Picky Comprehensively Detects High Resolution Structural Variants in Nanopore Long Reads

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.