Journal
GENOME RESEARCH
Volume 21, Issue 11, Pages 1916-1928Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.108753.110
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Funding
- National Institutes of Health [U54 HG004555-01]
- National Science Foundation [DBI 0644282]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [0644282] Funding Source: National Science Foundation
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The degeneracy of the genetic code allows protein-coding DNA and RNA sequences to simultaneously encode additional, overlapping functional elements. A sequence in which both protein-coding and additional overlapping functions have evolved under purifying selection should show increased evolutionary conservation compared to typical protein-coding genes-especially at synonymous sites. In this study, we use genome alignments of 29 placental mammals to systematically locate short regions within human ORFs that show conspicuously low estimated rates of synonymous substitution across these species. The 29-species alignment provides statistical power to locate more than 10,000 such regions with resolution down to nine-codon windows, which are found within more than a quarter of all human protein-coding genes and contain similar to 2% of their synonymous sites. We collect numerous lines of evidence that the observed synonymous constraint in these regions reflects selection on overlapping functional elements including splicing regulatory elements, dual-coding genes, RNA secondary structures, microRNA target sites, and developmental enhancers. Our results show that overlapping functional elements are common in mammalian genes, despite the vast genomic landscape.
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