Transcription influences the types of deletion and expansion products in an orientation-dependent manner from GAC•GTC repeats

被引:24
作者
Mochmann, LH [1 ]
Wells, RD [1 ]
机构
[1] Texas A&M Univ, System Hlth Sci Ctr, Inst Biosci & Technol, Ctr Genome Res, Houston, TX 77030 USA
关键词
D O I
10.1093/nar/gkh787
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The genetic instability of (GAC.GTC)(n) (where n = 6-74) was investigated in an Escherichia coli-based plasmid system. Prior work implicated the instability of a (GAC.GTC)(5) tract 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 cycles in vivo. A transcribed plasmid containing (GAC.GTC)(49) repeats led to large deletions (>3 repeats) after propagation in E.coli; however, if transcription was silenced by the LacI(Q) repressor, small expansions and deletions (<3 repeats) predominated the mutation spectra. In contrast, propagation of similar length but opposing orientation (GTC.GAC)(53) containing plasmid led to small instabilities that were unaffected by the repression of transcription. Thus, by inhibiting transcription, the genetic instability of (GAC.GTC)(49) repeats 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.
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页码:4469 / 4479
页数:11
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