Transcription influences the types of deletion and expansion products in an orientation-dependent manner from GAC*GTC repeats.
Transcription influences the types of deletion and expansion products in an orientation-dependent manner from GAC*GTC repeats.
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转录以方向依赖的方式影响 GAC*GTC 重复的缺失和扩展产物的类型。
DOI：
10.1093/nar/gkh787
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Wells,RobertD
中科院分区：
文献类型：
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作者：
Mochmann,LilianaH;Wells,RobertD
在大肠杆菌质粒系统中研究了（GAC·GTC）n（n = 6-74）的遗传不稳定性。先前的研究表明，软骨寡聚基质蛋白（COMP）基因中的（GAC·GTC）5 tract不稳定性与假性软骨发育不全和多发性骨骺发育不良的病因学有关。在体内多次复制循环后，研究了三联体重复序列长度和方向的影响。含有（GAC·GTC）49个重复序列的转录质粒在大肠杆菌中增殖后导致大的缺失（>3个重复序列）;然而，如果转录被LacIQ阻遏物沉默，则小的扩增和缺失（<3个重复序列）占主导地位。相反，含有长度相似但方向相反的（GTC·GAC）53质粒的繁殖导致了不受转录抑制影响的小的不稳定性。因此，通过抑制转录，（GAC·GTC）49重复序列的遗传不稳定性与相反方向（GTC·GAC）53没有显著差异。我们推测，GAC·GTC重复序列的小的不稳定性是通过复制滑移实现的，而大的缺失事件是在GAC·GTC重复序列转录时发现的。在此，我们报告了第一个遗传学研究GAC·GTC重复序列不稳定性描述两种类型的突变模式，可以通过转录调节划分。沿着先前的生物物理学数据，这些结果为理解COMP基因中三联重复突变的遗传过程奠定了初步基础。
The genetic instability of (GAC•GTC)n(wheren= 6–74) was investigated in anEscherichia coli-based plasmid system. Prior work implicated the instability of a (GAC•GTC)5tract in the cartilage oligomeric matrix protein (COMP) gene to the 4, 6 or 7mers in the etiology of pseudoachondroplasia and multiple epiphyseal dysplasia. The effects of triplet repeat length and orientation were studied after multiple replication cyclesin vivo. A transcribed plasmid containing (GAC•GTC)49repeats led to large deletions (>3 repeats) after propagation inE.coli; however, if transcription was silenced by the LacIQrepressor, small expansions and deletions (<3 repeats) predominated the mutation spectra. In contrast, propagation of similar length but opposing orientation (GTC•GAC)53containing plasmid led to small instabilities that were unaffected by the repression of transcription. Thus, by inhibiting transcription, the genetic instability of (GAC•GTC)49repeats did not significantly differ from the opposing orientation, (GTC•GAC)53. We postulate that small instabilities of GAC•GTC repeats are achieved through replicative slippage, whereas large deletion events are found when GAC•GTC repeats are transcribed. Herein, we report the first genetic study on GAC•GTC repeat instability describing two types of mutational patterns that can be partitioned by transcription modulation. Along with prior biophysical data, these results lay the initial groundwork for understanding the genetic processes responsible for triplet repeat mutations in the COMP gene.