A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome?
A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome?
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DOI：
10.1101/gr.134395.111
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发表时间：
2012-06
期刊：
影响因子：
7
通讯作者：
Makova KD
中科院分区：
文献类型：
--
作者：
Fungtammasan A;Walsh E;Chiaromonte F;Eckert KA;Makova KD
染色体共同脆弱位点 (CFS) 是不稳定的基因组区域，在复制压力下断裂并参与结构变异。它们通常是癌症中染色体重排和病毒整合的位点。然而，CFS 在分子水平上的表征不足，因此难以通过计算进行预测。新推出的全基因组分析研究为我们提供了前所未有的机会，将 CFS 与其本地基因组背景的特征联系起来。在这里，我们使用多元逻辑回归将细胞遗传学定义的阿非迪霉素诱导的 CFS (aCFS) 的基因组景观与非脆弱位点的基因组景观进行了对比。我们还使用标准多元回归分析了 aCFS 断裂频率作为其基因组景观的函数。我们表明，局部基因组特征是包含 aCFS 的区域（解释逻辑回归模型中约 77% 的偏差）和 aCFS 断裂频率（解释标准回归模型中约 45% 的方差）的有效预测因子。在我们的最佳模型（具有最高的解释力）中，aCFS 主要位于 G 阴性染色体带中并远离着丝粒，富含 Alu 重复序列，并且具有较高的 DNA 灵活性。在替代模型中，CpG 岛密度、转录起始位点密度、H3K4me1 覆盖度和单核苷酸微卫星覆盖度是重要的预测因子。此外，当 aCFS 与进化上保守的染色体断点共处时，它具有很高的脆弱性。我们的模型可以预测以更高分辨率绘制的 aCFS 的脆弱性。重要的是，我们在此确定的基因组特征作为脆弱性的重要预测因素，使我们能够对 aCFS 的分子机制得出有价值的推论。
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.
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影响因子：
3.5
作者：
Furey, TS;Haussler, D
通讯作者：
Haussler, D
影响因子：
7
作者：
Costantini, M;Clay, O;Bernardi, G
通讯作者：
Bernardi, G
影响因子：
21.3
作者：
Chan, Kok Lung;Palmai-Pallag, Timea;Hickson, Ian D.
通讯作者：
Hickson, Ian D.
影响因子：
12.3
作者：
Ananda G;Chiaromonte F;Makova KD
通讯作者：
Makova KD
DOI：
10.1073/pnas.0708097105
发表时间：
2008-01-08
影响因子：
11.1
作者：
Durkin, Sandra G.;Ragland, Ryan L.;Glover, Thomas W.
通讯作者：
Glover, Thomas W.