Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model View Full Text


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Article Info

DATE

2018-06-06

AUTHORS

Seung-been Lee, Marsha M. Wheeler, Karynne Patterson, Sean McGee, Rachel Dalton, Erica L. Woodahl, Andrea Gaedigk, Kenneth E. Thummel, Deborah A. Nickerson

ABSTRACT

PURPOSE: Genotyping CYP2D6 is important for precision drug therapy because the enzyme it encodes metabolizes approximately 25% of drugs, and its activity varies considerably among individuals. Genotype analysis of CYP2D6 is challenging due to its highly polymorphic nature. Over 100 haplotypes (star alleles) have been defined for CYP2D6, some involving a gene conversion with its nearby nonfunctional but highly homologous paralog CYP2D7. We present Stargazer, a new bioinformatics tool that uses next-generation sequencing (NGS) data to call star alleles for CYP2D6 ( https://stargazer.gs.washington.edu/stargazerweb/ ). Stargazer is currently being extended for other pharmacogenes. METHODS: Stargazer identifies star alleles from NGS data by detecting single nucleotide variants, insertion-deletion variants, and structural variants. Stargazer detects structural variation, including gene deletions, duplications, and conversions, by calculating paralog-specific copy numbers from read depths. RESULTS: We applied Stargazer to the NGS data of 32 ethnically diverse HapMap trios that were genotyped by TaqMan assays, long-range polymerase chain reaction, quantitative multiplex polymerase chain reaction, high-resolution melting analysis, and/or Sanger sequencing. CYP2D6 genotyping by Stargazer was 99.0% concordant with the data obtained by these methods, and showed that 28.1% of the samples had structural variation including CYP2D6/CYP2D7 hybrids. CONCLUSION: Accurate genotyping of pharmacogenes with NGS and subsequent allele calling with Stargazer will aid the implementation of precision drug therapy. More... »

PAGES

361-372

References to SciGraph publications

  • 2007-10-31. The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2006-01-10. CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation in THE PHARMACOGENOMICS JOURNAL
  • 2016-07-07. Prediction of CYP2D6 phenotype from genotype across world populations in GENETICS IN MEDICINE
  • 2006-04-25. CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele in THE PHARMACOGENOMICS JOURNAL
  • 2014-07-30. Deep mutational scanning: a new style of protein science in NATURE METHODS
  • 2014-01-23. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2016-01-13. Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences in NPJ GENOMIC MEDICINE
  • 2016-06-07. High frequency of CYP2D6 ultrarapid metabolizers in Spain: controversy about their misclassification in worldwide population studies in THE PHARMACOGENOMICS JOURNAL
  • 2009-11. Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance in CLINICAL PHARMACOKINETICS
  • 2006-12-27. Cytochrome P4502D6 (CYP2D6) Gene Locus Heterogeneity: Characterization of Gene Duplication Events in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2006-07-04. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication in THE PHARMACOGENOMICS JOURNAL
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    32 schema:description PURPOSE: Genotyping CYP2D6 is important for precision drug therapy because the enzyme it encodes metabolizes approximately 25% of drugs, and its activity varies considerably among individuals. Genotype analysis of CYP2D6 is challenging due to its highly polymorphic nature. Over 100 haplotypes (star alleles) have been defined for CYP2D6, some involving a gene conversion with its nearby nonfunctional but highly homologous paralog CYP2D7. We present Stargazer, a new bioinformatics tool that uses next-generation sequencing (NGS) data to call star alleles for CYP2D6 ( https://stargazer.gs.washington.edu/stargazerweb/ ). Stargazer is currently being extended for other pharmacogenes. METHODS: Stargazer identifies star alleles from NGS data by detecting single nucleotide variants, insertion-deletion variants, and structural variants. Stargazer detects structural variation, including gene deletions, duplications, and conversions, by calculating paralog-specific copy numbers from read depths. RESULTS: We applied Stargazer to the NGS data of 32 ethnically diverse HapMap trios that were genotyped by TaqMan assays, long-range polymerase chain reaction, quantitative multiplex polymerase chain reaction, high-resolution melting analysis, and/or Sanger sequencing. CYP2D6 genotyping by Stargazer was 99.0% concordant with the data obtained by these methods, and showed that 28.1% of the samples had structural variation including CYP2D6/CYP2D7 hybrids. CONCLUSION: Accurate genotyping of pharmacogenes with NGS and subsequent allele calling with Stargazer will aid the implementation of precision drug therapy.
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    84 nature
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    86 next-generation sequencing data
    87 nucleotide variants
    88 number
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    90 paralog-specific copy numbers
    91 pharmacogenes
    92 polymerase chain reaction
    93 polymorphic nature
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    95 present Stargazer
    96 quantitative multiplex polymerase chain reaction
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