Segmental duplications and evolutionary plasticity at tumor chromosome break-prone regions
Segmental duplications and evolutionary plasticity at tumor chromosome break-prone regions
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DOI：
10.1101/gr.7010208
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发表时间：
2008-03-01
期刊：
影响因子：
7
通讯作者：
Kost-Alimova, Maria
中科院分区：
文献类型：
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作者：
Darai-Ramqvist, Eva;Sandlund, Agneta;Kost-Alimova, Maria
我们以前发现，进化上保守的染色体区域的边界往往与人类3 p12-p22内的肿瘤相关缺失断点相一致。此外，对3p21.3（CER 1）处频繁缺失区域的详细分析表明肿瘤断裂与基因复制之间存在关联。我们现在报告的分析54 3号染色体断裂的多点FISH（mpFISH）在10个癌源性细胞系。着丝粒区断裂成五条线。在具有高度复杂核型的细胞系中，断裂聚集在已知脆性位点附近，FRA 3B、FRA 3C和FRA 3D（三个细胞系），以及另外两个区域：3p12.3-p13（类似于75 Mb位置）和3q21.3-q22.1（类似于130 Mb位置）（六个细胞系）。所有位置均基于NCBI Build 36.1人类基因组序列显示。最后两个区域参与了灵长类进化过程中四个3号染色体倒位中的三个。在75、127和131 Mb位置的区域携带大的（类似于250 kb）节段性重复（肿瘤易断裂节段性重复[TBSD]）。TBSD同源序列分布在不同染色体上的15个位点。它们位于经常涉及癌相关断裂的条带内。其中13个参与了灵长类进化过程中的倒位; 10个在哺乳动物进化过程中被重复使用; 14个在人类中表现出拷贝数多态性。TBSD位点显示卫星重复序列、逆转录序列和其他片段重复的增加。我们建议，这些网站的不稳定性源于特定的组织的染色体区域，与位置在不同的CG含量isochore之间的边界，并与TBSDs和“不稳定因素”，包括卫星重复序列和逆转录病毒序列的存在。
We have previously found that the borders of evolutionarily conserved chromosomal regions often coincide with tumor-associated deletion breakpoints within human 3p12-p22. Moreover, a detailed analysis of a frequently deleted region at 3p21.3 (CER1) showed associations between tumor breaks and gene duplications. We now report on the analysis of 54 chromosome 3 breaks by multipoint FISH (mpFISH) in 10 carcinoma-derived cell lines. The centromeric region was broken in five lines. In lines with highly complex karyotypes, breaks were clustered near known fragile sites, FRA3B, FRA3C, and FRA3D (three lines), and in two other regions: 3p12.3-p13 (similar to 75 Mb position) and 3q21.3-q22.1 (similar to 130 Mb position) (six lines). All locations are shown based on NCBI Build 36.1 human genome sequence. The last two regions participated in three of four chromosome 3 inversions during primate evolution. Regions at 75, 127, and 131 Mb positions carry a large (similar to 250 kb) segmental duplication (tumor break-prone segmental duplication [TBSD]). TBSD homologous sequences were found at 15 sites on different chromosomes. They were located within bands frequently involved in carcinoma-associated breaks. Thirteen of them have been involved in inversions during primate evolution; 10 were reused by breaks during mammalian evolution; 14 showed copy number polymorphism in man. TBSD sites showed an increase in satellite repeats, retrotransposed sequences, and other segmental duplications. We propose that the instability of these sites stems from specific organization of the chromosomal region, associated with location at a boundary between different CG-content isochores and with the presence of TBSDs and "instability elements," including satellite repeats and retroviral sequences.