Pharmacogenomics


The Sequel System from PacBio


Single molecule, real-time (SMRT) sequencing pro- duces extremely long reads that fully span the CYP2D6 gene. Scientists have now demonstrated that SMRT sequencing offers accurate, base-level resolution even for the most complex elements within this gene. With a complete view of the CYP2D6 gene, it is now possible for scientists to achieve a more thorough understanding of drug metabolism for each new therapy considered. Meanwhile, the rise of population-based genome studies has shown that some clinically-relevant CYP2D6 variants are specific to certain popula- tions or ethnicities, offering better guidance for pharmacogenomic studies. By combining SMRT sequencing with those study results, it should be possible to assemble a complete database of CYP2D6 alleles and to better predict metaboliser phenotypes for a more straightforward path to selecting a target population that will respond most effectively to a drug.


CYP2D6 complexity


Located on chromosome 22, the CYP2D6 gene shares 97% of its sequence with the pseudogene CYP2D7P1, found only 10 kilobases away. The


Drug Discovery World Summer 2017


situation already presents a real challenge for genotyping or sequencing platforms, and is made even more complex by the presence of copy num- ber variation, structural variation and more. In this genetic morass, it is not enough to detect variants; proper classification of a CYP2D6 metaboliser profile requires that variants be phased into distinct haplotypes to resolve the precise number of functional or dysfunctional gene copies in an individual. When a gene dupli- cation is detected, for instance, technologies that cannot phase alleles usually have no way of dis- tinguishing between two copies of an allele with increased function or two copies of an allele with decreased function. Traditionally, scientists have used Sanger sequencing or genotyping platforms to profile the CYP2D6 gene. More recently, next-generation sequencing (NGS) has been incorporated as well. None of these approaches can provide a complete view of the gene and its breadth of variation, though. Genotyping tools are restricted to seeing known variants, and because there are so many catalogued alleles for this gene, most platforms must limit their queries to the top dozen or so


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