Comparative analysis of de novo assemblers for variation discovery in personal genomes. (11th April 2017)

• Record Type: Journal Article
• Authors: Tian, Shulan; Yan, Huihuang; Klee, Eric W; Kalmbach, Michael; Slager, Susan L
• Is Part Of: Briefings in bioinformatics. Volume 19:Number 5(2018:Sep.)
• Page Start: 893
• Page End: 904
• Publication Date: 2017-04-11
• Subjects: de Bruijn graph -- exome sequencing -- human leukocyte antigen -- de novo assembly -- string graph -- variant discovery; Genetics -- Data processing -- Periodicals; Molecular biology -- Data processing -- Periodicals; Genomes -- Data processing -- Periodicals; 572.80285
• DOI: 10.1093/bib/bbx037
• Languages: English
• ISSNs: 1467-5463

Abstract

Abstract: 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 few de novo assemblers 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, a de novo assembly workflow for haplotype-based variant discovery from whole-exome sequencing (WES) data. Using simulated human exome data, we compared SGVar with five variation-aware de novo assemblers and with BWA-MEM together with three haplotype- or local de novo assembly-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.