The evolution of transcription-associated biases of mutations across vertebrates

Abstract

Background: The interplay between transcription and mutational processes can lead to particular mutation patterns in transcribed regions of the genome. Transcription introduces several biases in mutational patterns; in particular it invokes strand specific mutations. In order to understand the forces that have shaped transcripts during evolution, one has to study mutation patterns associated with transcription across animals.

Results: Using multiple alignments of related species we estimated the regional single-nucleotide substitution patterns along genes in four vertebrate taxa: primates, rodents, laurasiatheria and bony fishes. Our analysis is focused on intronic and intergenic regions and reveals differences in the patterns of substitution asymmetries between mammals and fishes. In mammals, the levels of asymmetries are stronger for genes starting within CpG islands than in genes lacking this property. In contrast to all other species analyzed, we found a mutational pressure in dog and stickleback, promoting an increase of GC-contents in the proximity to transcriptional start sites.

Conclusions: We propose that the asymmetric patterns in transcribed regions are results of transcription associated mutagenic processes and transcription coupled repair, which both seem to evolve in a taxon related manner. We also discuss alternative mechanisms that can generate strand biases and involves error prone DNA polymerases and reverse transcription. A localized increase of the GC content near the transcription start site is a signature of biased gene conversion (BGC) that occurs during recombination and heteroduplex formation. Since dog and stickleback are known to be subject to rapid adaptations due to population bottlenecks and breeding, we further hypothesize that an increase in recombination rates near gene starts has been part of an adaptive process.

Figure 1

Ratios of complementary transition frequencies across vertebrates. There are four rows of panels and two columns of panels. The rows correspond to the four taxa analyzed in this study and the columns to the two types of ratios between complementary transition frequencies. Each panel consists of two sections: The left section is centered on the TSSs (left 0 k) and refers to 5 kbp of intergenic region upstream to the TSS and extends towards 5 kbp of intronic region downstream to the TSS. The right section on a panel is similarly centered on the 3'ends (right 0 k), while the analyzed regions extend from 5 kbp of intronic regions (upstream to the 3'end) to 5 kbp of intergenic regions downstream to the genes 3' ends. The ratios are plotted against the distance from the 5' and 3'ends of genes. Ratios are calculated along the non-template strand from pooled 200 bp windows of genes annotated for the reference species in each taxon. For CGI-genes the ratios are presented by thick lines, for nonCGI-genes ratios as thin lines.

Figure 2

The weak to strong bias along CGI-genes and their flanks. The frequencies of W→S (thick line), S→W (thin line), the stationary GC content (GC*, thick) and the GC content (thin) are plotted against distance from the 5'end and 3'end of genes and calculated along the non-template strand from pooled 200 bp windows of genes annotated for the reference species in each taxon. Only the results for CGI-genes are presented.