EVOLUTION
RNA landscape of evolution for optimal exon and intron discrimination
*Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724;
Department of Biomedical Engineering, State University of New York, Stony Brook, NY 11794; and
Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637
Contributed by Wen-Hsiung Li, February 20, 2008 (sent for review January 8, 2008)
Abstract
Accurate pre-mRNA splicing requires primary splicing signals, including the splice sites, a polypyrimidine tract, and a branch site, other splicing-regulatory elements (SREs). The SREs include exonic splicing enhancers (ESEs), exonic splicing silencers (ESSs), intronic splicing enhancers (ISEs), and intronic splicing silencers (ISSs), which are typically located near the splice sites. However, it is unclear to what extent splicing-driven selective pressure constrains exonic and intronic sequences, especially those distant from the splice sites. Here, we studied the distribution of SREs in human genes in terms of DNA strand-asymmetry patterns. Under a neutral evolution model, each mononucleotide or oligonucleotide should have a symmetric (Chargaff's second parity rule), or weakly asymmetric yet uniform, distribution throughout a pre-mRNA transcript. However, we found that large sets of unbiased, experimentally determined SREs show a distinct strand-asymmetry pattern that is inconsistent with the neutral evolution model, and reflects their functional roles in splicing. ESEs are selected in exons and depleted in introns and vice versa for ESSs. Surprisingly, this trend extends into deep intronic sequences, accounting for one third of the genome. Selection is detectable even at the mononucleotide level, so that the asymmetric base compositions of exons and introns are predictive of ESEs and ESSs. We developed a method that effectively predicts SREs based on strand asymmetry, expanding the current catalog of SREs. Our results suggest that human genes have been optimized for exon and intron discrimination through an RNA landscape shaped during evolution.
DNA strand asymmetry | exon and intron recognition | exon identity elements | intron identity elements | splicing-regulatory elements
Author contributions: C.Z. and M.Q.Z. designed research; C.Z. performed research; C.Z., W.-H.L., A.R.K. and M.Q.Z. analyzed data; and C.Z., W.-H.L., A.R.K., and M.Q.Z. wrote the paper.
The authors declare no conflict of interest.
To whom correspondence should be addressed. E-mail: mzhang{at}cshl.edu
© 2008 by The National Academy of Sciences of the USA
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