Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications

By A. Rimmer, H. Phan, I. Mathieson, Z. Iqbal, Stephen R. F. Twigg, A. Wilkie, G. McVean, Gerton A. Lunter. Nature Genetics, 2014

1,029 citations recorded by the source corpus.

High-throughput DNA sequencing technology has transformed genetic research and is starting to make an impact on clinical practice. However, analyzing high-throughput sequencing data remains challenging, particularly in clinical settings where accuracy and turnaround times are critical. We present a new approach to this problem, implemented in a software package called Platypus. Platypus achieves high sensitivity and specificity for SNPs, indels and complex polymorphisms by using local de novo assembly to generate candidate variants, followed by local realignment and probabilistic haplotype estimation. It is an order of magnitude faster than existing tools and generates calls from raw aligned read data without preprocessing. We demonstrate the performance of Platypus in clinically relevant experimental designs by comparing with SAMtools and GATK on whole-genome and exome-capture data, by identifying de novo variation in 15 parent-offspring trios with high sensitivity and specificity, and by estimating human leukocyte antigen genotypes directly from variant calls.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6ce0a82bc841445963aa9a3983c86afe3a249cca

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Citations in the corpus

The whole-genome landscape of medulloblastoma subtypes (2017, positive): “Raw calls for indels were obtained from Platypus (v.0.7.4) 44 .”
Next-Generation Sequencing Technology: Current Trends and Advancements (2023, neutral): “Cont.”
Scaling accurate genetic variant discovery to tens of thousands of samples (2017, methodology): “Reference sequence mismatches were probabilistically sorted using algorithms that took into account the reported base quality and context prior to calling variants [22].”
Computational pan-genomics: status, promises and challenges (2016, background): “Currently, first approaches for haplotyperesolved local assembly are being developed [113].”
SvABA: genome-wide detection of structural variants and indels by local assembly (2018, methodology): “Approaches such as PBHoney (English et al. 2014), MultiBreak-SV (Ritz et al. 2014), and HySA have been developed for extracting larger SVs from long sequences.”
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution (2017, methodology): “Indeed, despite being one of the most poly- 1260 Cell 171, 1259–1271, November 30, 2017 morphic regions of the human genome, an average of 1 (mean 0.84, range 0–7) informative heterozygous SNP in the three HLA class I genes was identified in 96 patients where copy-number analysis was possible from ”
A reference data set of 5.4 million phased human variants validated by genetic inheritance from sequencing a three-generation 17-member pedigree (2016, neutral): “We included variant calls from six different informatics pipelines (Conrad et al. 2011; Garrison and Marth 2012; Iqbal et al. 2012; Saunders et al. 2012; Raczy et al. 2013; Rimmer et al. 2014) and two different sequencing technologies (Bentley et al.”