Berthelot Camille, Muffato Matthieu, Abecassis Judith, Roest Crollius Hugues
Cell Rep. 2015 Mar 24;10(11):1913-24. doi: 10.1016/j.celrep.2015.02.046.
Genomic rearrangements are a major source of evolutionary divergence in eukaryotic genomes, a cause of genetic diseases and a hallmark of tumor cell progression, yet the mechanisms underlying their occurrence and evolutionary fixation are poorly understood. Statistical associations between breakpoints and specific genomic features suggest that genomes may contain elusive “fragile regions” with a higher propensity for breakage. Here, we use ancestral genome reconstructions to demonstrate a near-perfect correlation between gene density and evolutionary rearrangement breakpoints. Simulations based on functional features in the human genome show that this pattern is best explained as the outcome of DNA breaks that occur in open chromatin regions coming into 3D contact in the nucleus. Our model explains how rearrangements reorganize the order of genes in an evolutionary neutral fashion and provides a basis for understanding the susceptibility of “fragile regions” to breakage.
基因组重排是真核生物基因组进化分歧的主要来源、遗传疾病的一个成因以及肿瘤细胞进展的一个标志，然而对其发生和进化固定的潜在机制却知之甚少。断点与特定基因组特征之间的统计关联表明，基因组可能包含更易断裂的难以捉摸的“脆弱区域”。在这里，我们利用祖先基因组重建来证明基因密度与进化重排断点之间存在近乎完美的相关性。基于人类基因组功能特征的模拟表明，这种模式最好解释为发生在细胞核中三维接触的开放染色质区域的DNA断裂的结果。我们的模型解释了重排如何以进化中性的方式重新组织基因顺序，并为理解“脆弱区域”的易断裂性提供了基础。
