Methods that use a linear genome reference for genome sequencing data analysis are reference-biased. In the field of clinical genetics for rare diseases, a resulting reduction in genotyping accuracy in some regions has likely prevented the resolution of some cases. Pangenome graphs embed population variation into a reference structure. Although pangenome graphs have helped to reduce reference mapping bias, further performance improvements are possible. We introduce VG-Pedigree, a pedigree-aware workflow based on the pangenome-mapping tool of Giraffe and the variant calling tool DeepTrio using a specially trained model for Giraffe-based alignments. We demonstrate mapping and variant calling improvements in both single-nucleotide variants (SNVs) and insertion and deletion (indel) variants over those produced by alignments created using BWA-MEM to a linear-reference and Giraffe mapping to a pangenome graph containing data from the 1000 Genomes Project. We have also adapted and upgraded deleterious-variant (DV) detecting methods and programs into a streamlined workflow. We used these workflows in combination to detect small lists of candidate DVs among 15 family quartets and quintets of the Undiagnosed Diseases Program (UDP). All candidate DVs that were previously diagnosed using the Mendelian models covered by the previously published methods were recapitulated by these workflows. The results of these experiments indicate that a slightly greater absolute count of DVs are detected in the proband population than in their matched unaffected siblings.

中文翻译：

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用于稀有候选变异分析的完整的基于谱系的图形工作流程

使用线性基因组参考进行基因组测序数据分析的方法存在参考偏倚。在罕见病的临床遗传学领域，一些地区基因分型准确性的降低可能阻碍了一些病例的解决。Pangenome 图将种群变异嵌入到参考结构中。尽管泛基因组图有助于减少参考映射偏差，但进一步的性能改进是可能的。我们介绍了 VG-Pedigree，这是一种基于 Giraffe 的泛基因组映射工具和变体调用工具 DeepTrio 的谱系感知工作流，使用经过专门训练的基于 Giraffe 的比对模型。我们展示了单核苷酸变体 (SNV) 和插入和缺失 (indel) 变体的比对和变体调用改进，这些变体是通过使用 BWA-MEM 创建的比对到线性参考和长颈鹿映射到包含来自数据的泛基因组图产生的。千人基因组计划。我们还将有害变异 (DV) 检测方法和程序调整并升级为简化的工作流程。我们结合使用这些工作流程来检测未确诊疾病计划 (UDP) 的 15 个家庭四重奏和五重奏中的候选 DV 的小列表。这些工作流程概括了以前使用先前发布的方法涵盖的孟德尔模型诊断的所有候选 DV。