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      Multiple roles of the coding sequence 5′ end in gene expression regulation

      research-article

      1 , 2 , * , 1

      Nucleic Acids Research

      Oxford University Press

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          Abstract

          The codon composition of the coding sequence's (ORF) 5′ end first few dozen codons is known to be distinct to that of the rest of the ORF. Various explanations for the unusual codon distribution in this region have been proposed in recent years, and include, among others, novel regulatory mechanisms of translation initiation and elongation. However, due to the fact that many overlapping regulatory signals are suggested to be associated with this relatively short region, its research is challenging. Here, we review the currently known signals that appear in this region, the theories related to the way they regulate translation and affect the organismal fitness, and the debates they provoke.

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          Most cited references 87

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          The origins of genome complexity.

          Complete genomic sequences from diverse phylogenetic lineages reveal notable increases in genome complexity from prokaryotes to multicellular eukaryotes. The changes include gradual increases in gene number, resulting from the retention of duplicate genes, and more abrupt increases in the abundance of spliceosomal introns and mobile genetic elements. We argue that many of these modifications emerged passively in response to the long-term population-size reductions that accompanied increases in organism size. According to this model, much of the restructuring of eukaryotic genomes was initiated by nonadaptive processes, and this in turn provided novel substrates for the secondary evolution of phenotypic complexity by natural selection. The enormous long-term effective population sizes of prokaryotes may impose a substantial barrier to the evolution of complex genomes and morphologies.
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            Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution.

            Strikingly consistent correlations between rates of coding-sequence evolution and gene expression levels are apparent across taxa, but the biological causes behind the selective pressures on coding-sequence evolution remain controversial. Here, we demonstrate conserved patterns of simple covariation between sequence evolution, codon usage, and mRNA level in E. coli, yeast, worm, fly, mouse, and human that suggest that all observed trends stem largely from a unified underlying selective pressure. In metazoans, these trends are strongest in tissues composed of neurons, whose structure and lifetime confer extreme sensitivity to protein misfolding. We propose, and demonstrate using a molecular-level evolutionary simulation, that selection against toxicity of misfolded proteins generated by ribosome errors suffices to create all of the observed covariation. The mechanistic model of molecular evolution that emerges yields testable biochemical predictions, calls into question the use of nonsynonymous-to-synonymous substitution ratios (Ka/Ks) to detect functional selection, and suggests how mistranslation may contribute to neurodegenerative disease.
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              Evolution and tinkering.

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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                09 January 2015
                12 December 2014
                12 December 2014
                : 43
                : 1
                : 13-28
                Affiliations
                [1 ]Department of Biomedical Engineering, the Engineering Faculty, Tel Aviv University, Tel Aviv, Israel
                [2 ]The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +972 3 6405836; Fax: +972 3 6405836; Email: tamirtul@ 123456post.tau.ac.il
                Article
                10.1093/nar/gku1313
                4288200
                25505165
                0da6fee8-5eed-4879-bee8-63e819fdb805
                © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 16
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                January 2015

                Genetics

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