Dataset Information

Characterizing linkage disequilibrium and evaluating imputation power of human genomic insertion-deletion polymorphisms.

ABSTRACT:

Background

Indels are an important cause of human variation and central to the study of human disease. The 1000 Genomes Project Low-Coverage Pilot identified over 1.3 million indels shorter than 50 bp, of which over 890 were identified as potentially disruptive variants. Yet, despite their ubiquity, the local genomic characteristics of indels remain unexplored.

Results

Herein we describe population- and minor allele frequency-based differences in linkage disequilibrium and imputation characteristics for indels included in the 1000 Genomes Project Low-Coverage Pilot for the CEU, YRI and CHB+JPT populations. Common indels were well tagged by nearby SNPs in all studied populations, and were also tagged at a similar rate to common SNPs. Both neutral and functionally deleterious common indels were imputed with greater than 95% concordance from HapMap Phase 3 and OMNI SNP sites. Further, 38 to 56% of low frequency indels were tagged by low frequency SNPs. We were able to impute heterozygous low frequency indels with over 50% concordance. Lastly, our analysis also revealed evidence of ascertainment bias. This bias prevents us from extending the applicability of our results to highly polymorphic indels that could not be identified in the Low-Coverage Pilot.

Conclusions

Although further scope exists to improve the imputation of low frequency indels, our study demonstrates that there are already ample opportunities to retrospectively impute indels for prior genome-wide association studies and to incorporate indel imputation into future case/control studies.

SUBMITTER: Lu JT

PROVIDER: S-EPMC3334570 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Publications

Characterizing linkage disequilibrium and evaluating imputation power of human genomic insertion-deletion polymorphisms.

Lu James T JT Wang Yi Y Gibbs Richard A RA Yu Fuli F

Genome biology 20120229 2

<h4>Background</h4>Indels are an important cause of human variation and central to the study of human disease. The 1000 Genomes Project Low-Coverage Pilot identified over 1.3 million indels shorter than 50 bp, of which over 890 were identified as potentially disruptive variants. Yet, despite their ubiquity, the local genomic characteristics of indels remain unexplored.<h4>Results</h4>Herein we describe population- and minor allele frequency-based differences in linkage disequilibrium and imputat ...[more]

PMID: 22377349

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Project description:Copy number variations (CNVs) represent a large source of genetic variation in humans and have been increasingly studied for disease association. A deletion polymorphism of the gene encoding the cytosolic detoxification enzyme glutathione S-transferase theta 1 (GSTT1) has been extensively studied for cancer susceptibility (919 studies, from HuGE navigator, http://www.HuGEnavigator.net/). However, clear conclusions have not been reached. Since the GSTT1 gene is located within a genomic region of segmental duplications (SD), there may be a confounding effect from another, yet-uncharacterized CNV at the same locus. Here we describe a previously uncharacterized 38-kilo-base (kb) long deletion polymorphism of GSTT2B located within a 61-kb DNA inverted repeat. GSTT2B is a duplicated copy of GSTT2, the only paralogue of GSTT1 in humans. A newly developed PCR assay revealed that a microhomology-mediated breakpoint appears to be shared among individuals at high frequency. The GSTT2B deletion polymorphism was in strong linkage disequilibrium (LD) (D' = 0.841) with the neighboring GSTT1 deletion polymorphism in the Caucasian population. Alleles harboring a single deletion were significantly overrepresented (p = 2.22 x 10(-16)), suggesting a selection against alleles with both deletions. The deletion alleles are almost certainly the derived ones, because the GSTT2B-GSTT2-GSTT1 genes were strictly retained in chimpanzees. Extremely low GSTT2 mRNA expression was associated with the GSTT2B deletion, suggesting an influence of the deletion on the flanking region and loss of GSTT2 function. Genome-wide LD analysis between deletion polymorphisms further points to the uniqueness of two deletions, because strong LD between deletion polymorphisms might be very rare in humans. These results show a complex genomic organization and unexpected biological functions of CNVs within segmental duplications and emphasize the importance of detailed structural characterization for disease association studies.

Dataset Information

Characterizing linkage disequilibrium and evaluating imputation power of human genomic insertion-deletion polymorphisms.

Background

Results

Conclusions

Publications

Characterizing linkage disequilibrium and evaluating imputation power of human genomic insertion-deletion polymorphisms.

Similar Datasets

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