Impact and characterization of serial structural variations across humans and great apes

Abstract

Modern sequencing technology enables the detection of complex structural variation (SV) across genomes. However, extensive DNA rearrangements which arise through series of mutations, a phenomenon we term serial SV (sSV), remain understudied due to their complexity which overwhelms most SV callers. Here, we present NAHRwhals (https://github.com/WHops/NAHRwhals), a method to infer repeat-mediated series of SVs in genome assemblies. Applying NAHRwhals to 58 human assembled haplotypes reveals 37 sSV loci of various length and complexity. These sSVs explain otherwise cryptic variation in medically relevant regions such as the TPSAB1 gene, 8p23.1 deletion, DiGeorge, and Sotos syndrome. Local comparisons with great ape assemblies suggest that most human sSV loci have formed recently and with involvement of non-repeat-mediated processes. Our results show that NAHRwhals is able to reliably detect sSVs at scale and independent of species, which are more frequent and carry broader functional consequences than previous studies have suggested.