Abstract
BackgroundGenomes of higher eukaryotes have surprisingly long first introns and in some cases, the first introns have been shown to have higher conservation relative to other introns. However, the functional relevance of conserved regions in the first introns is poorly understood. Leveraging the recent ENCODE data, here we assess potential regulatory roles of conserved regions in the first intron of human genes.ResultsWe first show that relative to other downstream introns, the first introns are enriched for blocks of highly conserved sequences. We also found that the first introns are enriched for several chromatin marks indicative of active regulatory regions and this enrichment of regulatory marks is correlated with enrichment of conserved blocks in the first intron; the enrichments of conservation and regulatory marks in first intron are not entirely explained by a general, albeit variable, bias for certain marks toward the 5’ end of introns. Interestingly, conservation as well as proportions of active regulatory chromatin marks in the first intron of a gene correlates positively with the numbers of exons in the gene but the correlation is significantly weakened in second introns and negligible beyond the second intron. The first intron conservation is also positively correlated with the gene’s expression level in several human tissues. Finally, a gene-wise analysis shows significant enrichments of active chromatin marks in conserved regions of first introns, relative to the conserved regions in other introns of the same gene.ConclusionsTaken together, our analyses strongly suggest that first introns are enriched for active transcriptional regulatory signals under purifying selection.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-526) contains supplementary material, which is available to authorized users.
Highlights
Genomes of higher eukaryotes have surprisingly long first introns and in some cases, the first introns have been shown to have higher conservation relative to other introns
Our conclusions hold for all choices of alignment and threshold; here we only present the results based on mammalian conservation with PhastCons score threshold of 0.5
In our gene-specific analysis of enrichment of various regulatory signals in the conserved portion of the first intron, we found that in first introns, the conserved regions are favored by DNase I hypersensitivity sites (DHS), Transcription factor binding sites (TFBSs) binding, and H3K4me3, which suggests that the conserved region may have a role in active gene regulation
Summary
Genomes of higher eukaryotes have surprisingly long first introns and in some cases, the first introns have been shown to have higher conservation relative to other introns. It was shown that intronic sequences evolve faster than fourfold degenerate sites when splicing regulatory sequences were excluded [22]. These discrepancies can be partly ascribed to biases in the data sets with different ranges of lengths of introns studied [27]. Besides their obvious role in isoform regulation, introns have been shown to harbor regulatory signals and noncoding genes [30,31,32,33]. Overall, it is highly likely that portions of intronic sequences are evolving under selective constraints consistent with their functional importance
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