Selection Acts on DNA Secondary Structures to Decrease Transcriptional Mutagenesis

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Abstract
Single-stranded DNA is more subject to mutation than double stranded. During transcription, DNA is transiently single stranded and therefore subject to higher mutagenesis. However, if local intra-strand secondary structures are formed, some bases will be paired and therefore less sensitive to mutation than unpaired bases. Using complete genome sequences of Escherichia coli, we show that local intra-strand secondary structures can, as a consequence, be used to define an index of transcription-driven mutability. At gene level, we show that natural selection has favoured a reduced transcription-driven mutagenesis via the higher than expected frequency of occurrence of intra-strand secondary structures. Such selection is stronger in highly expressed genes and suggests a sequence-dependent way to control mutation rates and a novel form of selection affecting the evolution of synonymous mutations. Genome sequence evolution results from the interplay between mutagenesis and natural selection. Mutations occur as the result of biochemical or physical alteration of DNA and/or from the errors made by polymerases while replicating DNA. As many mutations tend to be detrimental to the organism's fitness, natural selection favours a decrease in mutation rate. Hence, many mechanisms have evolved to control mutation rate. The mechanisms described to date have relied on (i) the existence of enzymes repairing the damaged DNA or correcting mismatched bases, which are mechanisms having an effect on whole genome mutation rate, and (ii) the avoidance in the sequence of repetition that could be misread by the polymerases, which is a sequence-dependent local control of mutation rate. In the present paper, the authors suggest that another sequence-dependent control of mutation exists and shapes the overall evolution of the genome. Using a comparative analysis of Escherichia coli genomes, they show that local secondary structures that are formed during the transcription of genes into RNA can modulate the base-to-base mutation rate. Moreover, the authors show that natural selection seems to have favoured the occurrence of such structures to minimise mutability, especially in the most expressed genes. This paper proposes a new way in which gene sequences can be constrained by natural selection.