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Cytogenetically visible inversions are formed by multiple molecular mechanisms
Author(s) -
Pettersson Maria,
Grochowski Christopher M.,
Wincent Josephine,
Eisfeldt Jesper,
Breman Amy M.,
Cheung Sau W.,
Krepischi Ana C. V.,
Rosenberg Carla,
Lupski James R.,
Ottosson Jesper,
Lovmar Lovisa,
Gacic Jelena,
Lundberg Elisabeth S.,
Nilsson Daniel,
Carvalho Claudia M. B.,
Lindstrand Anna
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24106
Subject(s) - biology , genetics , digital polymerase chain reaction , chromosomal inversion , copy number variation , non allelic homologous recombination , comparative genomic hybridization , genome , chromothripsis , homologous recombination , gene rearrangement , polymerase chain reaction , gene , genome instability , recombination , dna , karyotype , chromosome , dna damage , genetic recombination
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.