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Chursov A.,TU Munich | Frishman D.,TU Munich | Frishman D.,Helmholtz Center Munich | Shneider A.,Cure Laboratory Inc.
Nucleic Acids Research | Year: 2013

Recent reports indicate that mutations in viral genomes tend to preserve RNA secondary structure, and those mutations that disrupt secondary structural elements may reduce gene expression levels, thereby serving as a functional knockout. In this article, we explore the conservation of secondary structures of mRNA coding regions, a previously unknown factor in bacterial evolution, by comparing the structural consequences of mutations in essential and nonessential Escherichia coli genes accumulated over 40 000 generations in the course of the 'longterm evolution experiment'. We monitored the extent to which mutations influence minimum free energy (MFE) values, assuming that a substantial change inMFE is indicative of structural perturbation. Our principal finding is that purifying selection tends to eliminate those mutations in essential genes that lead to greater changes of MFE values and, therefore, may be more disruptive for the corresponding mRNA secondary structures. This effect implies that synonymous mutations disrupting mRNA secondary structuresmay directly affect the fitness of the organism. These results demonstrate that the need to maintain intact mRNA structures imposes additional evolutionary constraints on bacterial genomes, which go beyond preservation of structure and function of the encoded proteins. © 2013 The Author(s). Source


Shneider A.M.,Cure Laboratory Inc.
Trends in Biochemical Sciences | Year: 2010

Often, new discoveries are not made at the moment when all of the necessary techniques and background knowledge become available. Instead, they are delayed as a result of mental inertia unrecognized by the scientist and/or the scientific community. In this paper, I introduce and classify various types of mental inertia that are common in science, using examples from the field of biology. © 2009 Elsevier Ltd. All rights reserved. Source


Chursov A.,TU Munich | Walter M.C.,Helmholtz Center Munich | Schmidt T.,Helmholtz Center Munich | Mironov A.,Russian Academy of Sciences | And 3 more authors.
Nucleic Acids Research | Year: 2012

It is generally accepted that functionally important RNA structure is more conserved than sequence due to compensatory mutations that may alter the sequence without disrupting the structure. For small RNA molecules sequence-structure relationships are relatively well understood. However, structural bioinformatics of mRNAs is still in its infancy due to a virtual absence of experimental data. This report presents the first quantitative assessment of sequence-structure divergence in the coding regions of mRNA molecules based on recently published transcriptome-wide experimental determination of their base paring patterns. Structural resemblance in paralogous mRNA pairs quickly drops as sequence identity decreases from 100 to 85-90. Structures of mRNAs sharing sequence identity below roughly 85 are essentially uncorrelated. This outcome is in dramatic contrast to small functional non-coding RNAs where sequence and structure divergence are correlated at very low levels of sequence similarity. The fact that very similar mRNA sequences can have vastly different secondary structures may imply that the particular global shape of base paired elements in coding regions does not play a major role in modulating gene expression and translation efficiency. Apparently, the need to maintain stable three-dimensional structures of encoded proteins places a much higher evolutionary pressure on mRNA sequences than on their RNA structures. © 2011 The Author(s). Source


Chursov A.,TU Munich | Kopetzky S.J.,TU Munich | Leshchiner I.,Harvard University | Leshchiner I.,Cure Laboratory Inc. | And 5 more authors.
RNA Biology | Year: 2012

For decades, cold-adapted, temperature-sensitive (ca/ts) strains of influenza A virus have been used as live attenuated vaccines. Due to their great public health importance it is crucial to understand the molecular mechanism(s) of cold adaptation and temperature sensitivity that are currently unknown. For instance, secondary RNA structures play important roles in influenza biology. Thus, we hypothesized that a relatively minor change in temperature (32-39°C) can lead to perturbations in influenza RNA structures and, that these structural perturbations may be different for mRNAs of the wild type (wt) and ca/ts strains. To test this hypothesis, we developed a novel in silico method that enables assessing whether two related RNA molecules would undergo (dis)similar structural perturbations upon temperature change. The proposed method allows identifying those areas within an RNA chain where dissimilarities of RNA secondary structures at two different temperatures are particularly pronounced, without knowing particular RNA shapes at either temperature. We identified such areas in the NS2, PA, PB2 and NP mRNAs. However, these areas are not identical for the wt and ca/ts mutants. Differences in temperature-induced structural changes of wt and ca/ts mRNA structures may constitute a yet unappreciated molecular mechanism of the cold adaptation/temperature sensitivity phenomena. © 2012 Landes Bioscience. Source

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