Boning up on mutations: assessing the significance of candidate disease-causing DNA sequence variation.

Boning up on mutations: assessing the significance of candidate disease-causing DNA sequence variation

Mutations in COL1A1 Gene Change Dentin Nanostructure: A response.

(Opening paragraph) The mild OI phenotype (commonly referred to as type I OI) displayed by the proband and its mode of inheritance revealed by the pedigree (Figure 3A) are wholly consistent with a causative sequence variant in either one of the genes encoding the constituent chains of type I collagen (COL1A1 or COL1A2). Sequence analysis should reveal a variant for which the proband is heterozygous. However, the upper sequencing trace in Figure 3B is consistent with the proband being homozygous for the two inserted bases. The expectation for a patient who is heterozygous for the inserted bases is a sequencing trace in which the sequences of the two COL1A1 alleles are out of register with one another beginning at the first inserted base. The superimposition of the sequences derived from the normal and mutant alleles should be apparent in the upper trace, but it is not. The trace ought to show three single C peaks at positions 1 to 3 followed by double peaks at positions 4 to 7: C+T, G+C, G+A & G+A respectively. A further anomaly is that the lower trace (CCCCGGA) and the upper trace (CCCTCAGGA), which is two bases longer, appear to be in exact register at their start and finish in spite of the length discrepancy. For that to happen the inserted T and A bases would need to create a rather large electrophoretic compression to compensate for the two inserted bases and that would be unlikely. It is also worth noting that the base caller used to analyse the raw sequence data has not called the T and A peaks in the upper trace and no confidence values are displayed for any of the peak sequence‐calls in either trace

The Human Collagen Mutation Database 1998

The collagens are a large and diverse family of proteins which are found in the extracellular matrix. In common with one another, the 19 known collagen types have triple-helical domains of variable length but they differ with respect to their overall size and the nature and location of their globular domains. Collagen mutations lead to heritable defects of connective tissues and mutation data for collagen types I and III are presented here. The mutation data are accessible on the world wide web at http://www.le.ac.uk/genetics/collagen

A common classification framework for histone sequence alterations in tumours: an expert consensus proposal

The description of genetic alterations in tumours is of increasing importance. In human genetics, and in pathology reports, sequence alterations are given using the human genome variation society (HGVS) guidelines for the description of such variants. However, there is less adherence to these guidelines for sequence variations in histone genes. Due to early cleavage of the N‐terminal methionine in most histones, the description of histone sequence alterations follows their own nomenclature and differs from the HGVS‐compliant numbering by omitting this first amino acid. Next generation sequencing reports, however, follow the HGVS guidelines and as a result, an unambiguous description of sequence variants in histones cannot be provided. The coexistence of these two nomenclatures leads to confusions for pathologists, oncologists, and researchers. This review provides an overview of tumour entities with sequence alterations of the H3‐3A gene (HGNC ID = HGNC:4764), highlights the problems associated with the coexistence of these two nomenclatures, and proposes a standard for the reporting of histone sequence variants that allows an unambiguous description of these variants according to HGVS principles. We hope that scientific journals will adopt the new notation, and that both geneticists and pathologists will include it in their reports. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

VariantValidator: Accurate validation, mapping and formatting of sequence variation descriptions.

The Human Genome Variation Society (HGVS) variant nomenclature is widely used to describe sequence variants in scientific publications, clinical reports and databases. However, the HGVS recommendations are complex and this often results in inaccurate variant descriptions being reported. The open-source hgvs Python package (https://github.com/biocommons/hgvs) provides a programmatic interface for parsing, manipulating, formatting and validating of variants according to the HGVS recommendations, but does not provide a user-friendly web interface. We have developed a web-based variant validation tool, VariantValidator (https://variantvalidator.org/), which utilizes the hgvs Python package and provides additional functionality to assist users who wish to accurately describe and report sequence-level variations that are compliant with the HGVS recommendations. VariantValidator was designed to ensure that users are guided through the intricacies of the HGVS nomenclature, e.g. if the user makes a mistake, VariantValidator automatically corrects the mistake if it can, or provides helpful guidance if it cannot. In addition, VariantValidator has the facility to interconvert genomic variant descriptions in HGVS and Variant Call Format (VCF) with a degree of accuracy which surpasses most competing solutions

Linking DNA structure and sequencing using model based learning

Such is the iconic status of DNA in modern life that we are used to seeing the double helix depicted in sculptures and paintings. In 2003 a set of UK postage stamps celebrated 50 years since the discovery of this structure, and in the same year DNA even graced the two pound coin. For students of biological disciplines, however, it is important that their understanding of this pivotal molecule runs rather deeper than this. Experience shows that some of the fundamental principles involved in the molecular biology of DNA are actually quite difficult for students to grasp when taught via either conventional lectures or practical classes. Successful acquisition of such knowledge is, however, crucial for the comprehension of more complex DNA processes. This workshop will offer the opportunity to participate in two interlinked ‘hands-on’ tutorials that have been designed to increase students’ understanding of both DNA structure and the importance of this structural knowledge in strategically significant technologies such as DNA sequencing. We also offer an evaluation of the exercise when piloted with second year undergraduates at the University of Leicester

Connecting diagnostic labs: Cafe Variome and DNA sequencing software

<p>During the FP7 project GEN2PHEN (http://www.gen2phen.org/) we developed the concept of sharing pointers to diagnostics data to facilitate the public exchange of the existence of information, avoiding the problem of directly exchanging diagnostics information.</p> <p>A minimal set of data was defined to point to variant/mutation information generated by diagnostics laboratories: required data are exact genomic positions of the detected variants and the source (which lab or user generated the data, or publication or public data base), optional information may include the amino acid or protein change, phenotype information, or an anonymised patient identifier. The project also developed a standard to exchange the information: VarioML (http://varioml.org/).</p> <p>We present Café Variome, which has been implemented as a federated market place for these pointers: a public instance has been created (http://www.cafevariome.org/) and populated with public data (such as dbSNP, 1000 Genomes…) or pointers to data (HGMD, LSDBs…). Users can either chose to submit directly to this public instance, or setup a local instance to share detailed data with selected collaborators (such as a national network or a disease-specific collaboration) and connect this instance to the public instance, sharing only pointers. The system has comprehensive management tools for fine-grained user control as well as data sharing control.</p> <p>Because manual data submission is error prone as well as a major barrier to usage, we implemented public APIs to allow both the submission and automated query automatically of data via secure internet connection. We will present two examples of this automatic transmission of pointer information: Gensearch for capillary DNA sequencing and GensearchNGS for NGS DNA sequencing.</p> <p> </p

Missense mutation distribution in collagen III.

<p>Missense mutation frequency along the residues of the collagen III chain. This demonstrates the non-random distribution of variation.</p

Major structural features and ligand binding sites for collagen III.

<p>Major structural features and ligand binding sites for collagen III.</p

The collαgen III fibril has a "flexi-rod" structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles.

Collagen III is critical to the integrity of blood vessels and distensible organs, and in hemostasis. Examination of the human collagen III interactome reveals a nearly identical structural arrangement and charge distribution pattern as for collagen I, with cell interaction domains, fibrillogenesis and enzyme cleavage domains, several major ligand-binding regions, and intermolecular crosslink sites at the same sites. These similarities allow heterotypic fibril formation with, and substitution by, collagen I in embryonic development and wound healing. The collagen III fibril assumes a "flexi-rod" structure with flexible zones interspersed with rod-like domains, which is consistent with the molecule's prominence in young, pliable tissues and distensible organs. Collagen III has two major hemostasis domains, with binding motifs for von Willebrand factor, α2β1 integrin, platelet binding octapeptide and glycoprotein VI, consistent with the bleeding tendency observed with COL3A1 disease-causing sequence variants