Substitutions Are Boring: Some Arguments about Parallel Mutations and High Mutation Rates.

Extant genomes are largely shaped by global transposition, copy-number fluctuation, and rearrangement of DNA sequences rather than by substitutions of single nucleotides. Although many of these large-scale mutations have low probabilities and are unlikely to repeat, others are recurrent or predictable in their effects, leading to stereotyped genome architectures and genetic variation in both eukaryotes and prokaryotes. Such recurrent, parallel mutation modes can profoundly shape the paths taken by evolution and undermine common models of evolutionary genetics. Similar patterns are also evident at the smaller scales of individual genes or short sequences. The scale and extent of this 'non-substitution' variation has recently come into focus through the advent of new genomic technologies; however, it is still not widely considered in genotype-phenotype association studies. In this review we identify common features of these disparate mutational phenomena and comment on the importance and interpretation of these mutational patterns.