Abstract
Haplotypes are often critical for the interpretation of genetic laboratory observations into medically actionable findings. Current massively parallel DNA sequencing technologies produce short sequence reads that are often unable to resolve haplotype information. Phasing short read data typically requires supplemental statistical phasing based on known haplotype structure in the population or parental genotypic data. Here we demonstrate that the MinION nanopore sequencer is capable of producing very long reads to resolve both variants and haplotypes of HLA-A, HLA-B and CYP2D6 genes important in determining patient drug response in sample NA12878 of CEPH/UTAH pedigree 1463, without the need for statistical phasing. Long read data from a single 24-hour nanopore sequencing run was used to reconstruct haplotypes, which were confirmed by HapMap data and statistically phased Complete Genomics and Sequenom genotypes. Our results demonstrate that nanopore sequencing is an emerging standalone technology with potential utility in a clinical environment to aid in medical decision-making.
Highlights
An important aspect of precision medicine is the study of how genes influence individual response to drug therapies, known as pharmacogenomics (PGx)
The importance of correct phasing of PGx genotypes is illustrated with the gene thiopurine methyltransferase (TPMT), which plays a critical role in the metabolism of thiopurine, a drug used to treat acute lymphoblastic leukemia
The rs1800460 variant is present in both *3A and *3B haplotypes while the rs1142345 variant is present in both *3A and *3C haplotypes
Summary
An important aspect of precision medicine is the study of how genes influence individual response to drug therapies, known as pharmacogenomics (PGx). PGx genotyping impacts the choice of drug dosing in many medical contexts. Diagnostic labs are exploring the use of whole genome or exome sequencing (WGS, WES) for PGx. existing methods have various limitations, which may lead to adverse drug responses. WGS and WES methods may fail to capture or provide adequate sequence coverage for certain PGx loci. Targeted genotyping approaches, such as Taqman (Life Technologies), Luminex (Luminex Corp.) or Sequenom (Agena Bioscience), can fail to detect novel loss-of-function mutations due to their selective interrogation of predefined genomic loci. A laboratory can send these PGx samples to a third party service for a fee, but may wait up to several months for a clinical report
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