Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes
- Michael F. Lin1,2,
- Pouya Kheradpour1,2,
- Stefan Washietl2,
- Brian J. Parker3,
- Jakob S. Pedersen3,5 and
- Manolis Kellis1,2,4,6
- 1Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 2Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark;
- 4The Broad Institute, Cambridge, Massachusetts 02139, USA
Abstract
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 ∼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.
Footnotes
-
↵6 Corresponding author.
E-mail manoli{at}mit.edu.
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.108753.110.
- Received April 5, 2010.
- Accepted June 15, 2010.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
Freely available online through the Genome Research Open Access option.
