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Hicks S.,Rice University | Wheeler D.A.,Human Genome Sequencing Center | Plon S.E.,Human Genome Sequencing Center | Plon S.E.,Baylor College of Medicine | Kimmel M.,Rice University
Human Mutation | Year: 2011

Multiple algorithms are used to predict the impact of missense mutations on protein structure and function using algorithm-generated sequence alignments or manually curated alignments. We compared the accuracy with native alignment of SIFT, Align-GVGD, PolyPhen-2, and Xvar when generating functionality predictions of well-characterized missense mutations (n = 267) within the BRCA1, MSH2, MLH1, and TP53 genes. We also evaluated the impact of the alignment employed on predictions from these algorithms (except Xvar) when supplied the same four alignments including alignments automatically generated by (1) SIFT, (2) Polyphen-2, (3) Uniprot, and (4) a manually curated alignment tuned for Align-GVGD. Alignments differ in sequence composition and evolutionary depth. Data-based receiver operating characteristic curves employing the native alignment for each algorithm result in area under the curve of 78-79% for all four algorithms. Predictions from the PolyPhen-2 algorithm were least dependent on the alignment employed. In contrast, Align-GVGD predicts all variants neutral when provided alignments with a large number of sequences. Of note, algorithms make different predictions of variants even when provided the same alignment and do not necessarily perform best using their own alignment. Thus, researchers should consider optimizing both the algorithm and sequence alignment employed in missense prediction. © 2011 Wiley-Liss, Inc. Source


News Article | August 15, 2016
Site: http://www.techtimes.com/rss/sections/earth.xml

The genome of a very hungry and "gluttonous" caterpillar known as the tobacco hornworm has been successfully sequenced by a team of international scientists. The Kansas State University-led research team has made the details of their genome sequence study available to the public in the hopes of opening up new research. "This project represents years of collaborative research across the world," says Professor Michael Kanost, a biochemistry expert from Kansas State and lead author of the genome study. The tobacco hornworm (Manduca sexta) earned the moniker "gluttonous caterpillar" because it eats so much before growing into the Carolina sphinx moth. The name Manduca means "glutton" in Latin. This hungry caterpillar, which is often found in the North, South and Central America, is considered a pest to gardeners. The insect chows on the leaves of tomato plants, and also feasts on eggplants, potato and pepper plants, scientists said. Weeds and crops from this plant family produce chemicals that prevent most insects from feeding on them, but not the tobacco hornworm. Scientists have become particularly interested on the caterpillar because of its physiology. Professor Kanost has been studying the tobacco hornworm for decades. He and study co-author Gary Blissard of Cornell University decided to start the collaborative research to sequence the tobacco hornworm's genome about seven years ago. The tobacco hornworm is a good model species to study because of its large size, which can stretch up to 4 inches (10 centimeters) long. This allows scientists to easily gather tissue samples from the caterpillar. The new research looks into the proteins in the caterpillar's blood and how these insects protect themselves against infections. Kanost and his team purified the DNA of the caterpillar and sent samples to the Baylor College of Medicine Human Genome Sequencing Center for the genome sequencing. According to Kanost, some of the same kind of proteins are present in both caterpillar and human blood. What's more, these proteins possess the same kind of functions in the immune system. Kanost says that by sequencing and studying the genome of the tobacco hornworm, scientists can compare the similarities and differences between humans and caterpillars in the evolution and function of immunity. Furthermore, the new study may also lead to the development of new methods for insect pest management, as well as the improvement of physiology, neurobiology and molecular biology research. Meanwhile, now that the genome of the tobacco hornworm is sequenced, Kanost and his colleagues can use proteomics — the study of proteins — to identify proteins in the blood and tissues of the caterpillar. Scientists can use the sequenced genome to make insect proteins for biochemical studies. Details of the new report are published in the journal Insect Biochemistry and Molecular Biology. © 2016 Tech Times, All rights reserved. Do not reproduce without permission.


Gardner A.F.,New England Biolabs | Wang J.,LaserGen | Wu W.,LaserGen | Karouby J.,New England Biolabs | And 7 more authors.
Nucleic Acids Research | Year: 2012

Recent developments of unique nucleotide probes have expanded our understanding of DNA polymerase function, providing many benefits to techniques involving next-generation sequencing (NGS) technologies. The cyclic reversible termination (CRT) method depends on efficient base-selective incorporation of reversible terminators by DNA polymerases. Most terminators are designed with 3'-O-blocking groups but are incorporated with low efficiency and fidelity. We have developed a novel class of 3'-OH unblocked nucleotides, called Lightning Terminators ™, which have a terminating 2-nitrobenzyl moiety attached to hydroxymethylated nucleobases. A key structural feature of this photocleavable group displays a 'molecular tuning' effect with respect to single-base termination and improved nucleotide fidelity. Using Therminator ™ DNA polymerase, we demonstrate that these 3'-OH unblocked terminators exhibit superior enzymatic performance compared to two other reversible terminators, 3'-O-amino-TTP and 3'-O-azidomethyl-TTP. Lightning Terminators ™ show maximum incorporation rates (k pol) that range from 35 to 45 nt/s, comparable to the fastest NGS chemistries, yet with catalytic efficiencies (k pol/KD) comparable to natural nucleotides. Pre-steady-state kinetic studies of thymidine analogs revealed that the major determinant for improved nucleotide selectivity is a significant reduction in k pol by >1000-fold over TTP misincorporation. These studies highlight the importance of structure-function relationships of modified nucleotides in dictating polymerase performance. © The Author(s) 2012. Source


Biesecker L.G.,National Human Genome Research Institute | Burke W.,University of Washington | Kohane I.,Boston Childrens Hospital | Plon S.E.,Human Genome Sequencing Center | Zimmern R.,PHG Foundation
Nature Reviews Genetics | Year: 2012

We are entering an era in which the cost of clinical whole-genome and targeted sequencing tests is no longer prohibitive to their application. However, currently the infrastructure is not in place to support both the patient and the physicians that encounter the resultant data. Here, we ask five experts to give their opinions on whether clinical data should be treated differently from other medical data, given the potential use of these tests, and on the areas that must be developed to improve patient outcome. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Preidis G.A.,Baylor College of Medicine | Saulnier D.M.,Baylor College of Medicine | Blutt S.E.,Baylor College of Medicine | Mistretta T.-A.,Baylor College of Medicine | And 11 more authors.
Journal of Pediatric Gastroenterology and Nutrition | Year: 2012

Objectives: Beneficial microbes and probiotics are promising agents for the prevention and treatment of enteric and diarrheal diseases in children; however, little is known about their in vivo mechanisms of action. We used a neonatal mouse model of rotavirus diarrhea to gain insight into how probiotics ameliorate acute gastroenteritis. Methods: Rotavirus-infected mice were treated with 1 of 2 strains of human-derived Lactobacillus reuteri. We assessed intestinal microbiome composition with 16S metagenomic sequencing, enterocyte migration and proliferation with 5-bromo-2′-deoxyuridine, and antibody and cytokine concentrations with multiplex analyses of intestinal explant cultures. Results: Probiotics reduced diarrhea duration, improved intestinal histopathology, and enhanced intestinal microbiome richness and phylogenetic diversity. The magnitude of reduction of diarrhea by probiotics was strain specific and influenced by nutritional status. L reuteri DSM 17938 reduced diarrhea duration by 0, 1, and 2 days in underweight, normal weight, and overweight pups, respectively. The magnitude of reduction of diarrhea duration correlated with increased enterocyte proliferation and migration. Strain ATCC PTA 6475 reduced diarrhea duration by 1 day in all of the mice without increasing enterocyte proliferation. Both probiotic strains decreased concentrations of proinflammatory cytokines, including macrophage inflammatory protein-1α and interleukin-1β, in all of the animals, and increased rotavirus-specific antibodies in all but the underweight animals. Body weight also influenced the host response to rotavirus, in terms of diarrhea duration, enterocyte turnover, and antibody production. Conclusions: These data suggest that probiotic enhancement of enterocyte proliferation, villus repopulation, and virus-specific antibodies may contribute to diarrhea resolution, and that nutritional status influences the host response to both beneficial microbes and pathogens. © 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Source

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