Etablissement Français du Sang (EFS) - Bretagne, Brest, France.
Semin Cancer Biol. 2010 Aug;20(4):222-33. doi: 10.1016/j.semcancer.2010.05.007. Epub 2010 Jun 9.
Genomic rearrangements in inherited disease and cancer involve gross alterations of chromosomes or large chromosomal regions and can take the form of deletions, duplications, insertions, inversions or translocations. The characterization of a considerable number of rearrangement breakpoints has now been accomplished at the nucleotide sequence level, thereby providing an invaluable resource for the detailed study of the mutational mechanisms which underlie genomic recombination events. A better understanding of these mutational mechanisms is vital for improving the design of mutation detection strategies. At least five categories of mutational mechanism are known to give rise to genomic rearrangements: (i) homologous recombination including non-allelic homologous recombination (NAHR), gene conversion, single strand annealing (SSA) and break-induced replication (BIR), (ii) non-homologous end joining (NHEJ), (iii) microhomology-mediated replication-dependent recombination (MMRDR), (iv) long interspersed element-1 (LINE-1 or L1)-mediated retrotransposition and (v) telomere healing. Focussing on the first three of these general mechanisms, we compare and contrast their hallmark characteristics, and discuss the role of various local DNA sequence features (e.g. recombination-promoting motifs, repetitive sequences and sequences capable of non-B DNA formation) in mediating the recombination events that underlie gross genomic rearrangements. Finally, we explore how studies both at the level of the gene (using the neurofibromatosis type-1 gene as an example) and the whole genome (using data derived from cancer genome sequencing studies) are shaping our understanding of the impact of genomic rearrangements as a cause of human genetic disease.
遗传疾病和癌症中的基因组重排涉及染色体或大片段染色体的巨大改变，其形式可以是缺失、重复、插入、倒位或易位。现在已经在核苷酸序列水平上完成了相当数量的重排断点的特征描述，从而为详细研究导致基因组重组事件的突变机制提供了宝贵的资源。更好地了解这些突变机制对于改进突变检测策略的设计至关重要。已知至少有五类突变机制会导致基因组重排：（i）同源重组，包括非等位同源重组（NAHR）、基因转换、单链退火（SSA）和断裂诱导复制（BIR），（ii）非同源末端连接（NHEJ），（iii）微同源介导的复制依赖性重组（MMRDR），（iv）长散布元件-1（LINE-1 或 L1）介导的反转录转座和（v）端粒愈合。我们聚焦于这三个一般机制，比较和对比它们的特征，并讨论各种局部 DNA 序列特征（例如促进重组的基序、重复序列和能够形成非 B DNA 的序列）在介导导致基因组重排的重组事件中的作用。最后，我们探讨了在基因水平（以神经纤维瘤病 1 型基因为例）和整个基因组水平（使用来自癌症基因组测序研究的数据）的研究如何影响我们对基因组重排作为人类遗传疾病原因的理解。
