Comparative analysis of de novo assemblers for variation discovery in personal genomes.
Comparative analysis of de novo assemblers for variation discovery in personal genomes.
复制标题
用于个人基因组变异发现的从头组装程序的比较分析。
DOI：
10.1093/bib/bbx037
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发表时间：
2018
影响因子：
9.5
通讯作者：
Slager,SusanL
中科院分区：
文献类型：
--
作者：
Tian,Shulan;Yan,Huihuang;Klee,EricW;Kalmbach,Michael;Slager,SusanL
目前的变体发现方法通常依赖于映射到参考序列的初始读段。它们的有效性受到参考中存在的缺口、潜在的错误组装、具有高序列相似性的重复区域和高序列分歧区域的限制。此外，基于作图的方法对大的INDEL和复杂的变异不太敏感，并且在个人基因组中提供很少的相位信息。已经开发了一些新的组装器，通过从组装图、微组装和全基因组组装中直接调用变体来识别变体，但主要用于全基因组测序（WGS）数据。我们开发了SGVar和novoassembly工作流程，用于从全外显子组测序（WES）数据中发现基于单体型的变体。使用模拟的人类外显子组数据，我们比较了SGVar与五个变异感知的novoassemblers和BWA-MEM与三个单倍型或本地novoassembly-based调用者。SGVar在灵敏度和测序错误的容忍度方面优于其他组装器。我们概括了来自北方和西欧血统（CEU）三人组的犹他州居民的全基因组和外显子组数据的结果，表明SGVar在6号染色体的高度分化的人类白细胞抗原（HLA）区域和非HLA区域均具有高灵敏度。特别地，SGVar对测序错误、k聚体选择、趋异水平和覆盖深度是稳健的。与基于映射的方法不同，SGVar能够分辨远程相位并从WES中识别大的INDEL，更突出的是从WGS中识别。我们的结论是，SGVar代表了一个理想的平台，为WES为基础的变异发现在高度不同的区域和整个基因组。
Current variant discovery approaches often rely on an initial read mapping to the reference sequence. Their effectiveness is limited by the presence of gaps, potential misassemblies, regions of duplicates with a high-sequence similarity and regions of high-sequence divergence in the reference. Also, mapping-based approaches are less sensitive to large INDELs and complex variations and provide little phase information in personal genomes. A fewde novoassemblers have been developed to identify variants through direct variant calling from the assembly graph, micro-assembly and whole-genome assembly, but mainly for whole-genome sequencing (WGS) data. We developed SGVar, ade novoassembly workflow for haplotype-based variant discovery from whole-exome sequencing (WES) data. Using simulated human exome data, we compared SGVar with five variation-awarede novoassemblers and with BWA-MEM together with three haplotype- or localde novoassembly-based callers. SGVar outperforms the other assemblers in sensitivity and tolerance of sequencing errors. We recapitulated the findings on whole-genome and exome data from a Utah residents with Northern and Western European ancestry (CEU) trio, showing that SGVar had high sensitivity both in the highly divergent human leukocyte antigen (HLA) region and in non-HLA regions of chromosome 6. In particular, SGVar is robust to sequencing error, k-mer selection, divergence level and coverage depth. Unlike mapping-based approaches, SGVar is capable of resolving long-range phase and identifying large INDELs from WES, more prominently from WGS. We conclude that SGVar represents an ideal platform for WES-based variant discovery in highly divergent regions and across the whole genome.