Sensitive alignment using paralogous sequence variants improves long-read mapping and variant calling in segmental duplications.
Sensitive alignment using paralogous sequence variants improves long-read mapping and variant calling in segmental duplications.
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使用旁系同源序列变体的灵敏比对改善了长读段映射和片段重复中的变体识别。
DOI：
10.1093/nar/gkaa829
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发表时间：
2020-11-04
影响因子：
14.9
通讯作者：
Bansal V
中科院分区：
文献类型：
--
作者：
Prodanov T;Bansal V
表征人类基因组重复区域的能力受到短读测序技术的读取长度的限制。尽管太平洋生物科学公司（PacBio）和牛津纳米孔技术公司等长读测序技术有可能克服这一限制，但具有高序列同一性的长片段重复对长读定位构成了挑战。我们描述了一种概率方法，DuploMap，旨在提高段重复中长读映射的准确性。它使用现有的长读比对器分析映射到片段重复的读取，并利用旁系序列变异（psv）——旁系序列之间的序列差异——来区分多个比对位置。在模拟数据集上，DuploMap在保持较高精度的同时，提高了包括Minimap2（74.3-90.6%）和BLASR（82.9-90.7%）在内的多个长读比对器的高置信正确率。在多个全基因组长读数据集中，相对于Minimap2， DuploMap在片段重复中比对了额外的8-21%的读段，具有较高的置信度。使用DuploMap-aligned PacBio循环共识测序reads，额外的8.9 Mb DNA序列可被映射，变体调用获得更高的F1分数，并鉴定出链接阅读数据支持的额外14713个变体。最后，我们证明了在片段复制中有很大一部分psv与变体重叠，并对短读变体调用产生不利影响。
The ability to characterize repetitive regions of the human genome is limited by the read lengths of short-read sequencing technologies. Although long-read sequencing technologies such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies can potentially overcome this limitation, long segmental duplications with high sequence identity pose challenges for long-read mapping. We describe a probabilistic method, DuploMap, designed to improve the accuracy of long-read mapping in segmental duplications. It analyzes reads mapped to segmental duplications using existing long-read aligners and leverages paralogous sequence variants (PSVs)—sequence differences between paralogous sequences—to distinguish between multiple alignment locations. On simulated datasets, DuploMap increased the percentage of correctly mapped reads with high confidence for multiple long-read aligners including Minimap2 (74.3–90.6%) and BLASR (82.9–90.7%) while maintaining high precision. Across multiple whole-genome long-read datasets, DuploMap aligned an additional 8–21% of the reads in segmental duplications with high confidence relative to Minimap2. Using DuploMap-aligned PacBio circular consensus sequencing reads, an additional 8.9 Mb of DNA sequence was mappable, variant calling achieved a higher F1 score and 14 713 additional variants supported by linked-read data were identified. Finally, we demonstrate that a significant fraction of PSVs in segmental duplications overlaps with variants and adversely impacts short-read variant calling.
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