TY - JOUR
T1 - Stargazer
T2 - a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model
AU - Lee, Seung been
AU - Wheeler, Marsha M.
AU - Patterson, Karynne
AU - McGee, Sean
AU - Dalton, Rachel
AU - Woodahl, Erica L.
AU - Gaedigk, Andrea
AU - Thummel, Kenneth E.
AU - Nickerson, Deborah A.
N1 - Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - CYP2D6 genotyping
KW - next-generation sequencing
KW - pharmacogenomics
KW - star alleles
KW - structural variation
UR - http://www.scopus.com/inward/record.url?scp=85048091920&partnerID=8YFLogxK
U2 - 10.1038/s41436-018-0054-0
DO - 10.1038/s41436-018-0054-0
M3 - Article
C2 - 29875422
AN - SCOPUS:85048091920
SN - 1098-3600
VL - 21
SP - 361
EP - 372
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 2
ER -