Pharmacogenomics


For example, an effort to produce a reference- grade genome assembly for a Korean individual led to the identification of a clinically relevant CYP2D6 duplication. Scientists at Seoul National University and other institutions combined many technologies, including SMRT sequencing, to gen- erate a high-quality, de novo assembly from a Korean genome3. With long-read sequence data, they were able to build a highly-contiguous assem- bly and identify thousands of structural variants that had never been seen before. They also phased the genome, creating separate assemblies for each haplotype. With that foundation, the team examined cer- tain areas of interest in greater depth, including the CYP2D6 gene. The individual sequence harboured a duplication of the gene in one allele, a finding that likely has clinical relevance for that person’s ability to metabolise drugs.


Several recent population studies have highlight- ed the difference in allele frequencies among vari- ous groups. For instance, scientists compared the results of CYP2D6 profiles among people of Ashkenazi Jewish descent and North American Caucasians or Argentines, finding in both cases that ultra-rapid metaboliser profiles were signifi- cantly more common in the Ashkenazi popula- tion4. That echoed previous findings that Ashkenazi Jews more frequently had increased CYP2D6 metabolic activity but expanded the com- parison to populations outside the US This infor- mation could have important implications for ther- apeutic


selection and dosing Ashkenazi descent.


In an analysis of the Thai population, a team assessed the activity of CYP2D6 and many other genes related to drug metabolism, absorption and more5. Results of the genetic variants found in


Drug Discovery World Summer 2017 for people of


nearly 200 Thai individuals were compared to publicly-available HapMap data for Caucasian, African and Asian populations. The team uncov- ered variants in CYP2D6 and other genes that showed statistically significant differences in allele frequency between Thais and the other groups. “The results could explain clinical variability in pharmacokinetics and pharmacodynamics of drugs in Thais based on genetic variations,” the scientists concluded in their publication. In a final example, scientists found greater nat- ural genetic diversity in CYP2D6 alleles in African populations compared to other groups6. While increased genetic diversity among Africans is widely accepted in general, these particular find- ings suggest that differences in drug metabolism- related genes could explain why more adverse drug reactions are reported among people in Africa. The team’s analysis highlights “a need for optimisation of drug therapy and drug develop- ment there,” the scientists reported in their paper, calling for new efforts to “discover uniquely African alleles and to identify populations at a potentially increased risk of drug-induced adverse events or drug inefficacy.”


Moving forward The ability to fully resolve CYP2D6 with SMRT sequencing affords us new opportunities to improve the success rates in drug discovery and development. One obvious benefit is that it is now possible to conduct enough sequencing to charac- terise the breadth of natural genetic variation for CYP2D6 – and eventually for all genes related to drug metabolism. It is remarkable to realise that our understanding of CYP2D6 activity is no longer limited by technology, but by the availability of samples. That is a much more straightforward


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The SMRT Sequencing Process Step 1: Fluorescent phospholinked labelled nucleotides are introduced into the ZMW. Step 2: The base being incorporated is held in the detection volume for tens of milliseconds, producing a bright flash of light. Step 3: The phosphate chain is cleaved, releasing the attached dye molecule. Step 4-5: The process repeats


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