| 41. |
- Schaafsma, Gerard C. P., et al.
(författare)
-
Genetic Variation in Bruton Tyrosine Kinase
- 2015
-
Ingår i: Agammaglobulinemia. - Cham : Springer International Publishing. - 9783319227146 ; , s. 75-85
-
Bokkapitel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by variations in the gene encoding for Bruton's tyrosine kinase (BTK). Patients with XLA have decreased numbers of mature B cells, lack all immunoglobulin isotypes, and therefore have susceptibility to severe bacterial infections. XLA-causing variations are collected into BTKbase freely available at http://structure.bmc.lu.se/idbase/BTKbase/. Details of the variations are provided at DNA, RNA, and protein levels, using standardized systematic names and a plain English description. In addition, clinical details from the patients are provided when available. BTKbase contains variation entries for 1362 patients from 1198 unrelated families altogether for 742 unique molecular events. The localization of the variations on the gene and protein for BTK can be analyzed by clicking sequences on web pages. The distribution of the variations in the five structural domains is approximately according to the length of the domains, except for the TH and SH3 domains. The most frequently affected sites are CpG dinucleotides. The majority of the amino acid substitutions are structural affecting protein fold or stability. Detailed statistics is provided highlighting variation types, affected domains, exons and introns, as well as structural consequences.
|
|
| 42. |
- Schaafsma, Gerard C.P., et al.
(författare)
-
Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases
- 2017
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 38:7, s. 839-848
-
Tidskriftsartikel (refereegranskat)abstract
- Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions (AASs) in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbor the largest proportion of harmful variants (42.1%), whereas the non-disease group of proteins not known to have a disease association and not involved in the housekeeping functions had the lowest number of harmful variants (4.2%). Differences in the proportions of the harmful and benign variants are wide within each group, but they still show clear differences between the groups. Frequently appearing protein domains show a wide spectrum of variant frequencies, whereas no major protein structural class-specific differences were noticed. AAS types in the original and variant residues showed distinctive patterns, which are shared by all the protein groups. The observations are relevant for understanding genetic bases of diseases, variation interpretation, and for the development of methods for that purpose.
|
|
| 43. |
- Schaafsma, Gerard C P, et al.
(författare)
-
Representativeness of variation benchmark datasets
- 2018
-
Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 19:1, s. 461-461
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Benchmark datasets are essential for both method development and performance assessment. These datasets have numerous requirements, representativeness being one. In the case of variant tolerance/pathogenicity prediction, representativeness means that the dataset covers the space of variations and their effects.RESULTS: We performed the first analysis of the representativeness of variation benchmark datasets. We used statistical approaches to investigate how proteins in the benchmark datasets were representative for the entire human protein universe. We investigated the distributions of variants in chromosomes, protein structures, CATH domains and classes, Pfam protein families, Enzyme Commission (EC) classifications and Gene Ontology annotations in 24 datasets that have been used for training and testing variant tolerance prediction methods. All the datasets were available in VariBench or VariSNP databases. We tested also whether the pathogenic variant datasets contained neutral variants defined as those that have high minor allele frequency in the ExAC database. The distributions of variants over the chromosomes and proteins varied greatly between the datasets.CONCLUSIONS: None of the datasets was found to be well representative. Many of the tested datasets had quite good coverage of the different protein characteristics. Dataset size correlates to representativeness but only weakly to the performance of methods trained on them. The results imply that dataset representativeness is an important factor and should be taken into account in predictor development and testing.
|
|
| 44. |
- Schaafsma, Gerard, et al.
(författare)
-
VariOtator, A Software Tool for Variation Annotation with the Variation Ontology.
- 2016
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 37:4, s. 344-349
-
Tidskriftsartikel (refereegranskat)abstract
- The Variation Ontology (VariO) is used for describing and annotating types, effects, consequences and mechanisms of variations. To facilitate easy and consistent annotations, the online application VariOtator was developed. For variation type annotations VariOtator is fully automated, accepting variant descriptions in Human Genome Variation Society (HGVS) format, and generating VariO terms, either with or without full lineage, i.e. all parent terms. When a coding DNA variant description with a reference sequence is provided, VariOtator checks the description first with Mutalyzer and then generates the predicted RNA and protein descriptions with their respective VariO annotations. For the other sublevels - function, structure and property - annotations cannot be automated, and VariOtator generates annotation based on provided details. For VariO terms relating to structure and property, one can use attribute terms as modifiers and Evidence Code (ECO) terms for annotating experimental evidence. There is an online batch version, and stand-alone batch versions to be used with a Leiden Open Variation Database (LOVD) download file. A SOAP web service allows client programs to access VariOtator programmatically. Thus, systematic variation effect and type annotations can be efficiently generated to allow easy use and integration of variations and their consequences. This article is protected by copyright. All rights reserved.
|
|
| 45. |
- Schaafsma, Gerard, et al.
(författare)
-
Varisnp, A Benchmark Database For Variations from dbSNP.
- 2015
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 36:2, s. 161-166
-
Tidskriftsartikel (refereegranskat)abstract
- For development and evaluation of methods for predicting the effects of variations, benchmark datasets are needed. Some previously developed datasets are available for this purpose, but newer and larger benchmark sets for benign variants have largely been missing. VariSNP datasets are selected from dbSNP. These subsets were filtered against disease-related variants in the ClinVar, UniProtKB/Swiss-Prot and PhenCode databases, to identify neutral or non-pathogenic cases. All variant descriptions include mapping to reference sequences on chromosomal, genomic, coding DNA and protein levels. The datasets will be updated with automated scripts on a regular basis and are freely available at https://structure.bmc.lu.se/VariSNP. This article is protected by copyright. All rights reserved.
|
|
| 46. |
- Shakur, Rameen, et al.
(författare)
-
Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
- 2021
-
Ingår i: npj Genomic Medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.
|
|
| 47. |
|
|
| 48. |
- Smith, Timothy D, et al.
(författare)
-
Standard development at the Human Variome Project.
- 2015
-
Ingår i: Database: the journal of biological databases and curation. - : Oxford University Press (OUP). - 1758-0463. ; 2015, s. 024-024
-
Tidskriftsartikel (refereegranskat)abstract
- The Human Variome Project (HVP) is a world organization working towards facilitating the collection, curation, interpretation and free and open sharing of genetic variation information. A key component of HVP activities is the development of standards and guidelines. HVP Standards are systems, procedures and technologies that the HVP Consortium has determined must be used by HVP-affiliated data sharing infrastructure and should be used by the broader community. HVP guidelines are considered to be beneficial for HVP affiliated data sharing infrastructure and the broader community to adopt. The HVP also maintains a process for assessing systems, processes and tools that implement HVP Standards and Guidelines. Recommended System Status is an accreditation process designed to encourage the adoption of HVP Standards and Guidelines. Here, we describe the HVP standards development process and discuss the accepted standards, guidelines and recommended systems as well as those under acceptance. Certain HVP Standards and Guidelines are already widely adopted by the community and there are committed users for the others.
|
|
| 49. |
- Teku, Gabriel, et al.
(författare)
-
Identification of core T cell network based on immunome interactome.
- 2014
-
Ingår i: BMC Systems Biology. - : Springer Science and Business Media LLC. - 1752-0509. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI) networks facilitate investigation and identification of proteins important for particular processes or diseases and reduces time and costs of experimental verification. Modeling the dynamics of very large PPI networks is computationally costly.
|
|
| 50. |
- Teku, Gabriel N., et al.
(författare)
-
Pan-cancer analysis of neoepitopes
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yield neoantigens that are detected by the immune system. Neoantigens can lead to immune response and tumor rejection. Although neoantigen load and occurrence have been widely studied, a detailed pan-cancer analysis of the occurrence and characterization of neoepitopes is missing. We investigated the proteome-wide amino acid substitutions in 8-, 9-, 10-, and 11-mer peptides in 30 cancer types with the NetMHC 4.0 software. 11,316,078 (0.24%) of the predicted 8-, 9-, 10-, and 11-mer peptides were highly likely neoepitope candidates and were derived from 95.44% of human proteins. Binding affinity to MHC molecules is just one of the many epitope features. The most likely epitopes are those which are detected by several MHCs and of several peptide lengths. 9-mer peptides are the most common among the high binding neoantigens. 0.17% of all variants yield more than 100 neoepitopes and are considered as the best candidates for any application. Amino acid distributions indicate that variants at all positions in neoepitopes of any length are, on average, more hydrophobic than the wild-type residues. We characterized properties of neoepitopes in 30 cancer types and estimated the likely numbers of tumor-derived epitopes that could induce an immune response. We found that amino acid distributions, at all positions in neoepitopes of all lengths, contain more hydrophobic residues than the wild-type sequences implying that the hydropathy nature of neoepitopes is an important property. The neoepitope characteristics can be employed for various applications including targeted cancer vaccine development for precision medicine.
|
|
