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Genome-wide functional analysis of human 5' untranslated region introns.

Cenik C, Derti A, Mellor JC, Berriz GF, Roth FP - Genome Biol. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, 250 Longwood Avenue, SGMB-322, Boston, MA 02115, USA. cancenik@fas.harvard.edu.

ABSTRACT

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.

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The effect of 5'-proximal coding intron presence on gene expression. (a) Smoothed histogram of the mean expression level with respect to presence/absence of 5'-proximal coding region introns (5PCIs). A kernel density estimator was fitted to the expression data and the corresponding probability density is plotted as a function of the mean expression level. The black line corresponds to the probability density for transcripts without any 5'UTR introns or any 5PCIs. The red line represents the probability density for 5'UTR intronless transcripts that have 5PCIs. The vertical line represents the top 5% of mean expression level of all genes without 5'UTR introns.
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Figure 6: The effect of 5'-proximal coding intron presence on gene expression. (a) Smoothed histogram of the mean expression level with respect to presence/absence of 5'-proximal coding region introns (5PCIs). A kernel density estimator was fitted to the expression data and the corresponding probability density is plotted as a function of the mean expression level. The black line corresponds to the probability density for transcripts without any 5'UTR introns or any 5PCIs. The red line represents the probability density for 5'UTR intronless transcripts that have 5PCIs. The vertical line represents the top 5% of mean expression level of all genes without 5'UTR introns.

Mentions: To assess the possible effect of 5' proximity on gene expression, we analyzed microarray data from the human gene expression atlas for 5UI-lacking genes. We found that genes with 5PCIs were more highly expressed on average (one-sided Wilcoxon rank sum test, P = 6e-08; Figure 6). We also observed a 2.3- and 3.7-fold enrichment for genes with 5PCIs among the most highly expressed top 5% and 1% of genes, respectively (Fisher's Exact Test, P = 4e-15 and P = 4e-09, respectively; Figure 6). The correlation between high expression and 5PCI presence was evident without any consideration of these introns' lengths. In contrast, no expression difference was observed between genes with or without 5UIs, on average, but short 5UIs were highly enriched among the most highly expressed genes (Figure 2c). These results suggest that early introns (both 5PCIs and 5UIs) are associated with the most highly expressed genes, but that this correlation is limited to short introns for 5UIs.


Genome-wide functional analysis of human 5' untranslated region introns.

Cenik C, Derti A, Mellor JC, Berriz GF, Roth FP - Genome Biol. (2010)

The effect of 5'-proximal coding intron presence on gene expression. (a) Smoothed histogram of the mean expression level with respect to presence/absence of 5'-proximal coding region introns (5PCIs). A kernel density estimator was fitted to the expression data and the corresponding probability density is plotted as a function of the mean expression level. The black line corresponds to the probability density for transcripts without any 5'UTR introns or any 5PCIs. The red line represents the probability density for 5'UTR intronless transcripts that have 5PCIs. The vertical line represents the top 5% of mean expression level of all genes without 5'UTR introns.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864569&req=5

Figure 6: The effect of 5'-proximal coding intron presence on gene expression. (a) Smoothed histogram of the mean expression level with respect to presence/absence of 5'-proximal coding region introns (5PCIs). A kernel density estimator was fitted to the expression data and the corresponding probability density is plotted as a function of the mean expression level. The black line corresponds to the probability density for transcripts without any 5'UTR introns or any 5PCIs. The red line represents the probability density for 5'UTR intronless transcripts that have 5PCIs. The vertical line represents the top 5% of mean expression level of all genes without 5'UTR introns.
Mentions: To assess the possible effect of 5' proximity on gene expression, we analyzed microarray data from the human gene expression atlas for 5UI-lacking genes. We found that genes with 5PCIs were more highly expressed on average (one-sided Wilcoxon rank sum test, P = 6e-08; Figure 6). We also observed a 2.3- and 3.7-fold enrichment for genes with 5PCIs among the most highly expressed top 5% and 1% of genes, respectively (Fisher's Exact Test, P = 4e-15 and P = 4e-09, respectively; Figure 6). The correlation between high expression and 5PCI presence was evident without any consideration of these introns' lengths. In contrast, no expression difference was observed between genes with or without 5UIs, on average, but short 5UIs were highly enriched among the most highly expressed genes (Figure 2c). These results suggest that early introns (both 5PCIs and 5UIs) are associated with the most highly expressed genes, but that this correlation is limited to short introns for 5UIs.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, 250 Longwood Avenue, SGMB-322, Boston, MA 02115, USA. cancenik@fas.harvard.edu.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus