A palindrome-mediated mechanism distinguishes translocations involving LCR-B of chromosome 22q11.2
A palindrome-mediated mechanism distinguishes translocations involving LCR-B of chromosome 22q11.2
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DOI：
10.1093/hmg/ddh004
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Emanuel, BS
中科院分区：
文献类型：
--
作者：
Gotter, AL;Shaikh, TH;Emanuel, BS
两个已知的反复发生的构象易位，t（11;22）和t(17;22)，以及一个非反复发生的t(4;22)，显示衍生染色体连接到22q11.2低拷贝重复B （LCR-B）区域的一个共同位点。这个断点位于两个富含at的反向重复之间，形成一个近乎完美的回文。11q23、17q11和4q35配对染色体的断点也位于回文序列的中心附近。在目前的工作中，涉及LCR-B的第四个易位的断点，一个平衡的室管膜瘤相关的t(1;22)，不仅定位了这种连接相对于已知基因，而且还进一步了解了这些重排的机制。使用FISH映射将22q11.2断点定位为LCR-B，将1p21断点定位为单个BAC克隆。STS定位将1p21.2的断点缩小到一个1990 bp的富含at的区域，并通过巢式PCR扩增了连接片段。结片段衍生序列表明，1p21.2断点分裂了一个278 nt的回文，能够形成茎环二级结构。相比之下，数据库中克隆的1p21.2参考基因组序列没有表现出这种结构，这表明区域基因组不稳定的倾向可能是这种重排的病因。鉴于其与已知的染色体脆性位点（FRA）序列的相似性，该多态性1p21.2序列可能代表fr1位点之一。通过对易位断点周围涉及LCR-B的序列与不涉及该区域的序列的二级结构的比较分析，表明前者具有形成茎环结构的独特能力。形成这些构型的相对可能性似乎与易位发生率有关。进一步的分析表明，构造易位一般发生在熔点相似和二级结构倾向的序列之间。
Two known recurrent constitutional translocations, t(11;22) and t(17;22), as well as a non-recurrent t(4;22), display derivative chromosomes that have joined to a common site within the low copy repeat B (LCR-B) region of 22q11.2. This breakpoint is located between two AT-rich inverted repeats that form a nearly perfect palindrome. Breakpoints within the 11q23, 17q11 and 4q35 partner chromosomes also fall near the center of palindromic sequences. In the present work the breakpoints of a fourth translocation involving LCR-B, a balanced ependymoma-associated t(1;22), were characterized not only to localize this junction relative to known genes, but also to further understand the mechanism underlying these rearrangements. FISH mapping was used to localize the 22q11.2 breakpoint to LCR-B and the 1p21 breakpoint to single BAC clones. STS mapping narrowed the 1p21.2 breakpoint to a 1990 bp AT-rich region, and junction fragments were amplified by nested PCR. Junction fragment-derived sequence indicates that the 1p21.2 breakpoint splits a 278 nt palindrome capable of forming stem-loop secondary structure. In contrast, the 1p21.2 reference genomic sequence from clones in the database does not exhibit this configuration, suggesting a predisposition for regional genomic instability perhaps etiologic for this rearrangement. Given its similarity to known chromosomal fragile site (FRA) sequences, this polymorphic 1p21.2 sequence may represent one of the FRA1 loci. Comparative analysis of the secondary structure of sequences surrounding translocation breakpoints that involve LCR-B with those not involving this region indicate a unique ability of the former to form stem-loop structures. The relative likelihood of forming these configurations appears to be related to the rate of translocation occurrence. Further analysis suggests that constitutional translocations in general occur between sequences of similar melting temperature and propensity for secondary structure.