Long-read sequencing and structural variant characterization in 1,019 samples from the 1000 Genomes Project

Abstract

Structural variants (SVs) contribute significantly to human genetic diversity and disease^1–4. Previously, SVs have remained incompletely resolved by population genomics, with short-read sequencing facing limitations in capturing the whole spectrum of SVs at nucleotide resolution^5–7. Here we leveraged nanopore sequencing⁸ to construct an intermediate coverage resource of 1,019 long-read genomes sampled within 26 human populations from the 1000 Genomes Project. By integrating linear and graph-based approaches for SV analysis via pangenome graph-augmentation, we uncover 167,291 sequence-resolved SVs in these samples, considerably advancing SV characterization compared to population-wide short-read sequencing studies^3,4. Our analysis details diverse SV classes—deletions, duplications, insertions, and inversions—at population-scale. LINE-1 and SVA retrotransposition activities frequently mediate transductions^9,10 of unique sequences, with both mobile element classes transducing sequences at either the 3′- or 5′-end, depending on the source element locus. Furthermore, analyses of SV breakpoint junctions suggest a continuum of homology-mediated rearrangement processes are integral to SV formation, and highlight evidence for SV recurrence involving repeat sequences. Our open-access dataset underscores the transformative impact of long-read sequencing in advancing the characterisation of polymorphic genomic architectures, and provides a resource for guiding variant prioritisation in future long-read sequencing-based disease studies.