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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.


Stupi B.P.,LaserGen | Li H.,LaserGen | Wang J.,LaserGen | Wu W.,LaserGen | And 9 more authors.
Angewandte Chemie - International Edition | Year: 2012

A complete set of 2-nitrobenzyl-modified reversible terminators have been developed, which upon exposure to UV light generate natural hydroxymethyl nucleotides (see scheme). The combination of a stereospecific (S)-tert-butyl group (R) at the benzylic carbon and a 5-OMe group (R′) on the 2-nitrobenzyl ring substantially increase the rate of photochemical cleavage. For 7-deaza-7-hydroxymethyl-2′-deoxyguanosine, these modifications led to a rate increase of more than one order of magnitude. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


HOUSTON - (March 2, 2017) - The University of Texas Health Science Center at Houston (UTHealth), in collaboration with the Human Genome Sequencing Center at Baylor College of Medicine (HGSC), is a participant in a $500 million program of the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to bring whole genome sequencing and other "omic" technologies that monitor the expression of the genome in response to the environment to the forefront of clinical research. Through its TOPMed program, NHLBI is expanding its dedication to advancing the understanding of the underpinnings of complex diseases and how they develop. Previously, the HGSC was awarded funding by NHLBI to sequence whole genomes for TOPMed studies such as sickle cell disease, and venous thromboembolism and will continue to expand this effort in the next phase of the program. The new contract will span five years. In addition to the whole genome sequencing component, the TOPMed program will also provide analysis of other datatypes over the course of the contract period, including RNA transcription sequencing, DNA methylation, metabolomics profiles, and other "omics," including analysis of the microbiome. The initial award from NHLBI supports the whole genome sequencing of 20,000 samples at the HGSC in the first year of the program. To support this trans-omic approach, the HGSC will continue its ongoing collaboration with the Alkek Center for Metagenomics and Microbiome Research (CMMR) at Baylor and UTHealth School of Public Health, which would aid in executing the methylation and metabolomics tasks. The team was deemed eligible to perform all elements of these additional analyses. "The TOPMed program and resulting data will allow us to better understand the link between pediatric and adult disease genes, thereby creating enhanced diagnostics for adult diseases and disorders. There are direct clinical applications to improve and individualize care for these adult diseases within the Texas Medical Center," said Eric Boerwinkle, Ph.D., dean of UTHealth School of Public Health and associate director of the HGSC. "There is a significant need for large sample sizes; a need that goes beyond the research setting and into the clinic," said Richard Gibbs, Ph.D., director of the HGSC and professor of molecular and human genetics at Baylor. "We are grateful to be a part of the TOPMed program which will allow us to access this large sample number and obtain valuable insights into adult heart disease, sickle cell disease, atrial fibrillation and other heart, lung and hematologic disorders." The HGSC has been operational for more than 20 years, gaining international recognition as a large-scale DNA sequencing and analysis center, and is currently a Center for Complex Disease Genomics supported by the National Institutes of Health and the National Human Genome Research Institute. A key mission of the HGSC is to use genetic approaches to guide discovery and diagnosis of human disease, which offers insight into new therapeutic strategies, echoing the bench-to-bedside framework that is the foundation of the national Precision Medicine Initiative. This mission has been greatly enhanced and facilitated by a collaboration with Boerwinkle, who leads a group of population and data scientists at UTHealth with expertise in analyzing genomic information to discover new disease genes and improve diagnosis. The TOPMed project will better enable the HGSC and UTHealth to pursue this mission to move adult whole genome sequencing into the clinical setting, supporting the advance of precision medicine. The whole genome and other data made available by TOPMed has the capability to be analyzed to provide a more comprehensive picture of what factors may lead to, or protect against, common disease development. The UTHealth team is one of four analysis centers in the country catalyzing new discoveries using this data. The flow of data will begin with the HGSC, which will receive samples from NHLBI investigators. The HGSC will perform the whole genome sequencing, and is eligible for RNA sequencing, operably distributing the samples to UTHealth for methylation and metabolomics profiling, and to Baylor's CMMR for metagenomic analysis as program needs dictate. The data from all three sources would then be funneled into a data sharing portal and relayed back to TOPMed. -Adapted from a news release by Baylor College of Medicine


News Article | November 11, 2016
Site: www.eurekalert.org

The feeding habits responsible for the ecological success of the Asian long-horned beetle have been pinned down to their unique genes, according to new research published by the open access journal Genome Biology. By comparing the genome of the Asian long-horned beetle with 14 other insects, the researchers were able to identify a suite of genes, some unique to this species, that aid the digestion of woody plant material and are likely responsible for the beetles ability to thrive in woodland regions all over the world. The Asian long-horned beetle is a globally invasive species capable of inflicting severe damage on many economically important trees. The potential economic impact in the United States, if uncontrolled, has been estimated at $889 billion. Dr Duane McKenna, co-lead author from the University of Memphis, said: "Our detailed genomic analysis reveals that the Asian long-horned beetle has over 1,000 genes that aren't present in any other arthropod. We identified a total of 86 genes for enzymes called glycoside hydrolases - more than have been found in any other insect. These enzymes enable the beetle to digest woody plant material and detoxify plant chemicals and so indicate a genetic reason for their apparent success in feeding on trees worldwide". Wood is a poor source of nutrients so any organism capable of surviving on a diet of woody plant material must have evolved unique characteristics that allow effective digestion and maximum extraction of energy. Dr McKenna added: "The arsenal of glycoside hydrolase enzymes that the Asian long-horned beetle has allows it to degrade all of the main polysaccharides present in plant cell walls, releasing the sugars it needs for energy. Importantly, the range of enzymes this beetle has is highly diverse, which we believe allows it to breakdown many different molecules present across a wide range of woody plants." The Asian long-horned beetle completes its entire development living and feeding within the wood of trees. In its earliest stage the larvae are specialized wood-borers, feeding on plant tissue under the bark. Later in its life cycle the larvae tunnel deeper into the wood where they continue to feed throughout their development. Adult beetles emerge from the tree and spend their relatively short life-span feeding on external parts of the tree. Dr Stephen Richards, co-lead author from Baylor College of Medicine Human Genome Sequencing Center in Texas, United States, said: "In this case, when we fed beetle larvae on wood material from sugar maple trees we found that the activity of the glycoside hydrolase genes was increased, something not seen in larvae fed on an artificial diet. This experiment, along with our complementary analysis of the beetle genome, also revealed the specific set of genes, called CYP450 genes, which are involved in the detoxification of compounds encountered by the beetle when feeding on plant tissues." The Asian long-horned beetle, also known as Anoplophora glabripennis, belongs to the longhorn beetle family, which contains over 35,000 different species, making it the most diverse group of wood-feeding animals on Earth. According to the researchers this study has established a genomic basis for the invasiveness of the Asian long-horned beetle as well as the evolutionary success of beetles that feed on woody plants. Additionally, the identification of genes linked to key digestive and detoxification processes will ultimately provide novel tools for management of the Asian long-horned beetle and other invasive wood-boring pests. Dr Richards added: "This publically available genome is part of a larger group as a pilot for the i5K initiative to sequence 1000's of insects. We hope that in the long term this foundation information about how any species works can be made available to anyone interested in biology, from researchers addressing specific questions to high-school students and hobbyist entomologists at home." 1. Images of the Asian long-horned beetle are available here: https:/ Please credit image 1, 2 and 3 to David Lance. Please credit image 4 to Yunke Wu. 2. Research article: Genome of the Asian longhorned beetle (Anoplophora glabripennis), a globally significant invasive species, reveals key functional and evolutionary innovations at the beetle-plant interface Stephen Richards, Duane McKenna et al. Genome Biology 2016 During embargo period please contact Matthew Lam for a copy of the article. After the embargo lifts, the article will be available at the journal website here: https:/ Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central's open access policy. 3. Genome Biology publishes outstanding research in all areas of biology and biomedicine studied from a genomic and post-genomic perspective. The current impact factor is 11.313 and the journal is ranked 4th among research journals in the Genetics and Heredity category by Thomson Reuters. Genome Biology is the highest ranked Open Access journal in the category. 4. BioMed Central is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Nature, a major new force in scientific, scholarly, professional and educational publishing, created in May 2015 through the combination of Nature Publishing Group, Palgrave Macmillan, Macmillan Education and Springer Science+Business Media. http://www.


PubMed | McGill University, Hebrew University of Jerusalem, Baylor College of Medicine, Peking Union Medical College and 2 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle-eye-brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have identified recessive mutations in POMGNT1, which encodes an essential component in O-mannosylation pathway, in three unrelated families with autosomal recessive retinitis pigmentosa (RP), but without extraocular involvement. Enzymatic assay of these mutant alleles demonstrate that they greatly reduce the POMGNT1 enzymatic activity and are likely to be hypomorphic. Immunohistochemistry shows that POMGNT1 is specifically expressed in photoreceptor basal body. Taken together, our work identifies a novel disease-causing gene for RP and indicates that proper protein O-mannosylation is not only essential for early organ development, but also important for maintaining survival and function of the highly specialized retinal cells at later stages.


News Article | November 11, 2016
Site: phys.org

By comparing the genome of the Asian long-horned beetle with 14 other insects, the researchers were able to identify a suite of genes, some unique to this species, that aid the digestion of woody plant material and are likely responsible for the beetles ability to thrive in woodland regions all over the world. The Asian long-horned beetle is a globally invasive species capable of inflicting severe damage on many economically important trees. The potential economic impact in the United States, if uncontrolled, has been estimated at $889 billion. Dr Duane McKenna, co-lead author from the University of Memphis, said: "Our detailed genomic analysis reveals that the Asian long-horned beetle has over 1,000 genes that aren't present in any other arthropod. We identified a total of 86 genes for enzymes called glycoside hydrolases - more than have been found in any other insect. These enzymes enable the beetle to digest woody plant material and detoxify plant chemicals and so indicate a genetic reason for their apparent success in feeding on trees worldwide". Wood is a poor source of nutrients so any organism capable of surviving on a diet of woody plant material must have evolved unique characteristics that allow effective digestion and maximum extraction of energy. Dr McKenna added: "The arsenal of glycoside hydrolase enzymes that the Asian long-horned beetle has allows it to degrade all of the main polysaccharides present in plant cell walls, releasing the sugars it needs for energy. Importantly, the range of enzymes this beetle has is highly diverse, which we believe allows it to breakdown many different molecules present across a wide range of woody plants." The Asian long-horned beetle completes its entire development living and feeding within the wood of trees. In its earliest stage the larvae are specialized wood-borers, feeding on plant tissue under the bark. Later in its life cycle the larvae tunnel deeper into the wood where they continue to feed throughout their development. Adult beetles emerge from the tree and spend their relatively short life-span feeding on external parts of the tree. Dr Stephen Richards, co-lead author from Baylor College of Medicine Human Genome Sequencing Center in Texas, United States, said: "In this case, when we fed beetle larvae on wood material from sugar maple trees we found that the activity of the glycoside hydrolase genes was increased, something not seen in larvae fed on an artificial diet. This experiment, along with our complementary analysis of the beetle genome, also revealed the specific set of genes, called CYP450 genes, which are involved in the detoxification of compounds encountered by the beetle when feeding on plant tissues." The Asian long-horned beetle, also known as Anoplophora glabripennis, belongs to the longhorn beetle family, which contains over 35,000 different species, making it the most diverse group of wood-feeding animals on Earth. According to the researchers this study has established a genomic basis for the invasiveness of the Asian long-horned beetle as well as the evolutionary success of beetles that feed on woody plants. Additionally, the identification of genes linked to key digestive and detoxification processes will ultimately provide novel tools for management of the Asian long-horned beetle and other invasive wood-boring pests. Dr Richards added: "This publically available genome is part of a larger group as a pilot for the i5K initiative to sequence 1000's of insects. We hope that in the long term this foundation information about how any species works can be made available to anyone interested in biology, from researchers addressing specific questions to high-school students and hobbyist entomologists at home." More information: Duane D. McKenna et al, Genome of the Asian longhorned beetle (Anoplophora glabripennis), a globally significant invasive species, reveals key functional and evolutionary innovations at the beetle–plant interface, Genome Biology (2016). DOI: 10.1186/s13059-016-1088-8


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.


Pickering C.R.,Baylor College of Medicine | Zhang J.,Baylor College of Medicine | Yoo S.Y.,Baylor College of Medicine | Bengtsson L.,Human Genome Sequencing Center | And 23 more authors.
Cancer Discovery | Year: 2013

The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we conducted comprehensive genomic analysis of gene expression, copy number, methylation, and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, and TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of caspase-8 (CASP8) defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers. SIGNIFICANCE: This is the first integrated genomic analysis of OSCC. Only through integrated multiplatform analysis was it possible to identify four key pathways. We also discovered a new disease subtype associated with CASP8 and HRAS mutation. Finally, many candidate targetable events were found and provide hope for future genomically driven therapeutic strategies. © 2013 American Association for Cancer Research.


Preidis G.A.,Baylor College of Medicine | Preidis G.A.,Texas Childrens Hospital | Saulnier D.M.,Baylor College of Medicine | Saulnier D.M.,Texas Childrens Hospital | And 12 more authors.
FASEB Journal | Year: 2012

Beneficial microbes and probiotics show promise for the treatment of pediatric gastrointestinal diseases. However, basic mechanisms of probiosis are not well understood, and most investigations have been performed in germ-free or microbiome-depleted animals. We sought to functionally characterize probiotichost interactions in the context of normal early development. Outbred CD1 neonatal mice were orally gavaged with one of two strains of human-derived Lactobacillus reuteri or an equal volume of vehicle. Transcriptome analysis was performed on enterocyte RNA isolated by laser-capture microdissection. Enterocyte migration and proliferation were assessed by labeling cells with 5-bromo-2′-deoxyuridine, and fecal microbial community composition was determined by 16S metagenomic sequencing. Probiotic ingestion altered gene expression in multiple canonical pathways involving cell motility. L. reuteri strain DSM 17938 dramatically increased enterocyte migration (3-fold), proliferation (34%), and crypt height (29%) compared to vehicle-treated mice, whereas strain ATCC PTA 6475 increased cell migration (2-fold) without affecting crypt proliferative activity. In addition, both probiotic strains increased the phylogenetic diversity and evenness between taxa of the fecal microbiome 24 h after a single probiotic gavage. These experiments identify two targets of probiosis in early development, the intestinal epithelium and the gut microbiome, and suggest novel mechanisms for probiotic strain-specific effects. © FASEB.


News Article | August 15, 2016
Site: www.techtimes.com

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.

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