A microhomology-mediated break-induced replication model for the origin of human copy number variation.
Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristic...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2621351?pdf=render |
| _version_ | 1828771857763926016 |
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| author | P J Hastings Grzegorz Ira James R Lupski |
| author_facet | P J Hastings Grzegorz Ira James R Lupski |
| author_sort | P J Hastings |
| collection | DOAJ |
| description | Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2-5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3' tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication. |
| first_indexed | 2024-12-11T14:33:09Z |
| format | Article |
| id | doaj.art-279bbc5a03504eeb986609af0109184e |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-11T14:33:09Z |
| publishDate | 2009-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-279bbc5a03504eeb986609af0109184e2022-12-22T01:02:18ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-01-0151e100032710.1371/journal.pgen.1000327A microhomology-mediated break-induced replication model for the origin of human copy number variation.P J HastingsGrzegorz IraJames R LupskiChromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2-5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3' tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.http://europepmc.org/articles/PMC2621351?pdf=render |
| spellingShingle | P J Hastings Grzegorz Ira James R Lupski A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genetics |
| title | A microhomology-mediated break-induced replication model for the origin of human copy number variation. |
| title_full | A microhomology-mediated break-induced replication model for the origin of human copy number variation. |
| title_fullStr | A microhomology-mediated break-induced replication model for the origin of human copy number variation. |
| title_full_unstemmed | A microhomology-mediated break-induced replication model for the origin of human copy number variation. |
| title_short | A microhomology-mediated break-induced replication model for the origin of human copy number variation. |
| title_sort | microhomology mediated break induced replication model for the origin of human copy number variation |
| url | http://europepmc.org/articles/PMC2621351?pdf=render |
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