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Nat Commun. 2016 Sep 8;7:12817. doi: 10.1038/ncomms12817.

Rare variant phasing and haplotypic expression from RNA sequencing with phASER.

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New York Genome Center, New York, NY, 10013, USA.
Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA.
Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA.


Haplotype phasing of genetic variants is important for clinical interpretation of the genome, population genetic analysis and functional genomic analysis of allelic activity. Here we present phASER, an accurate approach for phasing variants that are overlapped by sequencing reads, including those from RNA sequencing (RNA-seq), which often span multiple exons due to splicing. Using diverse RNA-seq data we demonstrate that this provides more accurate phasing of rare variants compared with population-based phasing and allows phasing of variants in the same gene up to hundreds of kilobases away that cannot be obtained from DNA sequencing (DNA-seq) reads. We show that in the context of medical genetic studies this improves the resolution of compound heterozygotes. Additionally, phASER provides measures of haplotypic expression that increase power and accuracy in studies of allelic expression. In summary, phasing using RNA-seq and phASER is accurate and improves studies where rare variant haplotypes or allelic expression is needed.

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