Key result
Transcription through GAC/GTC repeats promotes large deletions, whereas inhibition yields small expansions and deletions.
Transcription influences the mutational patterns of GAC*GTC repeats, with active transcription leading to large deletions and silenced transcription leading to small instabilities via replicative slippage.
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Transcription modulates repeat instability in animal models; leaves open relevance to human repeat-expansion disorders pending clinical studies.
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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Liliana H. Mochmann (2004) studied Genetic instability of triplet repeats. Transcription modulation and repeat orientation vs. Opposing orientation or repressed transcription was evaluated on Types and amounts of deletion and expansion products. Transcription through GAC/GTC repeats promotes large deletion products in long repeat tracts in an orientation-dependent manner, whereas inhibition of transcription leads to small expansions and deletions.
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