Rare variant phasing using paired tumor:normal sequence data
Abstract 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....
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | BMC Bioinformatics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12859-019-2753-1 |
| _version_ | 1818528539073314816 |
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| author | Alexandra R. Buckley Trey Ideker Hannah Carter Nicholas J. Schork |
| author_facet | Alexandra R. Buckley Trey Ideker Hannah Carter Nicholas J. Schork |
| author_sort | Alexandra R. Buckley |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-11T06:51:14Z |
| format | Article |
| id | doaj.art-daab7d52caad4dc49cd6adbf28b52d31 |
| institution | Directory Open Access Journal |
| issn | 1471-2105 |
| language | English |
| last_indexed | 2024-12-11T06:51:14Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Bioinformatics |
| spelling | doaj.art-daab7d52caad4dc49cd6adbf28b52d312022-12-22T01:16:55ZengBMCBMC Bioinformatics1471-21052019-05-0120111110.1186/s12859-019-2753-1Rare variant phasing using paired tumor:normal sequence dataAlexandra R. Buckley0Trey Ideker1Hannah Carter2Nicholas J. Schork3Biomedical Sciences Graduate Program, University of California, San DiegoDivision of Medical Genetics, Department of Medicine, University of California San DiegoDivision of Medical Genetics, Department of Medicine, University of California San DiegoHuman Biology Program, J. Craig Venter InstituteAbstract 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.http://link.springer.com/article/10.1186/s12859-019-2753-1Variant phasingCancer germlineCancer genomics |
| spellingShingle | Alexandra R. Buckley Trey Ideker Hannah Carter Nicholas J. Schork Rare variant phasing using paired tumor:normal sequence data BMC Bioinformatics Variant phasing Cancer germline Cancer genomics |
| 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 | Variant phasing Cancer germline Cancer genomics |
| url | http://link.springer.com/article/10.1186/s12859-019-2753-1 |
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