Comparative genomics and mammalian promoter evolution

Although there is general agreement on the importance of regulatory changes in molecular evolution we are still in the early stages of examining the evolution of the genomic regions that are most rich in regulatory information: promoters. This review outlines strategies to combine CAGE data with other datasets to perform meta-analyses of mammalian promoter evolution. We consider the advantages of CAGE data for the identification of promoter regions and demonstrate how these regions can be used to investigate the spatial distribution of constraints within promoters as well as differences in the pattern of constraint between promoter functional classes (CpG island containing, TATA box containing etc). Comparative genomics together with CAGE derived promoter regions have also allowed important insights into the complex evolutionary dynamics of promoters across mammalian orders. All measurable rates of evolutionary divergence have been shown to vary, both between functional classes of promoters and between different lineages. The most dramatic differences are found between the primate lineage and other non-primate mammals, with a pronounced acceleration in primates now reported by several groups. The causes of such differences remain unknown, but positive selection of favourable variants, elevated mutation rates and disrupted purifying selection mediated by low population sizes have all been suggested as possible explanations. Comparative genomics alone cannot determine the relative importance of each of these causes, however recent additional datasets may allow us to address this question.