Abstract
Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short‐read whole‐genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy‐number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end‐joining (8/13, 62%) or microhomology‐mediated break‐induced replication (5/13, 38%). Our study indicates that short‐read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication‐based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy‐number variation potentially contributing to the overall phenotypic presentation of those patients.
Highlights
Inversions are a class of structural variation (SV) abundant in the human genome, first described as events involving two breakpoints and a 180° turn of the genomic segment in‐between (Kaiser, 1984)
Two inversions were identified in multiple unrelated individuals: inv(12)(p11.2q13), which were inherited in all cases, and inv(10)(p11.2q21), which was confirmed to be inherited in 2/5 carriers and found to likely be a rare founder variant (Gilling et al, 2006)
Five inversions (38%) presented templated insertions or copy‐number amplification seemingly mediated by replicative repair involving template switching which is consistent with fork‐stalling and template‐switching (FoSTeS)/microhomology‐mediated break‐induced replication (MMBIR)
Summary
Inversions are a class of structural variation (SV) abundant in the human genome, first described as events involving two breakpoints and a 180° turn of the genomic segment in‐between (Kaiser, 1984). Challenges associated with the detection of large chromosomal inversions has limited our understanding of the clinical consequences for this type of structural aberration. While chromosomal karyotyping is restricted by the resolution in detecting these structural events (>5–10 Mb), ‐generation sequencing (NGS) is restrained by high rates of false‐positive and false‐negative results, requiring extensive use of orthogonal methodologies for validation (Chaisson et al, 2019; Puig, Casillas, Villatoro, & Caceres, 2015). Recent data suggest that large inversions are often flanked by genomic repeats (Chaisson et al, 2019), especially segmental duplications, contributing to both the mapping and detection challenges associated with using NGS. Smaller sized (>5‐10 Mb) (below the resolution of karyotyping but visible by molecular analysis) may occur quite frequently (Flores et al, 2007)
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