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5. A plugin for the Ensembl Variant Effect Predictor that uses MaxEntScan to predict variant spliceogenicity.

Author

Berger, B, Shamsani, J, Kazakoff, SH, Armean, IM, McLaren, W, Parsons, MT, Thompson, BA, O'Mara, TA, Hunt, SE, Waddell, N, Spurdle, AB, Berger, B, Shamsani, J, Kazakoff, SH, Armean, IM, McLaren, W, Parsons, MT, Thompson, BA, O'Mara, TA, Hunt, SE, Waddell, N, and Spurdle, AB

Abstract

SUMMARY: Assessing the pathogenicity of genetic variants can be a complex and challenging task. Spliceogenic variants, which alter mRNA splicing, may yield mature transcripts that encode non-functional protein products, an important predictor of Mendelian disease risk. However, most variant annotation tools do not adequately assess spliceogenicity outside the native splice site and thus the disease-causing potential of variants in other intronic and exonic regions is often overlooked. Here, we present a plugin for the Ensembl Variant Effect Predictor that packages MaxEntScan and extends its functionality to provide splice site predictions using a maximum entropy model. The plugin incorporates a sliding window algorithm to predict splice site loss or gain for any variant that overlaps a transcript feature. We also demonstrate the utility of the plugin by comparing our predictions to two mRNA splicing datasets containing several cancer-susceptibility genes. AVAILABILITY AND IMPLEMENTATION: Source code is freely available under the Apache License, Version 2.0: https://github.com/Ensembl/VEP_plugins. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Published
2019

7. Haplosaurus computes protein haplotypes for use in precision drug design.

Author

Spooner, W, McLaren, W, Slidel, T, Finch, DK, Butler, R, Campbell, J, Eghobamien, L, Rider, D, Kiefer, CM, Robinson, MJ, Hardman, C, Cunningham, F, Vaughan, T, Flicek, P, Huntington, CC, Spooner, W, McLaren, W, Slidel, T, Finch, DK, Butler, R, Campbell, J, Eghobamien, L, Rider, D, Kiefer, CM, Robinson, MJ, Hardman, C, Cunningham, F, Vaughan, T, Flicek, P, and Huntington, CC

Abstract

Selecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world protein sequence variability and their prevalence. For one in seven genes, their most common protein haplotype differs from the reference sequence and a similar number differs on their most common haplotype between human populations. Three case studies show how knowledge of the range of commonly encountered protein forms predicted in populations leads to insights into therapeutic efficacy. Haplosaurus and its associated database is expected to find broad applications in many disciplines using protein sequences and particularly impactful for therapeutics design.

Published
2018

9. Views of Our Readers

Author

Peet, William, Brown,, Ralph S., McLaren, W. G., Koessler, Maximilian, and Kizer, Benjamin H.

Published
1950

10. Views of Our Readers

Author

Howard, Earl E., Walker, Thomas F., Wilson, Wesley T., Williams, Ira Jewell, Rice, Robert H., McLaren, W. G., Hallows, E. H., Burkhard, Myron J., and Cooper, Drury W.

Published
1949

11. Ensembl 2011

Author

Flicek, P., Amode, M. R., Barrell, D., Beal, K., Brent, S., Chen, Y., Clapham, P., Coates, G., Fairley, S., Fitzgerald, S., Gordon, L., Hendrix, M., Hourlier, T., Johnson, N., Kahari, A., Keefe, D., Keenan, S., Kinsella, R., Kokocinski, F., Kulesha, E., Larsson, P., Longden, I., McLaren, W., Overduin, B., Pritchard, B., Riat, H. S., Rios, D., Ritchie, G. R. S., Ruffier, M., Schuster, M., Sobral, D., Spudich, G., Tang, Y. A., Trevanion, S., Vandrovcova, J., Vilella, A. J., White, S., Wilder, S. P., Zadissa, A., Zamora, J., Aken, B. L., Birney, E., Cunningham, F., Dunham, I., Durbin, R., Fernandez-Suarez, X. M., Herrero, J., Hubbard, T. J. P., Parker, A., Proctor, G., Vogel, J., and Searle, S. M. J.

Subjects
0303 health sciences, Genetic Variation, Molecular Sequence Annotation, Articles, Genomics, Regulatory Sequences, Nucleic Acid, Rats, Mice, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Genetics, Animals, Humans, Software, Zebrafish, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The Ensembl project (http://www.ensembl.org) seeks to enable genomic science by providing high quality, integrated annotation on chordate and selected eukaryotic genomes within a consistent and accessible infrastructure. All supported species include comprehensive, evidence-based gene annotations and a selected set of genomes includes additional data focused on variation, comparative, evolutionary, functional and regulatory annotation. The most advanced resources are provided for key species including human, mouse, rat and zebrafish reflecting the popularity and importance of these species in biomedical research. As of Ensembl release 59 (August 2010), 56 species are supported of which 5 have been added in the past year. Since our previous report, we have substantially improved the presentation and integration of both data of disease relevance and the regulatory state of different cell types.

Published
2010
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12. Integrating common and rare genetic variation in diverse human populations

Author

Altshuler, D, Gibbs, R, Peltonen, L, Dermitzakis, E, Schaffner, S, Yu, F, Bonnen, P, de Bakker, P, Deloukas, P, Gabriel, S, Gwilliam, R, Hunt, S, Inouye, M, Jia, X, Palotie, A, Parkin, M, Whittaker, P, Chang, K, Hawes, A, Lewis, L, Ren, Y, Wheeler, D, Muzny, D, Barnes, C, Darvishi, K, Hurles, M, Korn, J, Kristiansson, K, Lee, C, McCarrol, SA, Nemesh, J, Keinan, A, Montgomery, S, Pollack, S, Price, A, Soranzo, N, Gonzaga-Jauregui, C, Anttila, V, Brodeur, W, Daly, M, Leslie, S, McVean, G, Moutsianas, L, Nguyen, H, Zhang, Q, Ghori, M, McGinnis, R, McLaren, W, Takeuchi, F, Grossman, SR, Shlyakhter, I, Hostetter, E, Sabeti, P, Adebamowo, C, Foster, M, Gordon, DR, Licinio, J, Manca, M, Marshall, P, Matsuda, I, Ngare, D, Wang, V, Reddy, D, Rotimi, C, Royal, C, Sharp, R, Zeng, C, Brooks, L, McEwen, J, Dermitzakis, Emmanouil, and Montgomery, Stephen

Subjects
DNA Copy Number Variations, Single-nucleotide polymorphism, Genome-wide association study, Human genetic variation, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genome, Human, 0302 clinical medicine, Population Groups, Population Groups/*genetics, Human Genome Project, Humans, ddc:576.5, Copy-number variation, International HapMap Project, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, SNP genotyping, Minor allele frequency, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of

Published
2010
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13. Large scale association analysis of novel genetic loci for coronary artery disease

Author

Amouyel, P., Arveiler, D., Boekholdt, S. M., Braund, P., Bruse, P., Bumpstead, S. J., Bugert, P., Cambien, F., Danesh, J., Deloukas, P., Doering, A., Ducimetiere, P., Dunn, R. M., El Mokhtari, N. E., Erdmann, J., Evans, A., Ewels, P., Ferrieres, J., Fischer, Matthias, Frossard, P., Garner, S., Gieger, C., Gohri, M. J. R., Goodall, A. H., Grosshennig, A., Hall, A., Hardwick, R., Haukijarvi, A., Hengstenberg, C., Illig, T., Karvanen, J., Kastelein, J., Kee, F., Khaw, K. T., Kluter, H., Konig, I. R., Kuulasmaa, K., Laiho, P., Luc, G., Marz, W., McGinnis, R., McLaren, W., Meisinger, C., Morrison, C., Ou, X., Ouwehand, W. H., Preuss, M., Proust, C., Ravindrarajah, R., Renner, W., Rice, K., Ruidavets, J. B., Saleheen, D., Salomaa, V., Samani, N. J., Sandhu, M. S., Schafer, A. S., Scholz, M., Schreiber, Stefan, Schunkert, H., Silander, K., Singh, R., Soranzo, N., Stark, K., Stegmayr, B., Stephens, J., Thompson, J., Tiret, L., Trip, M. D., van der Schoot, E., Virtamo, J., Wareham, N. J., Wichmann, H. E., Wiklund, P. G., Wright, B., Ziegler, A., Zwaginga, J. J., Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
Male, Risk, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, White People, Article, Coronary artery disease, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Family history, Aged, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Case-Control Studies, Female, business, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background— Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. Methods and Results— We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81×10 −21 ). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P =1.44×10 −7 ), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P =1.02×10 −3 ), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P =4.34×10 −4 ). The associations with 6q25.1 (rs6922269, P =0.020) and 2q36.3 (rs2943634, P =0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction ( P =0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P =1.86×10 −5 ) but not men (OR=1.03 [0.96 to 1.11], P =0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. Conclusions The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.

Published
2009
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14. Ensembl 2012

Author

Flicek, P., Amode, M. R., Barrell, D., Beal, K., Brent, S., Carvalho-Silva, D., Clapham, P., Coates, G., Fairley, S., Fitzgerald, S., Gil, L., Gordon, L., Hendrix, M., Hourlier, T., Johnson, N., Kahari, A. K., Keefe, D., Keenan, S., Kinsella, R., Komorowska, M., Koscielny, G., Kulesha, E., Larsson, P., Longden, I., McLaren, W., Muffato, M., Overduin, B., Pignatelli, M., Pritchard, B., Riat, H. S., Ritchie, G. R. S., Ruffier, M., Schuster, M., Sobral, D., Tang, Y. A., Taylor, K., Trevanion, S., Vandrovcova, J., White, S., Wilson, M., Wilder, S. P., Aken, B. L., Birney, E., Cunningham, F., Dunham, I., Durbin, R., Fernandez-Suarez, X. M., Harrow, J., Herrero, J., Hubbard, T. J. P., Parker, A., Proctor, G., Spudich, G., Vogel, J., Yates, A., Zadissa, A., and Searle, S. M. J.

Subjects
0303 health sciences, Genetic Variation, Molecular Sequence Annotation, Genomics, Articles, Rats, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene Expression Regulation, Databases, Genetic, Genetics, Animals, Humans, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.

Published
2011

24. Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy.

Author

Tan, J., Quinn, M. A., Pyman, J. M., Delaney, P. M., and McLaren, W. J.

Subjects
CERVICAL cancer diagnosis, PRECANCEROUS conditions, COLPOSCOPY, ACETIC acid, ENDOSCOPES, FLUORESCENCE, LONGITUDINAL method
Abstract

Objective A high resolution optical imaging device may offer a clinically useful adjunct to colposcopy for the diagnosis and assessment of cervical precancer. This study describes the clinical evaluation of a miniaturised confocal endomicroscope for the quantitative and qualitative assessment of cervical intraepithelial neoplasia (CIN) in vivo. Design A descriptive study ( n = 25) was performed to assess the usability of confocal endomicroscopy to image the cervix. A prospective study ( n = 15) then evaluated the diagnostic accuracy of the technique. Setting and population Patients undergoing colposcopy for treatment of CIN1-CIN3 were examined using confocal endomicroscopy. Methods A 5% solution of acetic acid was used to enhance the colposcopic features of the atypical region. Normal and abnormal regions of the cervix were then imaged following topical application of a fluorescent dye (acriflavine). Main outcome measures Confocal images were analysed to develop a scoring system to grade different levels of CIN. Microscopic features were correlated with histology from biopsy. Results Confocal endomicroscopy enabled microscopic imaging of cellular and subcellular structures in vivo at colposcopy. Imaging at increasing depth showed morphological features including dermal papillae, endocervical glands and the squamo-columnar junction. CIN was characterised by an increase in nuclear density, size and cellular atypia. The sensitivity for detection of CIN was 97%. The specificity for predicting the grade of abnormality was 80% for normal-CIN1 and 93% for CIN2-CIN3. Conclusions Confocal endomicroscopy is a sensitive imaging tool for detection and assessment of CIN. The technique enables in vivo imaging of cervical histology and the potential for ‘see-and-treat’ workflows. [ABSTRACT FROM AUTHOR]

Published
2009
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25. In vivo detection of experimental ulcerative colitis in rats using fiberoptic confocal imaging (FOCI).

Author

McLaren, Wendy, Anikijenko, Peter, Barkla, David, Delaney, Peter, King, Roger, McLaren, W, Anikijenko, P, Barkla, D, Delaney, T P, and King, R

Subjects
ANIMAL experimentation, BIOLOGICAL models, DEXTRAN, FIBER optics, DIGITAL image processing, INTESTINAL mucosa, MICROSCOPY, RATS, ULCERATIVE colitis
Abstract

Fiberoptic confocal imaging (FOCI) is a noninvasive microscopic technique that enables subsurface imaging of living tissue in vivo. The aim of the present study was to assess the suitability of FOCI for the in vivo detection of early subsurface changes in the mucosal architecture of the colon in a rat model of ulcerative colitis. Mild colitis was induced in Sprague-Dawley rats (180–250 g) by the oral ingestion of 5% (w/v) dextran sulfate sodium (DSS; Mr 40,000 Da) in drinking water. Control animals were provided with water ad libitum. After three, five or seven days of oral consumption of DSS, the mucosal surface of the colon of anesthetised rats was surgically exposed. Morphological changes in the mucosa were examined (Optiscan F900e personal confocal system with rigid endomicroscope attachment; excitation 488 nm argon ion laser, detection above 515 nm) following the topical application of a fluorescent dye (fluorescein, eosin, or acridine orange). Confocal images were correlated with conventional histology and clinical parameters including occult blood and stool consistency. Histological evaluation of colon sections demonstrated that DSS-induced colitis was characterized by focal loss of mucous crypts, loss of epithelial cells, and neutrophilic infiltration into the mucosa. The extent of mucosal damage was positively correlated with the time of ingestion of DSS. Morphological changes associated with disease activity could be detected microscopically in vivo using FOCI but were not evident by visual inspection of the colon surface. Acridine orange enabled imaging of the colonic crypts at the surface of the mucosa. Morphological changes associated with colitis, including inflammatory cell infiltrate, crypt loss, and crypt distortion, could be detected using this fluorophore. Application of fluorescein and eosin enabled subsurface imaging of the lamina propria surrounding the crypts; however, no change in structure was detected in association with colitic disease activity. This study has shown that the topical application of acridine orange enables in vivo imaging of early colitis in a rat model. FOCI may be suitable for the diagnosis and monitoring of human inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Published
2001
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27. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo

Author

Kiesslich, R., Burg, J., Vieth, M., Gnaendiger, J., Enders, M., Delaney, P., Polglase, A., McLaren, W., Janell, D., Thomas, S., Nafe, B., Galle, P.R., and Neurath, M.F.

Abstract

Background & Aims: Aconfocal laser endoscopy system has recently been developed that may allow subsurface imaging of living cells in colonic tissue in vivo. The aim of the present study was to assess its potential for prediction of histology during screening colonoscopy for colorectal cancer. Methods: Twenty-seven patients underwent colonoscopy with the confocal endoscope using acriflavine hydrochloride or fluorescein sodium with blue laser illumination. Furthermore, 42 patients underwent colonoscopy with this system using fluorescein sodium. Standardized locations and circumscript lesions were examined by confocal imaging before taking biopsy specimens. Confocal images were graded according to cellular and vascular changes and correlated with conventional histology in a prospective and blinded fashion. Results: Acriflavine hydrochloride and fluorescein sodium both yielded high-quality images. Whereas acriflavine hydrochloride strongly labeled the superficial epithelial cells, fluorescein sodium offered deeper imaging into the lamina propria. Fluorescein sodium was thus used for the prospective component of the study in which 13,020 confocal images from 390 different locations were compared with histologic data from 1038 biopsy specimens. Subsurface analysis during confocal laser endoscopy allowed detailed analysis of cellular structures. The presence of neoplastic changes could be predicted with high accuracy (sensitivity, 97.4%; specificity, 99.4%; accuracy, 99.2%). Conclusions: Confocal laser endoscopy is a novel diagnostic tool to analyze living cells during colonoscopy, thereby enabling virtual histology of neoplastic changes with high accuracy. These newly discovered diagnostic possibilities may be of crucial importance in clinical practice and lead to an optimized rapid diagnosis of neoplastic changes during ongoing colonoscopy.

Published
2004
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29. NEW BOOKS.

Author

Mclaren, W. W., Spahr, Walter E., Gras, N. S. B., Reed, Harold L., F. A. B., and Ellerman, F. J.

Subjects
BIBLIOGRAPHY, BOOKS -- Reviews, PRICE regulation, BANKING industry, NATIONAL currencies
Abstract

The article presents a bibliography of books related to finance. Some of the books included are: "The International Banks," by A.S.J. Baster; "Law of Negotiable Instruments, With Questions and Problems, and Text of Uniform Negotiable Instruments Law," by A.W. Bays; "Contemporary English and American Theories Concerning the Effect of Commercial Banking on the Supply of Physical Capital," by B.P. Beckwith; "A Guide to the Study of Money and Banking," by J.W. Bell; "The Depression Experience of Savings and Loan Associations in the United States," by M. Bodfish; "Bank Management: A Case Book," by J.F. Ebersole; and "Credit for the Wage Earner: A Selected Bibliography." The book "Prices in Colonial Pennsylvania," by A. Bezanson, R.D. Gray and M. Hussey, contribute valuable information on the commercial history of Philadelphia, the price history of particular commodities, and the history of the general price level. The prices considered are as follows: corn, wheat, tobacco, rice, four kinds of bread, flour, beef, pork, two kinds of salt, molasses, three kinds of staves, pitch, tar, turpentine, cotton, and gunpowder. The prices are all wholesale and are expressed in the currency of the Colony.

Published
1936

30. NEW BOOKS.

Author

Pitigliani, Fausto R., Handman, Max S., Davis, Horace B., McLaren, W. W., Knight, F. H., Remer, C. F., Flügel, Felix, and Carroll, Mollie Ray

Subjects
BIBLIOGRAPHY, BOOKS -- Reviews, BIOGRAPHIES, TOURISM
Abstract

The article presents a bibliography of books on economics. Some of the books included in the bibliography are "The Business Biography of John Wenamaker, Founder and Builder," by J.H. Appel; "Francesco di Marco da Prato: Notise e Documenti Sulla Mercatura Italiana del Secolo," by E. Bensa; "Commercial Geography," by A.P. Brigham; "British Opinion and the American Revolution," by D.M. Clark; "Capital and Labor Under Fascism," by C. Haider. The book "Deutschlands Zahlungsbilans, 1925: Zugleich Chronik der Auslandsbeziehungen der Deutschen Volkswirtschaft," by A. Heichen, is an effort to estimate the balance-sheet characteristics of German economic life in 1925, for the purpose of ascertaining the extent to which Germany is fulfilling her obligations under the Dawes plan. The author comes to the conclusion that Germany is doing so, not by taking a surplus from the normal functioning of her economic system, but by borrowing very heavily abroad. The estimates of various items, in the nature of the case, are highly problematic, when for instance the author is trying to ascertain the amount spent by German tourists abroad and foreign tourists in Germany, but the effort is ingenious, and one admires the clearness with which lie has handled a rather large body of material.

Published
1930

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