Abstract
BackgroundDuring transcription, the nontranscribed DNA strand becomes single-stranded DNA (ssDNA), which can form secondary structures. Unpaired bases in the ssDNA are less protected from mutagens and hence experience more mutations than do paired bases. These mutations are called transcription-associated mutations. Transcription-associated mutagenesis is increased under stress and depends on the DNA sequence. Therefore, selection might significantly influence protein-coding sequences in terms of the transcription-associated mutability per transcription event under stress to improve the survival of Escherichia coli.Methodology/Principal FindingsThe mutability index (MI) was developed by Wright et al. to estimate the relative transcription-associated mutability of bases per transcription event. Using the most stable fold of each ssDNA that have an average length n, MI was defined as (the number of folds in which the base is unpaired)/n×(highest –ΔG of all n folds in which the base is unpaired), where ΔG is the free energy. The MI values show a significant correlation with mutation data under stress but not with spontaneous mutations in E. coli. Protein sequence diversity is preferred under stress but not under favorable conditions. Therefore, we evaluated the selection pressure on MI in terms of the protein sequence diversity for all the protein-coding sequences in E. coli. The distributions of the MI values were lower at bases that could be substituted with each of the other three bases without affecting the amino acid sequence than at bases that could not be so substituted. Start codons had lower distributions of MI values than did nonstart codons.Conclusions/SignificanceOur results suggest that the majority of protein-coding sequences have evolved to promote protein sequence diversity and to reduce gene knockout under stress. Consequently, transcription-associated mutagenesis increases protein sequence diversity more effectively than does random mutagenesis under stress. Nonrandom transcription-associated mutagenesis under stress should improve the survival of E. coli.
Highlights
During transcription, the nontranscribed strand becomes single stranded, whereas the transcribed strand forms a complex with RNA polymerase and the nascent RNA transcript [1]
Calculation of mutability index (MI) Transcription-associated mutability per transcription event should be affected by the local secondary structures of the RNA transcript, on which the functions of noncoding genes depend
MI values for the 3,958,572 bases in the 4,132 protein-coding sequences of the E. coli K12 MG1655 genome were calculated according to the method described by Wright et al [28], and the negative MI values were converted to zero
Summary
The nontranscribed strand becomes single stranded, whereas the transcribed strand forms a complex with RNA polymerase and the nascent RNA transcript [1]. Transcription-associated mutagenesis should be active on the nontranscribed strands, in highly transcribed DNA regions, and in cells under stress where high levels of mutagens are active. E. coli cells would often contain one transcription-associated mutation and no other types of mutations in a genomic strand and no mutations in the other genomic strand until cell division when transcriptionassociated mutagenesis operates. In such cases, the unmutated genomic DNA strand of the cell is inherited by one of its two daughter cells. Selection might significantly influence protein-coding sequences in terms of the transcription-associated mutability per transcription event under stress to improve the survival of Escherichia coli
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