Department of Electrical and Computer Engineering, University of Maryland, College Park, Maryland 20742, USA.
Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genome Res. 2023 Jan;33(1):61-70. doi: 10.1101/gr.277075.122. Epub 2023 Jan 19.
High-throughput sequencing provides sufficient means for determining genotypes of clinically important pharmacogenes that can be used to tailor medical decisions to individual patients. However, pharmacogene genotyping, also known as star-allele calling, is a challenging problem that requires accurate copy number calling, structural variation identification, variant calling, and phasing within each pharmacogene copy present in the sample. Here we introduce Aldy 4, a fast and efficient tool for genotyping pharmacogenes that uses combinatorial optimization for accurate star-allele calling across different sequencing technologies. Aldy 4 adds support for long reads and uses a novel phasing model and improved copy number and variant calling models. We compare Aldy 4 against the current state-of-the-art star-allele callers on a large and diverse set of samples and genes sequenced by various sequencing technologies, such as whole-genome and targeted Illumina sequencing, barcoded 10x Genomics, and Pacific Biosciences (PacBio) HiFi. We show that Aldy 4 is the most accurate star-allele caller with near-perfect accuracy in all evaluated contexts, and hope that Aldy remains an invaluable tool in the clinical toolbox even with the advent of long-read sequencing technologies.
高通量测序为确定临床上重要的药物基因的基因型提供了充分的手段，可以根据个体患者的情况来定制医疗决策。然而，药物基因分型，也称为星等位基因检测，是一个具有挑战性的问题，需要在样本中存在的每个药物基因拷贝中进行准确的拷贝数调用、结构变异识别、变体调用和相位分析。在这里，我们介绍 Aldy 4，这是一种快速有效的药物基因分型工具，它使用组合优化来实现不同测序技术的准确星等位基因检测。Aldy 4 增加了对长读长的支持，并使用了新的相位模型以及改进的拷贝数和变体调用模型。我们将 Aldy 4 与当前最先进的星等位基因调用器在各种测序技术（如全基因组和靶向 Illumina 测序、条形码 10x Genomics 和 Pacific Biosciences (PacBio) HiFi）测序的大量和多样化的样本和基因上进行了比较。我们表明，Aldy 4 是最准确的星等位基因调用器，在所有评估的情况下都具有近乎完美的准确性，并且希望即使随着长读长测序技术的出现，Aldy 仍然是临床工具包中不可或缺的工具。
