GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

Abstract

We have developed a novel, integrated and comprehensive purity, ploidy, structural variant and copy number somatic analysis toolkit for whole genome sequencing data of paired tumor/normal samples. We show that the combination of using GRIDSS for somatic structural variant calling and PURPLE for somatic copy number alteration calling allows highly sensitive, precise and consistent copy number and structural variant determination, as well as providing novel insights for short structural variants and regions of complex local topology. LINX, an interpretation tool, leverages the integrated structural variant and copy number calling to cluster individual structural variants into higher order events and chains them together to predict local derivative chromosome structure. LINX classifies and extensively annotates genomic rearrangements including simple and reciprocal breaks, LINE, viral and pseudogene insertions, and complex events such as chromothripsis. LINX also comprehensively calls genic fusions including chained fusions. Finally, our toolkit provides novel visualisation methods providing insight into complex genomic rearrangements.

Comprehensive analysis of structural variants in breast cancer genomes using single-molecule sequencing

“…Further development of methods capable of incorporating SNPs, small indels, SVs, and large-scale CNVs, as well as examining somatic phylogenies and cancer clone trajectories, will require both shortand long-read sequencing, with long reads proving critical for sensitive and accurate inference of SVs. Integration of long-read SV analysis can also benefit methods (Aganezov et al 2019;Cameron et al 2019;Deshpande et al 2019) focusing on recovering linear organization of rearranged cancer genomes.…”

Recurrent SPECC1L–NTRK fusions in pediatric sarcoma and brain tumors

“…LINX, which clusters together contemporaneous individual copy-number changes and structural variant calls, was used to provide a visualization of the structure of derivative chromosomes ( Fig. 3 ; Cameron et al 2019 ). Patient 1 had a duplication encompassing the NTRK2 tyrosine kinase domain linked to the SPECC1L SMC domain (copy number = 2).…”

Unifying package managers, workflow engines, and containers: Computational reproducibility with BioNix

“…A total of 1.1 TB of (compressed) fastq input was processed, producing 755 GB of results (including alignments). The workflow is detailed in Example 7, and a full example executing the workflow on a publicly available melanoma dataset [ 29 ] is available in the BioNix repository.…”