-regulation of the regulated transcript. As a consequence, RNAs transcribed from two parental copies of this gene are unequally expressed in Rr heterozygotes, causing AI that can be revealed by measuring relative levels of the corresponding allelic transcripts. On the chromosome expressing gene X, there are SNPs (referred to as sites A) that can be tested for association with AI caused by the R site. In Figure 1A, some of these sites (SNP1 and SNP2) are found within the regulatory region, in the vicinity and in linkage with the R site. Polymorphic sites that are found within the transcript itself are used as informative markers, which allow distinguishing between allelic transcripts from the two copies of the chromosome and their expression levels. In this example, there is no linkage between the regulatory region and the transcribed region polymorphisms. Informative markers instrumental in revealing AI and those that are informative in locating the R site are physically separated. This emphasizes the difference between the AI detection and the mapping of the corresponding regulatory region. In practice the majority of cis-regulatory elements are very close to the transcript they control, and tightly linked to the informative markers.

Bottom Line: In this study, we introduce a genotype-based mapping test that does not require haplotype-phase inference to locate regulatory regions.The genotype-based test performed equally well with the experimental AI datasets, either from genome-wide cDNA hybridization arrays or from RNA sequencing.By avoiding the need of haplotype inference, the genotype-based test will suit AI analyses in population samples of unknown haplotype structure and will additionally facilitate the identification of cis-regulatory variants that are located far away from the regulated transcript.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche du CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

ABSTRACT
Identifying and understanding the impact of gene regulatory variation is of considerable importance in evolutionary and medical genetics; such variants are thought to be responsible for human-specific adaptation and to have an important role in genetic disease. Regulatory variation in cis is readily detected in individuals showing uneven expression of a transcript from its two allelic copies, an observation referred to as allelic imbalance (AI). Identifying individuals exhibiting AI allows mapping of regulatory DNA regions and the potential to identify the underlying causal genetic variant(s). However, existing mapping methods require knowledge of the haplotypes, which make them sensitive to phasing errors. In this study, we introduce a genotype-based mapping test that does not require haplotype-phase inference to locate regulatory regions. The test relies on partitioning genotypes of individuals exhibiting AI and those not expressing AI in a 2×3 contingency table. The performance of this test to detect linkage disequilibrium (LD) between a potential regulatory site and a SNP located in this region was examined by analyzing the simulated and the empirical AI datasets. In simulation experiments, the genotype-based test outperforms the haplotype-based tests with the increasing distance separating the regulatory region from its regulated transcript. The genotype-based test performed equally well with the experimental AI datasets, either from genome-wide cDNA hybridization arrays or from RNA sequencing. By avoiding the need of haplotype inference, the genotype-based test will suit AI analyses in population samples of unknown haplotype structure and will additionally facilitate the identification of cis-regulatory variants that are located far away from the regulated transcript.

Show MeSH
Related in: MedlinePlus