Finding exonic islands in a sea of non-coding sequence: splicing related constraints on protein composition and evolution are common in intron-rich genomes

Biased usage of amino acids near exon-intron boundaries is phylogenetically widespread and characteristic of species for which there are expected to be problems defining exons

Splicing and the Evolution of Proteins in Mammals

It is often supposed that a protein's rate of evolution and its amino acid content are determined by the function and anatomy of the protein. Here we examine an alternative possibility, namely that the requirement to specify in the unprocessed RNA, in the vicinity of intron–exon boundaries, information necessary for removal of introns (e.g., exonic splice enhancers) affects both amino acid usage and rates of protein evolution. We find that the majority of amino acids show skewed usage near intron–exon boundaries, and that differences in the trends for the 2-fold and 4-fold blocks of both arginine and leucine show this to be owing to effects mediated at the nucleotide level. More specifically, there is a robust relationship between the extent to which an amino acid is preferred/avoided near boundaries and its enrichment/paucity in splice enhancers. As might then be expected, the rate of evolution is lowest near intron–exon boundaries, at least in part owing to splice enhancers, such that domains flanking intron–exon junctions evolve on average at under half the rate of exon centres from the same gene. In contrast, the rate of evolution of intronless retrogenes is highest near the domains where intron–exon junctions previously resided. The proportion of sequence near intron–exon boundaries is one of the stronger predictors of a protein's rate of evolution in mammals yet described. We conclude that after intron insertion selection favours modification of amino acid content near intron–exon junctions, so as to enable efficient intron removal, these changes then being subject to strong purifying selection even if nonoptimal for protein function. Thus there exists a strong force operating on protein evolution in mammals that is not explained directly in terms of the biology of the protein

Clustering of Codons with Rare Cognate tRNAs in Human Genes Suggests an Extra Level of Expression Regulation

In species with large effective population sizes, highly expressed genes tend to be encoded by codons with highly abundant cognate tRNAs to maximize translation rate. However, there has been little evidence for a similar bias of synonymous codons in highly expressed human genes. Here, we ask instead whether there is evidence for the selection for codons associated with low abundance tRNAs. Rather than averaging the codon usage of complete genes, we scan the genes for windows with deviating codon usage. We show that there is a significant over representation of human genes that contain clusters of codons with low abundance cognate tRNAs. We name these regions, which on average have a 50% reduction in the amount of cognate tRNA available compared to the remainder of the gene, RTS (rare tRNA score) clusters. We observed a significant reduction in the substitution rate between the human RTS clusters and their orthologous chimp sequence, when compared to non–RTS cluster sequences. Overall, the genes with an RTS cluster have higher tissue specificity than the non–RTS cluster genes. Furthermore, these genes are functionally enriched for transcription regulation. As genes that regulate transcription in lower eukaryotes are known to be involved in translation on demand, this suggests that the mechanism of translation level expression regulation also exists within the human genome

The fitness cost of mis-splicing is the main determinant of alternative splicing patterns

Background Most eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of protein variants or to the regulation of gene expression via nonsense-mediated messenger RNA (mRNA) decay (NMD). However, a fraction of splice variants might correspond to spurious transcripts and the question of the relative proportion of splicing errors to functional splice variants remains highly debated. Results We propose a test to quantify the fraction of AS events corresponding to errors. This test is based on the fact that the fitness cost of splicing errors increases with the number of introns in a gene and with expression level. We analyzed the transcriptome of the intron-rich eukaryote Paramecium tetraurelia. We show that in both normal and in NMD-deficient cells, AS rates strongly decrease with increasing expression level and with increasing number of introns. This relationship is observed for AS events that are detectable by NMD as well as for those that are not, which invalidates the hypothesis of a link with the regulation of gene expression. Our results show that in genes with a median expression level, 92–98% of observed splice variants correspond to errors. We observed the same patterns in human transcriptomes and we further show that AS rates correlate with the fitness cost of splicing errors. Conclusions These observations indicate that genes under weaker selective pressure accumulate more maladaptive substitutions and are more prone to splicing errors. Thus, to a large extent, patterns of gene expression variants simply reflect the balance between selection, mutation, and drift

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011

Nature and diversity of amino acid abundance trends near exon-intron boundaries

Relative abundance of glutamine (Q), methionine (M), and lysine (K) as a function of distance from the boundary across 5' ends of exons is shown. Glutamine is significantly avoided near the boundary (rho = 0.86, < 1.84E-7), lysine is preferred (rho = -0.65, < 6.2E-5), whilst no significant trend is evident for methionine (rho = 0.096, = 0.59). Note that a negative slope/rho value indicates a preference near the exon-intron boundary. Typically, where patterns of preference/avoidance are evident, we observe quasi-monotonic decreases/increases in relative abundance across the sequence range analyzed.<p><b>Copyright information:</b></p><p>Taken from "Finding exonic islands in a sea of non-coding sequence: splicing related constraints on protein composition and evolution are common in intron-rich genomes"</p><p>http://genomebiology.com/2008/9/2/R29</p><p>Genome Biology 2008;9(2):R29-R29.</p><p>Published online 7 Feb 2008</p><p>PMCID:PMC2374712.</p><p></p

Frequency of nonsynonymous change as a function of distance from the exon-intron boundary

Amino acids are significantly more likely to be conserved near the exon-intron boundary comparing -(5', rho = 0.957, = 0; 3', rho = 0.96. = 0; N = 19,347 exons) and -(5', rho = 0.87, = 1.02E-07; 3', rho = 0.95, = 0; N = 7,545 exons). The trends appear approximately monotonous and linear. Location-dependent conservation levels also appear slightly higher near the boundary comparing -but this is not significant (5', rho = 0.11, = 0.55, N = 51; 3', rho = 0.11, = 0.55, N = 39; pooled 3'/5', rho = 0.12, = 0.51, N = 90) or of comparable monotony (but see Additional data file 9).<p><b>Copyright information:</b></p><p>Taken from "Finding exonic islands in a sea of non-coding sequence: splicing related constraints on protein composition and evolution are common in intron-rich genomes"</p><p>http://genomebiology.com/2008/9/2/R29</p><p>Genome Biology 2008;9(2):R29-R29.</p><p>Published online 7 Feb 2008</p><p>PMCID:PMC2374712.</p><p></p

Relative amino acid abundance of lysine (K) at 5' ends of exons in six species

Proportional usage of lysine all other amino acids is plotted against distance from the exon-intron boundary measured in amino acids. Variable degrees of preference for lysine near the boundary are evident for non-nematode species (Am, rho = -0.67, = 2.71E-05, β(slope) = -0.017; Dr, rho = -0.79, = 6.51E-07, β = -0.035; Dm, rho = -0.65, = 6.11E-05, β = -0.020; Hs, rho = -0.90, = 3.67E-09, β = -0.041) whereas nematodes show strong avoidance trends (Ce, rho = 0.89, = 5.26E-08, β = 0.030; Cb, rho = 0.92, = 0, β = 0.033).<p><b>Copyright information:</b></p><p>Taken from "Finding exonic islands in a sea of non-coding sequence: splicing related constraints on protein composition and evolution are common in intron-rich genomes"</p><p>http://genomebiology.com/2008/9/2/R29</p><p>Genome Biology 2008;9(2):R29-R29.</p><p>Published online 7 Feb 2008</p><p>PMCID:PMC2374712.</p><p></p

The rate of nonsynonymous evolution correlates negatively with the proportion of boundary-proximal sequence

is plotted as a function of the proportion of coding sequence located within 70 bp of an exon-intron boundary for orthologous genes (rho = -0.26, = 2.2E-16, N = 4,132) and -orthologous genes (rho = -0.08, = 6.18E-09, N = 5,248). The data have been divided into bins along regular decimal intervals (0.1, 0.2, and so on) and the mean within each bin plotted against the mean proportion of sequence near the boundary. The last (a) and first (b) three bins, respectively, have been pooled to obtain approximately equal bin sizes. Negative trends are present for both sets of aligned genes, but a departure from the general trend is evident for nematode genes with a low proportion of boundary-proximal sequence.<p><b>Copyright information:</b></p><p>Taken from "Finding exonic islands in a sea of non-coding sequence: splicing related constraints on protein composition and evolution are common in intron-rich genomes"</p><p>http://genomebiology.com/2008/9/2/R29</p><p>Genome Biology 2008;9(2):R29-R29.</p><p>Published online 7 Feb 2008</p><p>PMCID:PMC2374712.</p><p></p