Picky comprehensively detects high-resolution structural variants in nanopore long reads.

Abstract

Acquired genomic structural variants (SVs) are major hallmarks of the cancer genome, but they are challenging to reconstruct from short-read sequencing data. Here, we exploit the long-reads of the nanopore platform using our customized pipeline, Picky (https://github.com/TheJacksonLaboratory/Picky), to reveal SVs of diverse architecture in a breast cancer model. We identified the full spectrum of SVs with superior specificity and sensitivity relative to short-read analyses and uncovered repetitive DNA as the major source of variation. Examination of the genome-wide breakpoints at nucleotide-resolution uncovered micro-insertions as the common structural features associated with SVs. Breakpoint density across the genome is associated with propensity for inter-chromosomal connectivity and enriched in promoters and transcribed regions of the genome. Furthermore, an over-representation of reciprocal translocations from chromosomal double-crossovers was observed through phased SVs. We demonstrated that Picky analysis is an effective tool to uncover comprehensive SVs in cancer genomes from long-read data.