The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

Ensembl 2009.

The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases, and other information for chordate, selected model organism and disease vector genomes. As of release 51 (November 2008), Ensembl fully supports 45 species, and three additional species have preliminary support. New species in the past year include orangutan and six additional low coverage mammalian genomes. Major additions and improvements to Ensembl since our previous report include a major redesign of our website; generation of multiple genome alignments and ancestral sequences using the new Enredo-Pecan-Ortheus pipeline and development of our software infrastructure, particularly to support the Ensembl Genomes project (http://www.ensemblgenomes.org/).

Ensembl 2007.

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of chordate genome sequences. Over the past year the number of genomes available from Ensembl has increased from 15 to 33, with the addition of sites for the mammalian genomes of elephant, rabbit, armadillo, tenrec, platypus, pig, cat, bush baby, common shrew, microbat and european hedgehog; the fish genomes of stickleback and medaka and the second example of the genomes of the sea squirt (Ciona savignyi) and the mosquito (Aedes aegypti). Some of the major features added during the year include the first complete gene sets for genomes with low-sequence coverage, the introduction of new strain variation data and the introduction of new orthology/paralog annotations based on gene trees.

Effect of strength and proprioception training on eversion to inversion strength ratios in subjects with unilateral functional ankle instability.

OBJECTIVES: To examine the effect of six weeks of strength and proprioception training on eversion to inversion isokinetic strength ratios (E/I ratios) in subjects with unilateral functional ankle instability. METHODS: Thirty eight subjects were randomly assigned to one of four treatment groups: strength training (S); proprioception training (P); strength + proprioception training (B); control (C). Isokinetic strength was tested before and after training using a Kin Com 125 automatic positioning isokinetic dynamometer. Subtalar joint eversion and inversion motions were tested both concentrically and eccentrically through a range of motion involving 40 degrees. All peak torque and average torque values were normalised for body mass. E/I ratios were calculated from average torque and peak torque measures by taking the concentric eversion value and combining it with the eccentric inversion value. Data were analysed using a mixed model analysis of variance with repeated measures on the test factor. Average torque and peak torque E/I ratios at 30 and 120 degrees/s were analysed separately. RESULTS: There were no significant differences in average torque and peak torque E/I ratios of the functionally unstable ankle for any of the groups after training compared with before. CONCLUSIONS: Six weeks of strength and proprioception training (either alone or combined) had no effect on isokinetic measures of strength in subjects with self reported unilateral functional instability. Further studies examining this agonist (concentric) to antagonist (eccentric) muscle group strength ratio are needed.

Mining the draft human genome.

Now that the draft human genome sequence is available, everyone wants to be able to use it. However, we have perhaps become complacent about our ability to turn new genomes into lists of genes. The higher volume of data associated with a larger genome is accompanied by a much greater increase in complexity. We need to appreciate both the scale of the challenge of vertebrate genome analysis and the limitations of current gene prediction methods and understanding.

Assessment of novel fold targets in CASP4: predictions of three-dimensional structures, secondary structures, and interresidue contacts.

In the Novel Fold category, three types of predictions were assessed: three-dimensional structures, secondary structures, and residue-residue contacts. For predictions of three-dimensional models, CASP4 targets included 5 domains or structures with novel folds, and 13 on the borderline between Novel Fold and Fold Recognition categories. These elicited 1863 predictions of these and other targets by methods more general than comparative modeling or fold recognition techniques. The group of Bonneau, Tsai, Ruczinski, and Baker stood out as performing well with the greatest consistency. In many cases, several groups were able to predict fragments of the target correctly-often at a level somewhat larger than standard supersecondary structures-but were not able to assemble fragments into a correct global topology. The methods of Bonneau, Tsai, Ruczinski, and Baker have been successful in addressing the fragment assembly problem for many but not all the target structures.

A browser for expression data.

SUMMARY: We have written a fully extensible Java application for visually browsing expression data, and clusters of genes or experimental conditions calculated from that data. The application requires a run-time environment for Java2. AVAILABILITY: http://www. sanger.ac.uk/Users/mrp/java/ExpressionBrowser

Exploiting the septum for maximal tip control.

Manipulating tip projection and rotation is among the greater challenges in aesthetic surgery. Among common current techniques such as columellar struts and projecting tip grafts, all have considerable failure rates and/or complications. Powerful static and dynamic forces act on the tip, and unfortunately their magnitude and direction vary greatly from the time of surgery when decisions are made to the postoperative period. Traditional techniques have not taken sufficient advantage of the one neighboring stable structure--the septum. Through direct straddling, the medial crura on the septum or the more commonly applicable septal extension graft, tip placement at the end of surgery will vary minimally postoperatively.

SCOP: a structural classification of proteins database.

The Structural Classification of Proteins (SCOP) database provides a detailed and comprehensive description of the relationships of known protein structures. The classification is on hierarchical levels: the first two levels, family and superfamily, describe near and distant evolutionary relationships; the third, fold, describes geometrical relationships. The distinction between evolutionary relationships and those that arise from the physics and chemistry of proteins is a feature that is unique to this database so far. The sequences of proteins in SCOP provide the basis of the ASTRAL sequence libraries that can be used as a source of data to calibrate sequence search algorithms and for the generation of statistics on, or selections of, protein structures. Links can be made from SCOP to PDB-ISL: a library containing sequences homologous to proteins of known structure. Sequences of proteins of unknown structure can be matched to distantly related proteins of known structure by using pairwise sequence comparison methods to find homologues in PDB-ISL. The database and its associated files are freely accessible from a number of WWW sites mirrored from URL http://scop.mrc-lmb.cam.ac.uk/scop/

RMS/coverage graphs: a qualitative method for comparing three-dimensional protein structure predictions.

Evaluating a set of protein structure predictions is difficult as each prediction may omit different residues and different parts of the structure may have different accuracies. A method is described that captures the best results from a large number of alternative sequence-dependent structural superpositions between a prediction and the experimental structure and represents them as a single line on a graph. Applied to CASP2 and CASP3 data the best predictions stand out visually in most cases, as judged by manual inspection. The results from this method applied to CASP data are available from the URLs http:/(/)PredictionCenter. llnl.gov/casp3/results/th/ and http:/(/)www.sanger.ac.uk/ approximately th/casp/.

SCOP: a Structural Classification of Proteins database.

The Structural Classification of Proteins (SCOP) database provides a detailed and comprehensive description of the relationships of all known proteins structures. The classification is on hierarchical levels: the first two levels, family and superfamily, describe near and far evolutionary relationships; the third, fold, describes geometrical relationships. The distinction between evolutionary relationships and those that arise from the physics and chemistry of proteins is a feature that is unique to this database, so far. The database can be used as a source of data to calibrate sequence search algorithms and for the generation of population statistics on protein structures. The database and its associated files are freely accessible from a number of WWW sites mirrored from URL http://scop. mrc-lmb.cam.ac.uk/scop/

Assessing sequence comparison methods with reliable structurally identified distant evolutionary relationships.

Pairwise sequence comparison methods have been assessed using proteins whose relationships are known reliably from their structures and functions, as described in the SCOP database [Murzin, A. G., Brenner, S. E., Hubbard, T. & Chothia C. (1995) J. Mol. Biol. 247, 536-540]. The evaluation tested the programs BLAST [Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. (1990). J. Mol. Biol. 215, 403-410], WU-BLAST2 [Altschul, S. F. & Gish, W. (1996) Methods Enzymol. 266, 460-480], FASTA [Pearson, W. R. & Lipman, D. J. (1988) Proc. Natl. Acad. Sci. USA 85, 2444-2448], and SSEARCH [Smith, T. F. & Waterman, M. S. (1981) J. Mol. Biol. 147, 195-197] and their scoring schemes. The error rate of all algorithms is greatly reduced by using statistical scores to evaluate matches rather than percentage identity or raw scores. The E-value statistical scores of SSEARCH and FASTA are reliable: the number of false positives found in our tests agrees well with the scores reported. However, the P-values reported by BLAST and WU-BLAST2 exaggerate significance by orders of magnitude. SSEARCH, FASTA ktup = 1, and WU-BLAST2 perform best, and they are capable of detecting almost all relationships between proteins whose sequence identities are >30%. For more distantly related proteins, they do much less well; only one-half of the relationships between proteins with 20-30% identity are found. Because many homologs have low sequence similarity, most distant relationships cannot be detected by any pairwise comparison method; however, those which are identified may be used with confidence.

Bridge narrowing in ethnic noses.

In certain ethnic noses with a relative lack of dorsal projection, patients often request a narrowed appearance on frontal view. There is little debate about the benefits of dorsal augmentation, but considerable disagreement about concomitant osteotomies. In a series of six African-American and Asian rhinoplasties, the author has addressed the wide-bridge appearance with dorsal augmentation alone, without osteotomies. Gore-Tex or cartilage was used for the augmentation. All patients were satisfied with the apparent bridge narrowing on frontal view.

SCOP, Structural Classification of Proteins database: applications to evaluation of the effectiveness of sequence alignment methods and statistics of protein structural data.

The Structural Classification of Proteins (SCOP) database provides a detailed and comprehensive description of the relationships of all known protein structures. The classification is on hierarchical levels: the first two levels, family and superfamily, describe near and far evolutionary relationships; the third, fold, describes geometrical relationships. The distinction between evolutionary relationships and those that arise from the physics and chemistry of proteins is a feature that is unique to this database, so far. The database can be used as a source of data to calibrate sequence search algorithms and for the generation of population statistics on protein structures. The database and its associated files are freely accessible from a number of WWW sites mirrored from URL http://scop. mrc-lmb.cam.ac.uk/scop/.