LongAGE: defining breakpoints of genomic structural variants through optimal and memory efficient alignments of long reads

Defining the precise location of structural variations (SVs) at single-nucleotide breakpoint resolution is a challenging problem due to large gaps in alignment. Previously, Alignment with Gap Excision (AGE) enabled us to define breakpoints of SVs at single-nucleotide resolution; however, AGE requires a vast amount of memory when aligning a pair of long sequences. To address this, we developed a memory-efficient implementation-LongAGE-based on the classical Hirschberg algorithm. We demonstrate an application of LongAGE for resolving breakpoints of SVs embedded into segmental duplications on Pacific Biosciences (PacBio) reads that can be longer than 10 kb. Furthermore, we observed different breakpoints for a deletion and a duplication in the same locus, providing direct evidence that such multi-allelic copy number variants (mCNVs) arise from two or more independent ancestral mutations.

Automated summary

The study found that different breakpoints for deletions and duplications at the same locus provide direct evidence that these multi-allelic copy number variants arise from multiple independent ancestral mutations. To address the problem of large gaps in alignment affecting single-nucleotide breakpoint resolution, a memory-efficient implementation called LongAGE was developed.