Journal article
Frequent retrotransposition of endogenous genes in ERCC2-deficient cells derived from a patient with xeroderma pigmentosum
- Abstract:
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Background: Retrotransposition of protein-coding genes is thought to occur due to the existence of numerous processed pseudogenes in both animals and plants. Unlike retrotransposons including Alu and LINE-1, direct evidence of such retrotransposition events has not been reported to date. Even if such an event occurs in a somatic cell, it is almost impossible to detect it using bulk of cells as a sample. Single-cell analyses or other techniques are needed.
Methods: In order to examine genetic stability of stem cells, we have established induced pluripotent stem cell (iPSC) lines from several patients with DNA repair-deficiency disorders, such as ataxia telangiectasia and xeroderma pigmentosum, along with healthy controls. Performing whole-exome sequencing analyses of these parental and iPSC lines, we compiled somatic mutations accumulated by the deficiency of DNA repair mechanisms. Whereas most somatic mutations cannot be detected in bulk, cell reprogramming enabled us to observe all the somatic mutations which had occurred in the cell line. Patterns of somatic mutations should be distinctive depending on which DNA repair gene is impaired.
Results: The comparison revealed that deficiency of ATM and XPA preferentially gives rise to indels and single-nucleotide substitutions, respectively. On the other hand, deficiency of ERCC2 caused not only single-nucleotide mutations but also many retrotranspositions of endogenous genes, which were readily identified by examining removal of introns in whole-exome sequencing. Although the number was limited, those events were also detected in healthy control samples.
Conclusions: The present study exploits clonality of iPSCs to unveil somatic mutation sets that are usually hidden in bulk cell analysis. Whole-exome sequencing analysis facilitated the detection of retrotransposition mutations. The results suggest that retrotranspositions of human endogenous genes are more frequent than expected in somatic cells and that ERCC2 plays a defensive role against transposition of endogenous and exogenous DNA fragments.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 1.6MB, Terms of use)
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- Publisher copy:
- 10.1186/s13287-019-1381-z
Authors
- Publisher:
- BioMed Central
- Journal:
- Stem Cell Research and Therapy More from this journal
- Volume:
- 10
- Issue:
- 1
- Article number:
- 273
- Publication date:
- 2019-08-27
- Acceptance date:
- 2019-08-12
- DOI:
- EISSN:
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1757-6512
- Pmid:
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31455402
- Language:
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English
- Keywords:
- Pubs id:
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1048777
- Local pid:
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pubs:1048777
- Deposit date:
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2020-04-07
Terms of use
- Copyright holder:
- Aoto et al.
- Copyright date:
- 2019
- Rights statement:
- Copyright © 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Licence:
- CC Attribution (CC BY)
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