Genome-wide functional analysis of human 5′ untranslated region introns

Background: Approximately 35% of human genes contain introns within the 5'untranslated region (UTR). Introns in 5'UTRs differ from those in coding regions and 3'UTRs with respect to nucleotide composition, length distribution and density. Despite their presumed impact on gene regulation, the evolution and possible functions of 5'UTR introns remain largely unexplored. Results: We performed a genome-scale computational analysis of 5'UTR introns in humans. We discovered that the most highly expressed genes tended to have short 5'UTR introns rather than having long 5'UTR introns or lacking 5'UTR introns entirely. Although we found no correlation in 5'UTR intron presence or length with variance in expression across tissues, which might have indicated a broad role in expression-regulation, we observed an uneven distribution of 5'UTR introns amongst genes in specific functional categories. In particular, genes with regulatory roles were surprisingly enriched in having 5'UTR introns. Finally, we analyzed the evolution of 5'UTR introns in non-receptor protein tyrosine kinases (NRTK), and identified a conserved DNA motif enriched within the 5'UTR introns of human NRTKs. Conclusions: Our results suggest that human 5'UTR introns enhance the expression of some genes in a length-dependent manner. While many 5'UTR introns are likely to be evolving neutrally, their relationship with gene expression and overrepresentation among regulatory genes, taken together, suggest that complex evolutionary forces are acting on this distinct class of introns.