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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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Related in: MedlinePlus

Distribution of HERV susceptibility regions. Percentage of each chromosome consisting of potential HERV susceptibility regions. HERV, human endogenous retrovirus.
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Fig2: Distribution of HERV susceptibility regions. Percentage of each chromosome consisting of potential HERV susceptibility regions. HERV, human endogenous retrovirus.

Mentions: The 170 overlapping pairs that we predicted can be condensed into 70 susceptibility regions (Figure 1, purple bars). Overall, we estimate that 375 Mb (12.1%) of the HRG could potentially undergo HERV-mediated CNV. This predicted susceptibility, genome-wide, is considerably more than the 9% predicted by Sharp et al. [4] and the 6% predicted by Liu et al. [23] for CNVs mediated by NAHR between LCRs. Chromosome 19 was determined to have the largest fraction of reference sequences within susceptibility regions as a percentage of chromosome length (Figure 2).


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)

Distribution of HERV susceptibility regions. Percentage of each chromosome consisting of potential HERV susceptibility regions. 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

Fig2: Distribution of HERV susceptibility regions. Percentage of each chromosome consisting of potential HERV susceptibility regions. HERV, human endogenous retrovirus.
Mentions: The 170 overlapping pairs that we predicted can be condensed into 70 susceptibility regions (Figure 1, purple bars). Overall, we estimate that 375 Mb (12.1%) of the HRG could potentially undergo HERV-mediated CNV. This predicted susceptibility, genome-wide, is considerably more than the 9% predicted by Sharp et al. [4] and the 6% predicted by Liu et al. [23] for CNVs mediated by NAHR between LCRs. Chromosome 19 was determined to have the largest fraction of reference sequences within susceptibility regions as a percentage of chromosome length (Figure 2).

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