Samples used in this study.

Short tandem repeat (STR) variation is an often overlooked source of variation between genomes. STRs comprise about 3% of the human genome and are highly polymorphic. Some cause Mendelian disease, and others affect gene expression. Their contribution to common disease is not well-understood, but recent software tools designed to genotype STRs using short read sequencing data will help address this. Here, we compare software that genotypes common STRs and rarer STR expansions genome-wide, with the aim of applying them to population-scale genomes. By using the Genome-In-A-Bottle (GIAB) consortium and 1000 Genomes Project short-read sequencing data, we compare performance in terms of sequence length, depth, computing resources needed, genotyping accuracy and number of STRs genotyped. To ensure broad applicability of our findings, we also measure genotyping performance against a set of genomes from clinical samples with known STR expansions, and a set of STRs commonly used for forensic identification. We find that HipSTR, ExpansionHunter and GangSTR perform well in genotyping common STRs, including the CODIS 13 core STRs used for forensic analysis. GangSTR and ExpansionHunter outperform HipSTR for genotyping call rate and memory usage. ExpansionHunter denovo (EHdn), STRling and GangSTR outperformed STRetch for detecting expanded STRs, and EHdn and STRling used considerably less processor time compared to GangSTR. Analysis on shared genomic sequence data provided by the GIAB consortium allows future performance comparisons of new software approaches on a common set of data, facilitating comparisons and allowing researchers to choose the best software that fulfils their needs.短串联重复序列（Short Tandem Repeat, STR）变异是基因组间差异中常被忽视的来源之一。STR约占人类基因组的3%，且具有高度多态性。部分STR可引发孟德尔式遗传病，另有部分会影响基因表达。目前学界对其在常见疾病中的作用机制尚不明晰，但近期开发的基于短读长测序数据进行STR基因分型的软件工具，将为破解这一难题提供助力。本研究针对全基因组范围内可对常见STR及罕见STR扩增进行基因分型的软件展开对比，旨在将这些软件应用于群体规模的基因组研究中。本研究借助“瓶中基因组”（Genome-In-A-Bottle, GIAB）联盟与千人基因组计划（1000 Genomes Project）的短读长测序数据，从测序序列长度、测序深度、所需计算资源、基因分型准确性以及可分型STR数量等维度，对上述软件的性能进行对比。为确保研究结论具备广泛适用性，本研究还针对携带已知STR扩增的临床样本基因组集，以及常用于法医鉴定的STR位点集，对软件的基因分型性能进行了评测。研究发现，HipSTR、ExpansionHunter与GangSTR在常见STR基因分型中表现优异，其中涵盖了用于法医鉴定的13个CODIS核心STR位点。在基因分型检出率与内存占用方面，GangSTR与ExpansionHunter的表现优于HipSTR。在检测扩增STR的任务中，ExpansionHunter denovo（EHdn）、STRling与GangSTR的表现优于STRetch；且与GangSTR相比，EHdn与STRling的处理器耗时显著更低。依托GIAB联盟共享的基因组测序数据开展的本次分析，可为未来新软件工具的性能评测提供统一的基准数据集，便于不同研究间的横向对比，助力研究者选择契合自身需求的最优软件。