Abstract
We have surveyed the evolutionary trends of mammalian promoters and upstream sequences, utilising large sets of experimentally supported transcription start sites (TSSs). With 30,969 well-defined TSSs from mouse and 26,341 from human, there are sufficient numbers to draw statistically meaningful conclusions and to consider differences between promoter types. Unlike previous smaller studies, we have considered the effects of insertions, deletions, and transposable elements as well as nucleotide substitutions. The rate of promoter evolution relative to that of control sequences has not been consistent between lineages nor within lineages over time. The most pronounced manifestation of this heterotachy is the increased rate of evolution in primate promoters. This increase is seen across different classes of mutation, including substitutions and micro-indel events. We investigated the relationship between promoter and coding sequence selective constraint and suggest that they are generally uncorrelated. This analysis also identified a small number of mouse promoters associated with the immune response that are under positive selection in rodents. We demonstrate significant differences in divergence between functional promoter categories and identify a category of promoters, not associated with conventional protein-coding genes, that has the highest rates of divergence across mammals. We find that evolutionary rates vary both on a fine scale within mammalian promoters and also between different functional classes of promoters. The discovery of heterotachy in promoter evolution, in particular the accelerated evolution of primate promoters, has important implications for our understanding of human evolution and for strategies to detect primate-specific regulatory elements.
Highlights
Promoter architecture is complex in multicellular eukaryotes two key features seem to be universally shared: (i) a basal/core promoter region perhaps 100 bp upstream of the transcription start site (TSS) [1] and (ii) various widespread transcription factor binding sites (TFBSs) conferring specificity of transcription, generically referred to as enhancers
In summary, evolutionary rates vary both on a fine scale within mammalian promoters and between different functional classes of promoters
We have found evidence for increased rates of change in primate promoters relative to neutral control sequences expected to reflect the background, genomic mutation rates. This increase is seen across different classes of mutation, including substitutions and micro-indel events, and suggests distinct peculiarities in the spectrum of mutations suffered by primate promoters
Summary
Promoter architecture is complex in multicellular eukaryotes two key features seem to be universally shared: (i) a basal/core promoter region perhaps 100 bp upstream of the transcription start site (TSS) [1] and (ii) various widespread transcription factor binding sites (TFBSs) conferring specificity of transcription, generically referred to as enhancers. Cis-regulatory elements as far as ;1 Mb from the core promoter have been found [2], though the discovery and validation of regions so distant from the genes they influence presents substantial challenges. It seems that a proximal promoter region (;500 bp from the TSS) usually possesses all activity necessary to direct expression. In selected putative promoters, around a third of identified single nucleotide polymorphism variants resulted in altered expression [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
