902 research outputs found
Ebolavirus is evolving but not changing: No evidence for functional change in EBOV from 1976 to the 2014 outbreak
The 2014 epidemic of Ebola virus disease (EVD) has had a devastating impact in West Africa. Sequencing of ebolavirus (EBOV) from infected individuals has revealed extensive genetic variation, leading to speculation that the virus may be adapting to humans, accounting for the scale of the 2014 outbreak. We computationally analyze the variation associated with all EVD outbreaks, and find none of the amino acid replacements lead to identifiable functional changes. These changes have minimal effect on protein structure, being neither stabilizing nor destabilizing, are not found in regions of the proteins associated with known functions and tend to cluster in poorly constrained regions of proteins, specifically intrinsically disordered regions. We find no evidence that the difference between the current and previous outbreaks is due to evolutionary changes associated with transmission to humans. Instead, epidemiological factors are likely to be responsible for the unprecedented spread of EVD
Adaptive HIV-1 evolutionary trajectories are constrained by protein stability
Despite the use of combination antiretroviral drugs for the treatment of HIV-1 infection, the emergence of drug resistance remains a problem. Resistance may be conferred either by a single mutation or a concerted set of mutations. The involvement of multiple mutations can arise due to interactions between sites in the amino acid sequence as a consequence of the need to maintain protein structure. To better understand the nature of such epistatic interactions, we reconstructed the ancestral sequences of HIV-1's Pol protein, and traced the evolutionary trajectories leading to mutations associated with drug resistance. Using contemporary and ancestral sequences we modelled the effects of mutations (i.e. amino acid replacements) on protein structure to understand the functional effects of residue changes. Although the majority of resistance-associated sequences tend to destabilise the protein structure, we find there is a general tendency for protein stability to decrease across HIV-1's evolutionary history. That a similar pattern is observed in the non-drug resistance lineages indicates that non-resistant mutations, for example, associated with escape from the immune response, also impacts on protein stability. Maintenance of optimal protein structure therefore represents a major constraining factor to the evolution of HIV-1
Artefacts and biases affecting the evaluation of scoring functions on decoy sets for protein structure prediction
Motivation: Decoy datasets, consisting of a solved protein structure and numerous alternative native-like structures, are in common use for the evaluation of scoring functions in protein structure prediction. Several pitfalls with the use of these datasets have been identified in the literature, as well as useful guidelines for generating more effective decoy datasets. We contribute to this ongoing discussion an empirical assessment of several decoy datasets commonly used in experimental studies
Real-Time Quantitative Bronchoscopy
The determination of motion within a sequence of images remains one of the fundamental problems in computer vision after more than 30 years of research. Despite this work, there have been relatively few applications of these techniques to practical problems outside the fields of robotics and video encoding. In this paper, we present the continuing work to apply optical flow and egomotion recovery to the problem of measuring and navigating through the airway using a bronchoscope during a standard procedure, without the need for any additional data, localization systems or other external components. The current implementation uses a number of techniques to provide a range of numerical measurements and estimations to physicians in real time, using standard computer hardware
Sequencing and characterisation of rearrangements in three S. pastorianus strains reveals the presence of chimeric genes and gives evidence of breakpoint reuse
Gross chromosomal rearrangements have the potential to be evolutionarily
advantageous to an adapting organism. The generation of a hybrid species
increases opportunity for recombination by bringing together two homologous
genomes. We sought to define the location of genomic rearrangements in three
strains of Saccharomyces pastorianus, a natural lager-brewing yeast hybrid of
Saccharomyces cerevisiae and Saccharomyces eubayanus, using whole genome
shotgun sequencing. Each strain of S. pastorianus has lost species-specific
portions of its genome and has undergone extensive recombination, producing
chimeric chromosomes. We predicted 30 breakpoints that we confirmed at the
single nucleotide level by designing species-specific primers that flank each
breakpoint, and then sequencing the PCR product. These rearrangements are the
result of recombination between areas of homology between the two subgenomes,
rather than repetitive elements such as transposons or tRNAs. Interestingly,
28/30 S. cerevisiae- S. eubayanus recombination breakpoints are located within
genic regions, generating chimeric genes. Furthermore we show evidence for the
reuse of two breakpoints, located in HSP82 and KEM1, in strains of proposed
independent origin
Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation
Small-probe contact dot surface analysis, with all explicit hydrogen atoms added and their van der Waals contacts included, was used to choose between the two possible orientations for each of 1554 asparagine (Asn) and glutamine (Gln) side-chain amide groups in a dataset of 100 unrelated, high-quality protein crystal structures at 0.9 to 1.7 AÊ resolution. For the movable-H groups, each connected, closed set of local H-bonds was optimized for both H-bonds and van der Waals overlaps. In addition to the Asn/Gln ``¯ips'', this process included rotation of OH, SH, NH 3, and methionine methyl H atoms, ¯ip and protonation state of histidine rings, interaction with bound ligands, and a simple model of water interactions. However, except for switching N and O identity for amide ¯ips (or N and C identity for His ¯ips), no non-H atoms were shifted. Even in these very high-quality structures, about 20 % of the Asn/Gln side-chains required a 180 ¯ip to optimize H-bonding and/o
Protein Interactions from Complexes: A Structural Perspective
By combining crystallographic information with protein-interaction data obtained through traditional experimental means, this paper determines the most appropriate method for generating protein-interaction networks that incorporate data derived from protein complexes. We propose that a combined method should be considered; in which complexes composed of five chains or less are decomposed using the matrix model, whereas the spoke model is used to derive pairwise interactions for those with six chains or more. The results presented here should improve the accuracy and relevance of studies investigating the topology of protein-interaction networks
Correlation of microsynteny conservation and disease gene distribution in mammalian genomes
<p>Abstract</p> <p>Background</p> <p>With the completion of the whole genome sequence for many organisms, investigations into genomic structure have revealed that gene distribution is variable, and that genes with similar function or expression are located within clusters. This clustering suggests that there are evolutionary constraints that determine genome architecture. However, as most of the evidence for constraints on genome evolution comes from studies on yeast, it is unclear how much of this prior work can be extrapolated to mammalian genomes. Therefore, in this work we wished to examine the constraints on regions of the mammalian genome containing conserved gene clusters.</p> <p>Results</p> <p>We first identified regions of the mouse genome with microsynteny conservation by comparing gene arrangement in the mouse genome to the human, rat, and dog genomes. We then asked if any particular gene types were found preferentially in conserved regions. We found a significant correlation between conserved microsynteny and the density of mouse orthologs of human disease genes, suggesting that disease genes are clustered in genomic regions of increased microsynteny conservation.</p> <p>Conclusion</p> <p>The correlation between microsynteny conservation and disease gene locations indicates that regions of the mouse genome with microsynteny conservation may contain undiscovered human disease genes. This study not only demonstrates that gene function constrains mammalian genome organization, but also identifies regions of the mouse genome that can be experimentally examined to produce mouse models of human disease.</p
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