Repetitive DNA, genome evolution, and the adaptive evolution of mutation rates.

摘要

Tandemly repetitive DNAs of all motif lengths exhibit unique evolutionary properties that are not shared by nonrepetitive sequences. These include hypermutability and a unique mutational spectrum that favors insertions and deletions of single repeat motif units. Microsatellites (repeats with short motifs) are the most common type of tandem repeat, allowing high-resolution statistical analyses of their distributions. Although they have found their primary use as markers in population genetics (a use which, notably, requires the assumption of neutrality), they have also gained recent notoriety as both sources of human genetic disease and as mutational switches which allow pathogens to rapidly adapt to immune attacks (both situations deriving from distinctly nonneutral effects). My thesis represents an in-depth exploration of the forces which control the evolution of repetitive DNA, and hence control the divergence of microsatellite distributions and functionalities between different groups of organisms.; Many of my studies have involved identifying microsatellite sequences from genetic databases, designing primers to amplify them, and using comparative DNA sequencing to analyze their variability in natural populations. With this technique, I have demonstrated microsatellite hypervariability in the yeast Candida albicans, the eubacteria Escherichia coli and Mycoplasma gallisepticum, and human cytomegalovirus. I have also used computational bioinformatic techniques to compare microsatellite distributions in lower eukaryotes (Saccaromyces cerevisiae and Schizosaccharomyces pombe) and higher eukaryotes (primates, plants, fruit flies, nematodes and mice). This analysis demonstrated that in the majority of cases microsatellite mutations escape the eye of selection, and hence most repetitive DNA evolves primarily under the influence of mutation pressure. Within coding regions, however, selection appears to act very strongly against the products of specific types of microsatellite mutations. In two review articles, I have clarified the evolutionary implications of the functionally hypermutable microsatellites found in pathogens, a system which reveals the adaptive evolution of the process of mutation itself. Finally, I have shown that the small size and nonrepetitive nature of prokaryotic genomes is likely to be the result of a genome-wide bias toward deletion mutations. This deletion bias may represent one of a growing number of examples of selection-driven evolution of mutation rates.