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Rare variant phasing using paired tumor:normal sequence data
BACKGROUND: In standard high throughput sequencing analysis, genetic variants are not assigned to a homologous chromosome of origin. This process, called haplotype phasing, can reveal information important for understanding the relationship between genetic variants and biological phenotypes. For exa...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537421/ https://www.ncbi.nlm.nih.gov/pubmed/31132991 http://dx.doi.org/10.1186/s12859-019-2753-1 |
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author | Buckley, Alexandra R. Ideker, Trey Carter, Hannah Schork, Nicholas J. |
author_facet | Buckley, Alexandra R. Ideker, Trey Carter, Hannah Schork, Nicholas J. |
author_sort | Buckley, Alexandra R. |
collection | PubMed |
description | BACKGROUND: In standard high throughput sequencing analysis, genetic variants are not assigned to a homologous chromosome of origin. This process, called haplotype phasing, can reveal information important for understanding the relationship between genetic variants and biological phenotypes. For example, in genes that carry multiple heterozygous missense variants, phasing resolves whether one or both gene copies are altered. Here, we present a novel approach to phasing variants that takes advantage of unique properties of paired tumor:normal sequencing data from cancer studies. RESULTS: VAF phasing uses changes in variant allele frequency (VAF) between tumor and normal samples in regions of somatic chromosomal gain or loss to phase germline variants. We apply VAF phasing to 6180 samples from the Cancer Genome Atlas (TCGA) and demonstrate that our method is highly concordant with other standard phasing methods, and can phase an average of 33% more variants than other read-backed phasing methods. Using variant annotation tools designed to score gene haplotypes, we find a suggestive association between carrying multiple missense variants in a single copy of a cancer predisposition gene and earlier age of cancer diagnosis. CONCLUSIONS: VAF phasing exploits unique properties of tumor genomes to increase the number of germline variants that can be phased over standard read-backed methods in paired tumor:normal samples. Our phase-informed association testing results call attention to the need to develop more tools for assessing the joint effect of multiple genetic variants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12859-019-2753-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6537421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-65374212019-05-30 Rare variant phasing using paired tumor:normal sequence data Buckley, Alexandra R. Ideker, Trey Carter, Hannah Schork, Nicholas J. BMC Bioinformatics Methodology Article BACKGROUND: In standard high throughput sequencing analysis, genetic variants are not assigned to a homologous chromosome of origin. This process, called haplotype phasing, can reveal information important for understanding the relationship between genetic variants and biological phenotypes. For example, in genes that carry multiple heterozygous missense variants, phasing resolves whether one or both gene copies are altered. Here, we present a novel approach to phasing variants that takes advantage of unique properties of paired tumor:normal sequencing data from cancer studies. RESULTS: VAF phasing uses changes in variant allele frequency (VAF) between tumor and normal samples in regions of somatic chromosomal gain or loss to phase germline variants. We apply VAF phasing to 6180 samples from the Cancer Genome Atlas (TCGA) and demonstrate that our method is highly concordant with other standard phasing methods, and can phase an average of 33% more variants than other read-backed phasing methods. Using variant annotation tools designed to score gene haplotypes, we find a suggestive association between carrying multiple missense variants in a single copy of a cancer predisposition gene and earlier age of cancer diagnosis. CONCLUSIONS: VAF phasing exploits unique properties of tumor genomes to increase the number of germline variants that can be phased over standard read-backed methods in paired tumor:normal samples. Our phase-informed association testing results call attention to the need to develop more tools for assessing the joint effect of multiple genetic variants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12859-019-2753-1) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-27 /pmc/articles/PMC6537421/ /pubmed/31132991 http://dx.doi.org/10.1186/s12859-019-2753-1 Text en © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Methodology Article Buckley, Alexandra R. Ideker, Trey Carter, Hannah Schork, Nicholas J. Rare variant phasing using paired tumor:normal sequence data |
title | Rare variant phasing using paired tumor:normal sequence data |
title_full | Rare variant phasing using paired tumor:normal sequence data |
title_fullStr | Rare variant phasing using paired tumor:normal sequence data |
title_full_unstemmed | Rare variant phasing using paired tumor:normal sequence data |
title_short | Rare variant phasing using paired tumor:normal sequence data |
title_sort | rare variant phasing using paired tumor:normal sequence data |
topic | Methodology Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537421/ https://www.ncbi.nlm.nih.gov/pubmed/31132991 http://dx.doi.org/10.1186/s12859-019-2753-1 |
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