How homologous recombination generates a mutable genome
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How homologous recombination generates a mutable genome Matthew Hurles* Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK *Correspondence to: Tel: +44 (0)1223 495377; Fax. +44 (0)1223 494919; E-mail: [email protected] Date received (in revised form): 7th July 2005
Abstract Recombination and mutation have traditionally been regarded as independent evolutionary processes: the latter generates variation, which the former reshuffles. Recent studies, however, have suggested that allelic recombination influences the underlying mutation rate, as high mutation rates are inferred in regions of high recombination. Furthermore, recombination between duplicated sequences introduces structural variation into the human genome and facilitates the formation of clustered gene families. Comparisons of wholegenome sequences reveal the expansion of gene family clusters to be an important mode of genome evolution. The negative aspect of this genomic dynamism is the contribution of these rearrangements to genetic diseases. Keywords: homologous recombination, gene conversion, rearrangement
Introduction Homologous recombination (HR) is one of the fundamental mechanisms of DNA processing which, in various guises, is found in all phyla of life.1,2 HR is capable of playing several distinct roles within an individual organism. In sexually reproducing species, meiotic HR is a carefully regulated process that occurs at a defined stage of differentiation in specific cell types. By contrast, in the same species, HR also operates as a major mechanism of DNA repair in all cell types at all times. HR has been clearly co-opted for different functions throughout its deep evolutionary history. Similarly, HR has been exploited as a laboratory tool for, among other applications, genetic engineering in model organisms.3 The role of HR in DNA repair,4 somatic mutation5 and chromosomal engineering has been reviewed elsewhere; this paper will focus on meiotic HR and the recent studies demonstrating its impact on the mutability of mammalian genomes. Evolutionary geneticists have traditionally regarded mutation and recombination (along with selection and genetic drift) as relatively independent ‘forces of evolution’: while the former generates variation, the latter reshuffles existing variation into novel combinations. These ideas were formulated before DNA was identified as the molecule of inheritance,6 – 8 however, and well before any understanding two of the molecular mechanisms of mutation was gained. Recent comparative analyses of whole-genome sequences9 – 12 give a deeper appreciation of the distinct mutational mechanisms
operating to shape genomes over evolutionary timescales. The mutability of any genome can be considered to be the summation of the effects of the distinct mutational mechanisms that operate in that genome. These impacts can be quantified in terms of the rate of each mutational mechanism, the number of bases involved in the resultant mutation and the number of susceptible sites within the genome. Fi
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