Cytogenetically visible inversions are formed by multiple molecular mechanisms.

TitleCytogenetically visible inversions are formed by multiple molecular mechanisms.
Publication TypeJournal Article
Year of Publication2020
AuthorsPettersson, M, Grochowski, CM, Wincent, J, Eisfeldt, J, Breman, AM, Cheung, SW, Krepischi, ACV, Rosenberg, C, Lupski, JR, Ottosson, J, Lovmar, L, Gacic, J, Lundberg, ES, Nilsson, D, Carvalho, CMB, Lindstrand, A
JournalHum Mutat
Date Published2020 Nov
KeywordsChromosome Inversion, Comparative Genomic Hybridization, DNA End-Joining Repair, DNA Repair, Female, Gene Frequency, Haplotypes, Heterozygote, Homologous Recombination, Humans, Karyotyping, Male, Pedigree, Whole Genome Sequencing

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.

Alternate JournalHum Mutat
PubMed ID32906200
PubMed Central IDPMC7702065
Grant ListR03 HD092569 / HD / NICHD NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01 GM132589 / GM / NIGMS NIH HHS / United States

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