Prevalent uses and evolution of exonic regulatory sequences in the human genome

Abstract

BackgroundIt has long been known that exons can be used as cis-regulatory sequences such as enhancers. However, the prevalence of such dual-use of exons and how they evolve remain elusive. Our recently predicted highly accurate, large sets of cis-regulatory module candidates (CRMCs) and non-CRMCs in the human genome positioned us to address these questions. ResultsWe found that exonic transcription factor binding sites (TFBSs) occupied at least a third of the total exon lengths, and 96.7% of genes had exonic TFBSs. Both A/T and C/G in exonic TFBSs are more likely under evolutionary constraints than those in non-CRMC exons. Interestingly, exonic TFBSs in codons tend to encode loops rather than more critical helices and strands in protein structures, while exonic TFBSs in untranslated regions (UTRs) tend to avoid positions where known UTR-related functions are located. Moreover, active exonic TFBSs tend to be in close physical proximity to distal promoters whose immediately downstream genes have elevated transcription levels, suggesting that they might be involved in transcriptional regulation of target genes. It is highly possible that less critical positions in an exon that is physically close to a promoter can evolve into a TFBS when no non-exonic sequences are physically available to the promoter. ConclusionsExonic TFBSs might be more prevalent than originally thought and are likely in dual-use. Possible detrimental effects caused by such dual-use can be reduced by using less critical exonic positions. We proposed a parsimonious model to explain how a stretch of codons evolve into a TFBS.