Similar compositional biases are caused by very different mutational effects

Abstract

Compositional replication strand bias, commonly referred to as GC skew, is present in many genomes of prokaryotes, eukaryotes, and viruses. Although cytosine deamination in ssDNA (resulting in C→T changes on the leading strand) is often invoked as its major cause, the precise contributions of this and other substitution types are currently unknown. It is also unclear if the underlying mutational asymmetries are the same among taxa, are stable over time, or how closely the observed biases are to mutational equilibrium. We analyzed nearly neutral sites of seven taxa each with between three and six complete bacterial genomes, and inferred the substitution spectra of fourfold degenerate positions in nonhighly expressed genes. Using a bootstrap procedure, we extracted compositional biases associated with replication and identified the significant asymmetries. Although all taxa showed an overrepresentation of G relative to C on the leading strand (and imbalances between A and T), widely variable substitution asymmetries are noted. Surprisingly, all substitution types show significant asymmetry in at least one taxon, but none were universally biased in all taxa. Notably, in the two most biased genomes, A→G, rather than C→T, shapes the compositional bias. Given the variability in these biases, we propose that the process is multifactorial. Finally, we also find that most genomes are not at compositional equilibrium, and suggest that mutational-based heterotachy is deeply imprinted in the history of biological macromolecules. This shows that similar compositional biases associated with the same essential well-conserved process, replication, do not reflect similar mutational processes in different genomes, and that caution is required in inferring the roles of specific mutational biases on the basis of contemporary patterns of sequence composition.[Supplemental material is available online at www.genome.org.]The study of genome composition made direct and important contributions to our understanding of DNA structure and evolution well before complete genome sequences were available (Chargaff 1950;Sueoka 1962). Since then, many studies have attempted to infer mutational scenarios to account for compositional deviations such as asymmetric nucleotide composition on the two strands of replication. A major difficulty arises from the fact that 12 different substitutions are possible between the four nucleotides in DNA. Because very different sets of mutations may lead to similar compositional biases, it is usually a very speculative exercise to infer the grounds of the relevant mutational asymmetries just by analyzing compositional deviations. Since many different chemical attacks and repair mechanisms affect DNA mutations (Friedberg et al. 1995), it is even more difficult to unravel the biological basis of the mutational biases. The usual processes of inference also implicitly assume that compositional deviations reflect the current mutational biases affecting genomes. However, compositional deviations accumulate through milli...

Linking the DNA strand asymmetry to the spatio-temporal replication program

“…Strand asymmetries could result from the different error spectra of the two DNA polymerases [49]. Strand asymmetry associated to replication was observed across the whole life tree: in several bacterial strains [11,12,47,48,51,52], in viruses [12,53], in yeast [54], in mitochondria [55], and in human [13,18,19,49]. Very convincing demonstrations were reported recently in human [13] and S. cerevisiae [56].…”

“…Replication could induce strand asymmetries by several means [35,36,[47][48][49]. For instance the leading strand, when it serves as a template for the lagging synthesis of the complementary strand, is transiently in ssDNA, where it could be more exposed to mutagenic lesions [35,36].…”

Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition

“…On an evolutionary time scale, strand-biased replication infidelity could influence the base composition of genomes. Strand-biased nucleotide excesses seen in bacteria, yeasts (Gierlik et al 2000;Koren et al 2010), and mammals, including humans, have been associated with transcription (Green et al 2003;Touchon et al 2003;Polak and Arndt 2008;Mugal et al 2009) and replication (Touchon et al 2005;Rocha et al 2006;Chen et al 2011). In the S. cerevisiae genome (excluding subtelomeric DNA) (Gierlik et al 2000), there are excesses of C and A in lagging-strand templates and of G and T in leading-strand templates (Agier and Fischer 2012).…”

Genome rhetoric and the emergence of compositional bias

“…Despite many proposals, no single satisfactory explanation of skews and their diversity exists (7). Bacterial codon usage also seems complicated and multifactorial; there is evidence for translational selection resulting from uneven expression of the tRNAs (8,9), optimization of tRNA pools to the existing codon usage (10,11), and evidence for the primary role of neutral mutational pressure rather than selection (12,13).…”