Abstract
BackgroundBidirectional promoters are shared regulatory regions that influence the expression of two oppositely oriented genes. This type of regulatory architecture is found more frequently than expected by chance in the human genome, yet many specifics underlying the regulatory design are unknown. Given that the function of most orthologous genes is similar across species, we hypothesized that the architecture and regulation of bidirectional promoters might also be similar across species, representing a core regulatory structure and enabling annotation of these regions in additional mammalian genomes.ResultsBy mapping the intergenic distances of genes in human, chimpanzee, bovine, murine, and rat, we show an enrichment for pairs of genes equal to or less than 1,000 bp between their adjacent 5' ends ("head-to-head") compared to pairs of genes that fall in the same orientation ("head-to-tail") or whose 3' ends are side-by-side ("tail-to-tail"). A representative set of 1,369 human bidirectional promoters was mapped to orthologous sequences in other mammals. We confirmed predictions for 5' UTRs in nine of ten manual picks in bovine based on comparison to the orthologous human promoter set and in six of seven predictions in human based on comparison to the bovine dataset. The two predictions that did not have orthology as bidirectional promoters in the other species resulted from unique events that initiated transcription in the opposite direction in only those species. We found evidence supporting the independent emergence of bidirectional promoters from the family of five RecQ helicase genes, which gained their bidirectional promoters and partner genes independently rather than through a duplication process. Furthermore, by expanding our comparisons from pairwise to multispecies analyses we developed a map representing a core set of bidirectional promoters in mammals.ConclusionWe show that the orthologous positions of bidirectional promoters provide a reliable guide to directly annotate over one thousand regulatory regions in sequences of mammalian genomes, while also serving as a useful tool to predict 5' UTR positions and identify genes that are novel to a single species.
Highlights
Bidirectional promoters are shared regulatory regions that influence the expression of two oppositely oriented genes
Mapping bidirectional promoters in the cow genome Bidirectional promoters were predicted in the cow genome from in silico analyses of gene order, orientation and intergenic distances, analogous to our studies in the human and mouse genomes [4,7]
Our previous studies in the human and mouse genomes identified 5,000–6,000 bidirectional promoters whose intergenic distances were limited to 1,000 bp (i.e., "high stringency") [4,9], suggesting that the number of bidirectional promoters possible in the cow genome was as high as 6,000
Summary
Bidirectional promoters are shared regulatory regions that influence the expression of two oppositely oriented genes. Given that the function of most orthologous genes is similar across species, we hypothesized that the architecture and regulation of bidirectional promoters might be similar across species, representing a core regulatory structure and enabling annotation of these regions in additional mammalian genomes. The completed sequence of numerous vertebrate genomes has enabled rapid gene annotation across species using orthologous relationships This approach is feasible because purifying selection, acting on the open reading frames of coding exons and aimed at preserving encoded protein sequences, minimizes the sequence divergence that can occur. Similarity at the nucleotide level is reflected in the likeness of structure and function of the gene products produced in different species Additional features, such as non-coding functional elements, are maintained as conserved sequences across species through the action of purifying selection [1]. Given that precise computational methods are not yet developed for predicting promoter regions in newly assembled genomes, their annotation lags behind that of coding genes and enhancers
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