The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted
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ORIGINAL INVESTIGATION
The involvement of U‑type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications Takema Kato1 · Hidehito Inagaki1 · Syunsuke Miyai1 · Fumihiko Suzuki1 · Yuki Naru1 · Yasuko Shinkai1 · Asuka Kato1 · Kazuo Kanyama1 · Seiji Mizuno2 · Yukako Muramatsu3 · Toshiyuki Yamamoto4 · Mitsuhisa Shinya5,6 · Yukiko Tazaki5,6 · Sayuri Hiwatashi5,6 · Toshiro Ikeda5,6 · Mamoru Ozaki7 · Hiroki Kurahashi1,2 Received: 7 April 2020 / Accepted: 22 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract An inverted duplication with a terminal deletion (inv-dup-del) is one of the complex constitutional structural rearrangements that can occur in a chromosome. Although breakages of dicentric chromosome have been suggested, the precise mechanism of this is yet to be fully understood. In our present study, we investigated the genomic structure of 10 inv-dup-del cases to elucidate this mechanism. Two recurrent 8p inv-dup-del cases harbored a large copy-number-neutral region between the duplication and deletion in common. Although the other non-recurrent cases did not appear to have this copy-numberneutral region, refined sequencing analysis identified that they contained a small intervening region at the junction between the inverted and non-inverted segment. The size of this small intervening region ranged from 1741 to 3728 bp. Combined with a presence of microhomology at the junction, a resolution of the replication fork stalling through template switching within the same replication fork is suggested. We further observed two cases with mosaicism of the dicentric chromosome and various structural rearrangements related to the dicentric chromosome. Refined analysis allowed us to identify different breakpoints on the same chromosome in the same case, implicating multiple rounds of U-type formation and its breakage. From these results, we propose that a replication-based mechanism generates unstable dicentric chromosomes and that their breakage leads to the formation of inv-dup-dels and other related derivative chromosomes.
Introduction An inverted duplication with a concomitant terminal deletion (inv-dup-del) is one of the common complex chromosomal rearrangements (CCRs) that arises in humans (Weckselblatt and Rudd 2015). Inv-dup-del rearrangements develop mainly in two successive steps. The first of these is the formation of a symmetric dicentric chromosome, which is unstable during mitosis because two functional centromeres can act bidirectionally. The formation of this unstable intermediate leads to anaphase bridging, followed by asymmetric breakage between the two centromeres in a subsequent mitotic division. Finally, it forms a stable large monocentric chromosome with an inverted duplication contiguous to a distal deletion and a small monocentric chromosome with a deletion (Zuffardi et al. 2009).
* Hiroki Kurahashi kura@fujita‑hu.ac.jp Extended author information available on the last page of the article
Two possible mechanisms are curr
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