短读长胚系结构变异检测工具基准评测:多工具集成优于单工具,图基因组比对影响有限
Benchmarking short-read germline structural variant calling highlights advantages of using ensembles of tools and small impact of graph genome alignment
摘要
该研究基于新发布的高置信家系真值集与自建数据,系统评测14种短读长结构变异检测工具,并比较图基因组与线性参考比对效果。结果显示DRAGEN整体表现最佳,开源工具中Manta与Dysgu召回较高;多工具集成策略在部分场景可提升召回。频率过滤将下游解读负担降低近半,而图基因组比对仅带来有限性能提升。结论强调应按应用场景权衡准确性、召回、算力与临床解读负担来选择工具组合。
原文摘要
BACKGROUND: Structural variants (SVs) in the human genome play an important role in health and disease. Identification of SVs is commonly performed using short-read sequencing. However, because sequenced fragments are typically shorter than the variants themselves, accurate SV calling remains a challenging problem. Previous benchmarking studies consistently find substantial variability in performance among SV calling tools, with disagreements largely driven by differences in underlying algorithms. RESULTS: We evaluate 14 high-performing SV calling tools using four samples from a newly published, high-confidence pedigree-based truth set, together with an in-house dataset. Its recent release minimizes the likelihood that it was used for training by tools, thereby reducing the risk of over-fitting. We implemented frequency filtering that reduced the downstream variants interpretation load by nearly half. We also assess alignments from a graph genome assembly, but found only small effect on performance, compared to a linear reference. DRAGEN achieves the highest overall performance, with a mean recall of 0.36 and mean F1 score of 0.51. Among the open-source tools, Manta and Dysgu achieve the highest recall, both with a mean recall of 0.26, while Manta achieves the highest mean F1 score of 0.41. We also evaluate several multi-caller ensemble strategies, which in some settings achieved higher recall than any individual tool. Across both ensemble strategies, Dysgu, Octopus, Manta, and Tardis are part of the top-performing sets. CONCLUSIONS: Our findings highlight the importance of designing SV calling strategies using one or more tools according to the intended application, while balancing accuracy, recall, computational resources, reference choice, and clinical interpretation burden.
推荐理由:方法学严谨、对基因组结构变异检测有参考价值,但属于通用基因组学工具评测,与生殖医学、辅助生殖及胚胎多组学核心问题关联较弱,对本领域读者的直接可用性有限。
文献解读
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