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A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?
Chromosomal common fragile sites (CFSs) are unstable genomic regions that break under replication stress and are involved in structural variation. They frequently are sites of chromosomal rearrangements in cancer and of viral integration. However, CFSs are undercharacterized at the molecular level a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371707/ https://www.ncbi.nlm.nih.gov/pubmed/22456607 http://dx.doi.org/10.1101/gr.134395.111 |
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author | Fungtammasan, Arkarachai Walsh, Erin Chiaromonte, Francesca Eckert, Kristin A. Makova, Kateryna D. |
author_facet | Fungtammasan, Arkarachai Walsh, Erin Chiaromonte, Francesca Eckert, Kristin A. Makova, Kateryna D. |
author_sort | Fungtammasan, Arkarachai |
collection | PubMed |
description | Chromosomal common fragile sites (CFSs) are unstable genomic regions that break under replication stress and are involved in structural variation. They frequently are sites of chromosomal rearrangements in cancer and of viral integration. However, CFSs are undercharacterized at the molecular level and thus difficult to predict computationally. Newly available genome-wide profiling studies provide us with an unprecedented opportunity to associate CFSs with features of their local genomic contexts. Here, we contrasted the genomic landscape of cytogenetically defined aphidicolin-induced CFSs (aCFSs) to that of nonfragile sites, using multiple logistic regression. We also analyzed aCFS breakage frequencies as a function of their genomic landscape, using standard multiple regression. We show that local genomic features are effective predictors both of regions harboring aCFSs (explaining ∼77% of the deviance in logistic regression models) and of aCFS breakage frequencies (explaining ∼45% of the variance in standard regression models). In our optimal models (having highest explanatory power), aCFSs are predominantly located in G-negative chromosomal bands and away from centromeres, are enriched in Alu repeats, and have high DNA flexibility. In alternative models, CpG island density, transcription start site density, H3K4me1 coverage, and mononucleotide microsatellite coverage are significant predictors. Also, aCFSs have high fragility when colocated with evolutionarily conserved chromosomal breakpoints. Our models are predictive of the fragility of aCFSs mapped at a higher resolution. Importantly, the genomic features we identified here as significant predictors of fragility allow us to draw valuable inferences on the molecular mechanisms underlying aCFSs. |
format | Online Article Text |
id | pubmed-3371707 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-33717072012-12-01 A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? Fungtammasan, Arkarachai Walsh, Erin Chiaromonte, Francesca Eckert, Kristin A. Makova, Kateryna D. Genome Res Research Chromosomal common fragile sites (CFSs) are unstable genomic regions that break under replication stress and are involved in structural variation. They frequently are sites of chromosomal rearrangements in cancer and of viral integration. However, CFSs are undercharacterized at the molecular level and thus difficult to predict computationally. Newly available genome-wide profiling studies provide us with an unprecedented opportunity to associate CFSs with features of their local genomic contexts. Here, we contrasted the genomic landscape of cytogenetically defined aphidicolin-induced CFSs (aCFSs) to that of nonfragile sites, using multiple logistic regression. We also analyzed aCFS breakage frequencies as a function of their genomic landscape, using standard multiple regression. We show that local genomic features are effective predictors both of regions harboring aCFSs (explaining ∼77% of the deviance in logistic regression models) and of aCFS breakage frequencies (explaining ∼45% of the variance in standard regression models). In our optimal models (having highest explanatory power), aCFSs are predominantly located in G-negative chromosomal bands and away from centromeres, are enriched in Alu repeats, and have high DNA flexibility. In alternative models, CpG island density, transcription start site density, H3K4me1 coverage, and mononucleotide microsatellite coverage are significant predictors. Also, aCFSs have high fragility when colocated with evolutionarily conserved chromosomal breakpoints. Our models are predictive of the fragility of aCFSs mapped at a higher resolution. Importantly, the genomic features we identified here as significant predictors of fragility allow us to draw valuable inferences on the molecular mechanisms underlying aCFSs. Cold Spring Harbor Laboratory Press 2012-06 /pmc/articles/PMC3371707/ /pubmed/22456607 http://dx.doi.org/10.1101/gr.134395.111 Text en © 2012, Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/. |
spellingShingle | Research Fungtammasan, Arkarachai Walsh, Erin Chiaromonte, Francesca Eckert, Kristin A. Makova, Kateryna D. A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? |
title | A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? |
title_full | A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? |
title_fullStr | A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? |
title_full_unstemmed | A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? |
title_short | A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome? |
title_sort | genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371707/ https://www.ncbi.nlm.nih.gov/pubmed/22456607 http://dx.doi.org/10.1101/gr.134395.111 |
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