State-of-the-art structural variant calling: What went conceptually wrong and how to fix it?

Abstract

Structural variant (SV) calling belongs to the standard tools of modern bioinformatics for identifying and describing alterations in genomes. Initially, this work presents several complex genomic rearrangements that reveal conceptual ambiguities inherent to the SV representations of state-of-the-art SV callers. We contextualize these ambiguities theoretically as well as practically and propose a graph-based approach for resolving them. Our graph model unifies both genomic strands by using the concept of skew-symmetry; it supports graph genomes in general and pan genomes in specific. Instances of our model are inferred directly from seeds instead of the commonly used alignments that conflict with various types of SV as reported here. For yeast genomes, we practically compute adjacency matrices of our graph model and demonstrate that they provide highly accurate descriptions of one genome in terms of another. An open-source prototype implementation of our approach is available under the MIT license at https://github.com/ITBE-Lab/MA.