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

Campbell IM, Gambin T, Dittwald P, Beck CR, Shuvarikov A, Hixson P, Patel A, Gambin A, Shaw CA, Rosenfeld JA, Stankiewicz P - BMC Biol. (2014)

Bottom Line: Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats.We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm ABBR-R809, Houston, TX, USA. pawels@bcm.edu.

ABSTRACT

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.

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Genome-wide map of HERV-mediated genome instability. Chromosome ideograms with 70 predicted HERV susceptibility regions indicated in purple flanked by individual HERV elements indicated in red. Potentially HERV-mediated CNVs identified in the Baylor College of Medicine or Signature Genomics clinical databases are shown below the chromosome ideograms in cyan. HERV-mediated CNVs that have been molecularly confirmed in this study or the literature are indicated in yellow. CNV, copy-number variation; HERV, human endogenous retrovirus.
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Fig1: Genome-wide map of HERV-mediated genome instability. Chromosome ideograms with 70 predicted HERV susceptibility regions indicated in purple flanked by individual HERV elements indicated in red. Potentially HERV-mediated CNVs identified in the Baylor College of Medicine or Signature Genomics clinical databases are shown below the chromosome ideograms in cyan. HERV-mediated CNVs that have been molecularly confirmed in this study or the literature are indicated in yellow. CNV, copy-number variation; HERV, human endogenous retrovirus.

Mentions: Given previous studies of NAHR events, we hypothesized that directly oriented repetitive elements with high sequence identity could mediate recurrent deletions and reciprocal duplications. To this end, we searched for highly homologous pairs of HERV elements using RepeatMasker, allowing for small gaps between annotations (see Methods). We identified 170 such HERV pairs fitting our parameters genome-wide (Additional file 2: Table S1), with the largest number on chromosome 6, with 27 pairs (FigureĀ 1, red dots).


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

Campbell IM, Gambin T, Dittwald P, Beck CR, Shuvarikov A, Hixson P, Patel A, Gambin A, Shaw CA, Rosenfeld JA, Stankiewicz P - BMC Biol. (2014)

Genome-wide map of HERV-mediated genome instability. Chromosome ideograms with 70 predicted HERV susceptibility regions indicated in purple flanked by individual HERV elements indicated in red. Potentially HERV-mediated CNVs identified in the Baylor College of Medicine or Signature Genomics clinical databases are shown below the chromosome ideograms in cyan. HERV-mediated CNVs that have been molecularly confirmed in this study or the literature are indicated in yellow. CNV, copy-number variation; HERV, human endogenous retrovirus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4195946&req=5

Fig1: Genome-wide map of HERV-mediated genome instability. Chromosome ideograms with 70 predicted HERV susceptibility regions indicated in purple flanked by individual HERV elements indicated in red. Potentially HERV-mediated CNVs identified in the Baylor College of Medicine or Signature Genomics clinical databases are shown below the chromosome ideograms in cyan. HERV-mediated CNVs that have been molecularly confirmed in this study or the literature are indicated in yellow. CNV, copy-number variation; HERV, human endogenous retrovirus.
Mentions: Given previous studies of NAHR events, we hypothesized that directly oriented repetitive elements with high sequence identity could mediate recurrent deletions and reciprocal duplications. To this end, we searched for highly homologous pairs of HERV elements using RepeatMasker, allowing for small gaps between annotations (see Methods). We identified 170 such HERV pairs fitting our parameters genome-wide (Additional file 2: Table S1), with the largest number on chromosome 6, with 27 pairs (FigureĀ 1, red dots).

Bottom Line: Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats.We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm ABBR-R809, Houston, TX, USA. pawels@bcm.edu.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus