Format

Send to

Choose Destination
BMC Bioinformatics. 2019 May 27;20(1):265. doi: 10.1186/s12859-019-2753-1.

Rare variant phasing using paired tumor:normal sequence data.

Buckley AR1,2, Ideker T3,4,5, Carter H3,4,5, Schork NJ6,7,8.

Author information

1
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
2
Human Biology Program, J. Craig Venter Institute, La Jolla, CA, USA.
3
Division of Medical Genetics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
4
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
5
Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA, USA.
6
Human Biology Program, J. Craig Venter Institute, La Jolla, CA, USA. nschork@jcvi.org.
7
Department of Quantitative Medicine and Systems Biology, The Translational Genomics Research Institute, Phoenix, AZ, USA. nschork@jcvi.org.
8
Departments of Family Medicine and Public Health and Psychiatry, University of California San Diego, La Jolla, CA, USA. nschork@jcvi.org.

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.

KEYWORDS:

Cancer genomics; Cancer germline; Variant phasing

PMID:
31132991
PMCID:
PMC6537421
DOI:
10.1186/s12859-019-2753-1
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center