DNA shape and epigenomics distinguish the mechanistic origin of human genomic structural variations

Abstract

The recent advent of long-read whole genome sequencing has enabled us to create an accurate telomere-to-telomere reference genome, construct pangenome graphs, and compile precise catalogs of genomic structural variations (SVs). These comprehensive SV repositories provide an excellent opportunity to explore the role of SVs in genotype-phenotype associations and examine the mechanisms by which SVs are introduced through double-strand break (DSB) repair. Here, we employed comprehensive SV catalogs identified through various short- and long-read whole genome sequencing efforts to infer the underlying mechanisms of SV introduction based on their genomic and epigenomic profiles. Our findings indicate that high local DNA methylation and DNA shape-related features, such as low variations in propeller twist, support the origins of homology-driven SVs. Subsequently, we utilized an active-learning-based unsupervised clustering approach, revealing that the homology-dependent SVs show greater evidence of retaining ancestral recombination patterns compared to their homology-independent counterparts. Finally, our comparison of inherited and de novo SVs from healthy populations and rare disease cohorts showed distinct upstream H3K27me3 levels in de novo SVs from individuals with ultra-rare disorders. These findings highlight genome-wide characteristics that may influence the choice of repair mechanisms linked to heritable SV origins.