Stargazer：一款软件工具，用于从下一代测序数据中调用星型等位基因，以 CYP2D6 作为模型。
Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model.
机构信息
Department of Genome Sciences, School of Medicine, University of Washington, Seattle, Washington, USA.
Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, USA.
出版信息
Genet Med. 2019 Feb;21(2):361-372. doi: 10.1038/s41436-018-0054-0. Epub 2018 Jun 6.
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.
目的
对 CYP2D6 进行基因分型对于精准药物治疗非常重要，因为它所编码的酶代谢了大约 25%的药物，而且其活性在个体之间差异很大。由于其高度多态性，CYP2D6 的基因分型分析具有挑战性。已经定义了超过 100 种 CYP2D6 的单倍型（星等位基因），其中一些涉及与其附近无功能但高度同源的旁系同源基因 CYP2D7 的基因转换。我们介绍了 Stargazer，这是一种新的生物信息学工具，它使用下一代测序（NGS）数据来调用 CYP2D6 的星等位基因（https://stargazer.gs.washington.edu/stargazerweb/）。Stargazer 目前正在扩展到其他药物基因。
方法
Stargazer 通过检测单核苷酸变异、插入缺失变异和结构变异，从 NGS 数据中识别星等位基因。Stargazer 通过计算来自读取深度的旁系同源物特异性拷贝数来检测结构变异，包括基因缺失、重复和转换。
结果
我们将 Stargazer 应用于 32 个具有种族多样性的 HapMap 三体型的 NGS 数据，这些数据通过 TaqMan 测定法、长距离聚合酶链反应、定量多重聚合酶链反应、高分辨率熔解分析和/或 Sanger 测序进行了基因分型。Stargazer 对 CYP2D6 的基因分型与这些方法获得的数据 99.0%一致，并表明 28.1%的样本存在包括 CYP2D6/CYP2D7 杂种在内的结构变异。
结论
使用 NGS 对药物基因进行准确基因分型，然后使用 Stargazer 进行等位基因调用，将有助于实施精准药物治疗。
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