Cloned human FMR1 trinucleotide repeats exhibit a length- and orientation-dependent instability suggestive of in vivo lagging strand secondary structure
Cloned human FMR1 trinucleotide repeats exhibit a length- and orientation-dependent instability suggestive of in vivo lagging strand secondary structure
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DOI：
10.1093/nar/26.10.2353
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发表时间：
1998-05-15
影响因子：
14.9
通讯作者：
White, PJ
中科院分区：
文献类型：
--
作者：
Hirst, MC;White, PJ
正常人FMR 1基因含有一个遗传稳定的（CGG）（n）三核苷酸重复序列，通常携带散布的AGG三联体。重复数目的增加和散布的损失导致阵列不稳定，主要是扩增，导致FMR 1基因沉默。不稳定性与不间断（CGG）（n）重复序列的长度直接相关，并且被广泛认为与形成富含G的二级结构的增加的倾向相关，所述二级结构导致通过复制滑移的扩增。为了研究这一点，我们克隆了人类FMR1阵列的内部结构代表正常，中间和不稳定状态。在一个复制方向上，阵列显示长度依赖性不稳定性，缺失以极性方式发生。对于较长的阵列，这些延伸到FMR 1 5 '侧翼DNA中，终止于两个短CGG三联体阵列中的任一个。取向依赖性不稳定性表明二级结构形成于富含G的滞后链模板中，其解析导致阵列内缺失。这些数据为富含G的滞后链二级结构提供了直接的体内证据，该二级结构被认为参与了人类三联体扩增的过程。
The normal human FMR1 gene contains a genetically stable (CGG)(n) trinucleotide repeat which usually carries interspersed AGG triplets. An increase in repeat number and the loss of interspersions results in array instability, predominantly expansion, leading to FMR1 gene silencing. Instability is directly related to the length of the uninterrupted (CGG)(n) repeat and is widely assumed to be related to an increased propensity to form G-rich secondary structures which lead to expansion through replication slippage. In order to investigate this we have cloned human FMR1 arrays with internal structures representing the normal, intermediate and unstable states. In one replicative orientation, arrays show a length-dependent instability, deletions occurring in a polar manner. With longer arrays these extend into the FMR1 5'-flanking DNA, terminating at either of two short CGG triplet arrays. The orientation-dependent instability suggests that secondary structure forms in the G-rich lagging strand template, resolution of which results in intra-array deletion, These data provide direct in vivo evidence for a G-rich lagging strand secondary structure which is believed to be involved in the process of triplet expansion in humans.