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Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination

BACKGROUND: Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underl...

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Autores principales: Campbell, Ian M, Gambin, Tomasz, Dittwald, Piotr, Beck, Christine R, Shuvarikov, Andrey, Hixson, Patricia, Patel, Ankita, Gambin, Anna, Shaw, Chad A, Rosenfeld, Jill A, Stankiewicz, Paweł
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195946/
https://www.ncbi.nlm.nih.gov/pubmed/25246103
http://dx.doi.org/10.1186/s12915-014-0074-4
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author Campbell, Ian M
Gambin, Tomasz
Dittwald, Piotr
Beck, Christine R
Shuvarikov, Andrey
Hixson, Patricia
Patel, Ankita
Gambin, Anna
Shaw, Chad A
Rosenfeld, Jill A
Stankiewicz, Paweł
author_facet Campbell, Ian M
Gambin, Tomasz
Dittwald, Piotr
Beck, Christine R
Shuvarikov, Andrey
Hixson, Patricia
Patel, Ankita
Gambin, Anna
Shaw, Chad A
Rosenfeld, Jill A
Stankiewicz, Paweł
author_sort Campbell, Ian M
collection PubMed
description BACKGROUND: Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV). RESULTS: We developed parameters to identify HERV elements similar to those that mediate Yq12 rearrangements as well as recurrent deletions of 3q13.2q13.31. We used these parameters to identify HERV pairs genome-wide that may cause instability. Our analysis highlighted 170 pairs, flanking 12.1% of the genome. We cross-referenced these predicted susceptibility regions with CNVs from our clinical databases for potentially HERV-mediated rearrangements and identified 78 CNVs. We subsequently molecularly confirmed recurrent deletion and duplication rearrangements at four loci in ten individuals, including reciprocal rearrangements at two loci. Breakpoint sequencing revealed clustering in regions of high sequence identity enriched in PRDM9-mediated recombination hotspot motifs. CONCLUSIONS: The presence of deletions and reciprocal duplications suggests NAHR as the causative mechanism of HERV-mediated CNV, even though the length and the sequence homology of the HERV elements are less than currently thought to be required for NAHR. We propose that in addition to HERVs, other repetitive elements, such as long interspersed elements, may also be responsible for the formation of recurrent CNVs via NAHR. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-014-0074-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-41959462014-10-15 Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination Campbell, Ian M Gambin, Tomasz Dittwald, Piotr Beck, Christine R Shuvarikov, Andrey Hixson, Patricia Patel, Ankita Gambin, Anna Shaw, Chad A Rosenfeld, Jill A Stankiewicz, Paweł BMC Biol Research Article BACKGROUND: Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV). RESULTS: We developed parameters to identify HERV elements similar to those that mediate Yq12 rearrangements as well as recurrent deletions of 3q13.2q13.31. We used these parameters to identify HERV pairs genome-wide that may cause instability. Our analysis highlighted 170 pairs, flanking 12.1% of the genome. We cross-referenced these predicted susceptibility regions with CNVs from our clinical databases for potentially HERV-mediated rearrangements and identified 78 CNVs. We subsequently molecularly confirmed recurrent deletion and duplication rearrangements at four loci in ten individuals, including reciprocal rearrangements at two loci. Breakpoint sequencing revealed clustering in regions of high sequence identity enriched in PRDM9-mediated recombination hotspot motifs. CONCLUSIONS: The presence of deletions and reciprocal duplications suggests NAHR as the causative mechanism of HERV-mediated CNV, even though the length and the sequence homology of the HERV elements are less than currently thought to be required for NAHR. We propose that in addition to HERVs, other repetitive elements, such as long interspersed elements, may also be responsible for the formation of recurrent CNVs via NAHR. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-014-0074-4) contains supplementary material, which is available to authorized users. BioMed Central 2014-09-23 /pmc/articles/PMC4195946/ /pubmed/25246103 http://dx.doi.org/10.1186/s12915-014-0074-4 Text en © Campbell et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.
spellingShingle Research Article
Campbell, Ian M
Gambin, Tomasz
Dittwald, Piotr
Beck, Christine R
Shuvarikov, Andrey
Hixson, Patricia
Patel, Ankita
Gambin, Anna
Shaw, Chad A
Rosenfeld, Jill A
Stankiewicz, Paweł
Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
title Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
title_full Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
title_fullStr Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
title_full_unstemmed Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
title_short Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
title_sort human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195946/
https://www.ncbi.nlm.nih.gov/pubmed/25246103
http://dx.doi.org/10.1186/s12915-014-0074-4
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