Chuzhanova Nadia, Abeysinghe Shaun S, Krawczak Michael, Cooper David N
Department of Computer Science, Cardiff University, Cardiff, UK.
Hum Mutat. 2003 Sep;22(3):245-51. doi: 10.1002/humu.10253.
Translocations and gross deletions are responsible for a significant proportion of both cancer and inherited disease. Although such gene rearrangements are nonuniformly distributed in the human genome, the underlying mutational mechanisms remain unclear. We have studied the potential involvement of various types of repetitive sequence elements in the formation of secondary structure intermediates between the single-stranded DNA ends that recombine during rearrangements. Complexity analysis was used to assess the potential of these ends to form secondary structures, the maximum decrease in complexity consequent to a gross rearrangement being used as an indicator of the type of repeat and the specific DNA ends involved. A total of 175 pairs of deletion/translocation breakpoint junction sequences available from the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] were analyzed. Potential secondary structure was noted between the 5' flanking sequence of the first breakpoint and the 3' flanking sequence of the second breakpoint in 49% of rearrangements and between the 5' flanking sequence of the second breakpoint and the 3' flanking sequence of the first breakpoint in 36% of rearrangements. Inverted repeats, inversions of inverted repeats, and symmetric elements were found in association with gross rearrangements at approximately the same frequency. However, inverted repeats and inversions of inverted repeats accounted for the vast majority (83%) of deletions plus small insertions, symmetric elements for one-half of all antigen receptor-mediated translocations, while direct repeats appear only to be involved in mediating simple deletions. These findings extend our understanding of illegitimate recombination by highlighting the importance of secondary structure formation between single-stranded DNA ends at breakpoint junctions.
易位和大片段缺失在癌症和遗传性疾病中占相当大的比例。尽管此类基因重排在人类基因组中的分布并不均匀，但其潜在的突变机制仍不清楚。我们研究了各种类型的重复序列元件在重排过程中发生重组的单链DNA末端之间二级结构中间体形成过程中的潜在作用。复杂性分析用于评估这些末端形成二级结构的潜力，将大规模重排导致的复杂性最大降低用作重复类型和所涉及的特定DNA末端的指标。我们分析了从大规模重排断点数据库[GRaBD；www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html]中获得的总共175对缺失/易位断点连接序列。在49%的重排中，在第一个断点的5'侧翼序列与第二个断点的3'侧翼序列之间发现了潜在的二级结构，在36%的重排中，在第二个断点的5'侧翼序列与第一个断点的3'侧翼序列之间发现了潜在的二级结构。发现反向重复、反向重复的倒位和对称元件与大规模重排的关联频率大致相同。然而，反向重复和反向重复的倒位占缺失加小插入的绝大多数（83%），对称元件占所有抗原受体介导的易位的一半，而直接重复似乎仅参与介导简单缺失。这些发现通过强调断点连接处单链DNA末端之间二级结构形成的重要性，扩展了我们对非法重组的理解。
