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Deciphering the complexity of simple chromosomal insertions by genome sequencing

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Abstract

Chromosomal insertions are thought to be rare structural rearrangements. The current understanding of the underlying mechanisms of their origin is still limited. In this study, we sequenced 16 cases with apparent simple insertions previously identified by karyotyping and/or chromosomal microarray analysis. Using mate-pair genome sequencing (GS), we identified all 16 insertions and revised previously designated karyotypes in 75.0% (12/16) of the cases. Additional cryptic rearrangements were identified in 68.8% of the cases (11/16). The incidence of additional cryptic rearrangements in chromosomal insertions was significantly higher compared to balanced translocations and inversions reported in other studies by GS. We characterized and classified the cryptic insertion rearrangements into four groups, which were not mutually exclusive: (1) insertion segments were fragmented and their subsegments rearranged and clustered at the insertion site (10/16, 62.5%); (2) one or more cryptic subsegments were not inserted into the insertion site (5/16, 31.3%); (3) segments of the acceptor chromosome were scattered and rejoined with the insertion segments (2/16, 12.5%); and (4) copy number gains were identified in the flanking regions of the insertion site (2/16, 12.5%). In addition to the observation of these chromothripsis- or chromoanasynthesis-like events, breakpoint sequence analysis revealed microhomology to be the predominant feature. However, no significant correlation was found between the number of cryptic rearrangements and the size of the insertion. Overall, our study provide molecular characterization of karyotypically apparent simple insertions, demonstrate previously underappreciated complexities, and evidence that chromosomal insertions are likely formed by nonhomologous end joining and/or microhomology-mediated replication-based DNA repair.

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Data availability

The genome sequencing data of five samples used in this study have been made available on the CNGB Nucleotide Sequence Archive (CNSA: https://db.cngb.org/cnsa) under the accession number CNP0000078. For the other 12 cases, raw sequencing data have not been made available because most subjects did not consent to such sharing.

Code availability

NA.

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Funding

This project is supported by the National Natural Science Foundation of China (31801042, 81741004 and 81741009), the Health and Medical Research Fund (04152666, 07180576), and Direct Grant (2019.051).

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Author notes

  1. Zirui Dong, Matthew Hoi Kin Chau and Yanyan Zhang contributed equally.

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China

    Zirui Dong, Matthew Hoi Kin Chau, Yanyan Zhang, Xiaofan Zhu, Tak Yeung Leung, Yvonne K. Kwok & Kwong Wai Choy

  2. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China

    Zirui Dong, Matthew Hoi Kin Chau, Yanyan Zhang, Xiaofan Zhu, Tak Yeung Leung & Kwong Wai Choy

  3. Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China

    Zirui Dong, Matthew Hoi Kin Chau, Yanyan Zhang, Xiaofan Zhu & Kwong Wai Choy

  4. Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Peng Dai & Xiangdong Kong

  5. Baylor College of Medicine Joint Center For Medical Genetics, The Chinese University of Hong Kong, Hong Kong, China

    Tak Yeung Leung, Sau Wai Cheung & Kwong Wai Choy

  6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Paweł Stankiewicz & Sau Wai Cheung

Authors
  1. Zirui Dong
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  2. Matthew Hoi Kin Chau
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  3. Yanyan Zhang
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  4. Peng Dai
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  7. Xiangdong Kong
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  8. Yvonne K. Kwok
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  9. Paweł Stankiewicz
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  10. Sau Wai Cheung
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  11. Kwong Wai Choy
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Contributions

SWC, ZD, MHKC, TYL and KWC designed the study. SWC and MHKC collected the samples. MHKC, YZ performed mate-pair sequencing. ZD, MHKC, PD, XK, PS and YK performed the analysis and data interpretation. MHKC, PD and YZ conducted the validation. ZD, MHKC, PS, SWC and KWC wrote the manuscript.

Corresponding authors

Correspondence to Sau Wai Cheung or Kwong Wai Choy.

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Dong, Z., Chau, M.H.K., Zhang, Y. et al. Deciphering the complexity of simple chromosomal insertions by genome sequencing. Hum Genet 140, 361–380 (2021). https://doi.org/10.1007/s00439-020-02210-x

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