Investigation on the role of nsSNPs in HNPCC genes – a bioinformatics approach

<p>Abstract</p> <p>Background</p> <p>A central focus of cancer genetics is the study of mutations that are causally implicated in tumorigenesis. The identification of such causal mutations not only provides insight into cancer biology but also presents anticancer therapeutic targets and diagnostic markers. Missense mutations are nucleotide substitutions that change an amino acid in a protein, the deleterious effects of these mutations are commonly attributed to their impact on primary amino acid sequence and protein structure.</p> <p>Methods</p> <p>The method to identify functional SNPs from a pool, containing both functional and neutral SNPs is challenging by experimental protocols. To explore possible relationships between genetic mutation and phenotypic variation, we employed different bioinformatics algorithms like Sorting Intolerant from Tolerant (SIFT), Polymorphism Phenotyping (PolyPhen), and PupaSuite to predict the impact of these amino acid substitutions on protein activity of mismatch repair (MMR) genes causing hereditary nonpolyposis colorectal cancer (HNPCC).</p> <p>Results</p> <p>SIFT classified 22 of 125 variants (18%) as 'Intolerant." PolyPhen classified 40 of 125 amino acid substitutions (32%) as "Probably or possibly damaging". The PupaSuite predicted the phenotypic effect of SNPs on the structure and function of the affected protein. Based on the PolyPhen scores and availability of three-dimensional structures, structure analysis was carried out with the major mutations that occurred in the native protein coded by <it>MSH2 and MSH6 </it>genes. The amino acid residues in the native and mutant model protein were further analyzed for solvent accessibility and secondary structure to check the stability of the proteins.</p> <p>Conclusion</p> <p>Based on this approach, we have shown that four nsSNPs, which were predicted to have functional consequences (<it>MSH2</it>-Y43C, <it>MSH6</it>-Y538S, <it>MSH6</it>-S580L, <it>and MSH6</it>-K854M), were already found to be associated with cancer risk. Our study demonstrates the presence of other deleterious mutations and also endorses with <it>in vivo </it>experimental studies.</p

In Silico profiling of deleterious amino acid substitutions of potential pathological importance in haemophlia A and haemophlia B

<p>Abstract</p> <p>Background</p> <p>In this study, instead of current biochemical methods, the effects of deleterious amino acid substitutions in <it>F8 and F9 </it>gene upon protein structure and function were assayed by means of computational methods and information from the databases. Deleterious substitutions of <it>F8 and F9 </it>are responsible for Haemophilia A and Haemophilia B which is the most common genetic disease of coagulation disorders in blood. Yet, distinguishing deleterious variants of <it>F8 and F9 </it>from the massive amount of nonfunctional variants that occur within a single genome is a significant challenge.</p> <p>Methods</p> <p>We performed an <it>in silico </it>analysis of deleterious mutations and their protein structure changes in order to analyze the correlation between mutation and disease. Deleterious nsSNPs were categorized based on empirical based and support vector machine based methods to predict the impact on protein functions. Furthermore, we modeled mutant proteins and compared them with the native protein for analysis of protein structure stability.</p> <p>Results</p> <p>Out of 510 nsSNPs in <it>F8</it>, 378 nsSNPs (74%) were predicted to be 'intolerant' by SIFT, 371 nsSNPs (73%) were predicted to be 'damaging' by PolyPhen and 445 nsSNPs (87%) as 'less stable' by I-Mutant2.0. In <it>F9</it>, 129 nsSNPs (78%) were predicted to be intolerant by SIFT, 131 nsSNPs (79%) were predicted to be damaging by PolyPhen and 150 nsSNPs (90%) as less stable by I-Mutant2.0. Overall, we found that I-Mutant which emphasizes support vector machine based method outperformed SIFT and PolyPhen in prediction of deleterious nsSNPs in both <it>F8 </it>and <it>F9</it>.</p> <p>Conclusions</p> <p>The models built in this work would be appropriate for predicting the deleterious amino acid substitutions and their functions in gene regulation which would be useful for further genotype-phenotype researches as well as the pharmacogenetics studies. These <it>in silico </it>tools, despite being helpful in providing information about the nature of mutations, may also function as a first-pass filter to determine the substitutions worth pursuing for further experimental research in other coagulation disorder causing genes.</p

Asymmetric magnetic reconnection with a flow shear and applications to the magnetopause

We perform a theoretical and numerical study of anti-parallel 2D magnetic reconnection with asymmetries in the density and reconnecting magnetic field strength in addition to a bulk flow shear across the reconnection site in the plane of the reconnecting fields, which commonly occurs at planetary magnetospheres. We predict the speed at which an isolated X-line is convected by the flow, the reconnection rate, and the critical flow speed at which reconnection no longer takes place for arbitrary reconnecting magnetic field strengths, densities, and upstream flow speeds, and confirm the results with two-fluid numerical simulations. The predictions and simulation results counter the prevailing model of reconnection at Earth's dayside magnetopause which says reconnection occurs with a stationary X-line for sub-Alfvenic magnetosheath flow, reconnection occurs but the X-line convects for magnetosheath flows between the Alfven speed and double the Alfven speed, and reconnection does not occur for magnetosheath flows greater than double the Alfven speed. We find that X-line motion is governed by momentum conservation from the upstream flows, which are weighted differently in asymmetric systems, so the X-line convects for generic conditions including sub-Alfvenic upstream speeds. For the reconnection rate, while the cutoff condition for symmetric reconnection is that the difference in flows on the two sides of the reconnection site is twice the Alfven speed, we find asymmetries cause the cutoff speed for asymmetric reconnection to be higher than twice the asymmetric form of the Alfven speed. The results compare favorably with an observation of reconnection at Earth's polar cusps during a period of northward interplanetary magnetic field, where reconnection occurs despite the magnetosheath flow speed being more than twice the magnetosheath Alfven speed, the previously proposed suppression condition.Comment: 46 pages, 7 figures, abstract abridged here, accepted to Journal of Geophysical Research - Space Physic

Anitmicrobial Effects of Chemically Modified Essential Oils

Undergraduate Basi

Particle-in-cell simulation study of the scaling of asymmetric magnetic reconnection with in-plane flow shear

We investigate magnetic reconnection in systems simultaneously containing asymmetric (anti-parallel) magnetic fields, asymmetric plasma densities and temperatures, and arbitrary in-plane bulk flow of plasma in the upstream regions. Such configurations are common in the high-latitudes of Earth's magnetopause and in tokamaks. We investigate the convection speed of the X-line, the scaling of the reconnection rate, and the condition for which the flow suppresses reconnection as a function of upstream flow speeds. We use two-dimensional particle-in-cell simulations to capture the mixing of plasma in the outflow regions better than is possible in fluid modeling. We perform simulations with asymmetric magnetic fields, simulations with asymmetric densities, and simulations with magnetopause-like parameters where both are asymmetric. For flow speeds below the predicted cutoff velocity, we find good scaling agreement with the theory presented in Doss et al., J.~Geophys.~Res., 120, 7748 (2015). Applications to planetary magnetospheres, tokamaks, and the solar wind are discussed.Comment: 17 pages, 4 figures, submitted to Physics of Plasma