| 61. |
- Vihinen, Mauno
(författare)
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Functional effects of protein variants
- 2021
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Ingår i: Biochimie. - : Elsevier BV. - 0300-9084. ; 180, s. 104-120
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Tidskriftsartikel (refereegranskat)abstract
- Genetic and other variations frequently affect protein functions. Scientific articles can contain confusing descriptions about which function or property is affected, and in many cases the statements are pure speculation without any experimental evidence. To clarify functional effects of protein variations of genetic or non-genetic origin, a systematic conceptualisation and framework are introduced. This framework describes protein functional effects on abundance, activity, specificity and affinity, along with countermeasures, which allow cells, tissues and organisms to tolerate, avoid, repair, attenuate or resist (TARAR) the effects. Effects on abundance discussed include gene dosage, restricted expression, mis-localisation and degradation. Enzymopathies, effects on kinetics, allostery and regulation of protein activity are subtopics for the effects of variants on activity. Variation outcomes on specificity and affinity comprise promiscuity, specificity, affinity and moonlighting. TARAR mechanisms redress variations with active and passive processes including chaperones, redundancy, robustness, canalisation and metabolic and signalling rewiring. A framework for pragmatic protein function analysis and presentation is introduced. All of the mechanisms and effects are described along with representative examples, most often in relation to diseases. In addition, protein function is discussed from evolutionary point of view. Application of the presented framework facilitates unambiguous, detailed and specific description of functional effects and their systematic study.
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| 62. |
- Vihinen, Mauno
(författare)
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Generic model for biological regulation
- 2022
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Ingår i: F1000Research. - : F1000 Research Ltd. - 2046-1402. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- A substantial portion of molecules in an organism are involved in regulation of a wide spectrum of biological processes. Several models have been presented for various forms of biological regulation, including gene expression regulation and physiological regulation; however, a generic model is missing. Recently a new unifying theory in biology, poikilosis, was presented. Poikilosis indicates that all systems display intrinsic heterogeneity, which is a normal state. The concept of poikilosis allowed development of a model for biological regulation applicable to all types of regulated systems. The perturbation-lagom-TATAR countermeasures-regulator (PLTR) model combines the effects of perturbation and lagom (allowed and sufficient extent of heterogeneity) in a system with tolerance, avoidance, repair, attenuation and resistance (TARAR) countermeasures, and possible regulators. There are three modes of regulation, two of which are lagom-related. In the first scenario, lagom is maintained, both intrinsic (passive) and active TARAR countermeasures can be involved. In the second mode, there is a shift from one lagom to another. In the third mode, reguland regulation, the regulated entity is the target of a regulatory shift, which is often irreversible or requires action of another regulator to return to original state. After the shift, the system enters to lagom maintenance mode, but at new lagom extent. The model is described and elaborated with examples and applications, including medicine and systems biology. Consequences of non-lagom extent of heterogeneity are introduced, along with a novel idea for therapy by reconstituting biological processes to lagom extent, even when the primary effect cannot be treated.
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| 63. |
- Vihinen, Mauno
(författare)
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Guidelines for reporting and using prediction tools for genetic variation analysis
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 34:2, s. 275-282
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Tidskriftsartikel (refereegranskat)abstract
- Computational prediction methods are widely used for analysis of human genome sequence variants and their effects on gene/protein function, splice site aberration, pathogenicity, and disease risk. New methods are frequently developed. We believe that guidelines are essential for those writing articles about new prediction methods, as well as for those applying these tools in their research, so that the necessary details are reported. This will enable readers to gain the full picture of technical information, performance, and interpretation of results, and to facilitate comparisons of related methods. Here we provide instructions on how to describe new methods, report datasets, and assess the performance of predictive tools. We also discuss what details of predictor implementation are essential for authors to understand. Similarly, these guidelines for the use of predictors provide instructions on what needs to be delineated in the text, as well as how researchers can avoid unwarranted conclusions. They are applicable to most prediction methods currently utilized. By applying these guidelines, authors will help reviewers, editors, and readers to more fully comprehend prediction methods and their use.
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| 64. |
- Vihinen, Mauno
(författare)
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Guidelines for systematic reporting of sequence alignments
- 2020
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Ingår i: Biology Methods and Protocols. - : Oxford University Press (OUP). - 2396-8923. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Bioinformatics methods are increasingly needed and used to analyze and interpret extensive datasets many of which are produced by diverse high-throughput technologies. Unfortunately, it is quite common that published articles do not contain sufficient information to allow the reader to fully comprehend and repeat computational and other studies. Guidelines were developed for reporting studies and results from sequence alignment. Brief and concise checklist of required data items was compiled making it easy to provide necessary details. Implementation of the guidelines requires similar meticulous attitude toward details as other parts of publications. If the journal does not allow reporting full details in the main article, it can be provided in supplementary material. It is important to make the alignments available. Systematic and detailed description of bioinformatics analyses adds to the value of papers and makes it easier for the scientific community to evaluate, understand, verify, and extend the published articles and their results.
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| 65. |
- Vihinen, Mauno
(författare)
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How to Define Pathogenicity, Health, and Disease?
- 2017
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 38:2, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- Scientific and clinical communities produce ever increasing amounts of data and details about health and disease. Our ability to understand and utilize this information is limited because of imprecise language and lack of well-defined concepts. This problem involves also the principal concepts of health, disease, and pathogenicity. Here, a systematic model is presented for pathogenicity, as well as for health and disease. It has three components: extent, modulation, and severity, which jointly define the continuum of pathogenicity. The model is population based, and once implemented, it can be used for numerous purposes such as diagnosis, patient stratification, prognosis, finding phenotype–genotype correlations, or explaining adverse drug reactions. The new model has several benefits including health economy by allowing evidence-based personalized/precision medicine.
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| 66. |
- Vihinen, Mauno
(författare)
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How to evaluate performance of prediction methods? Measures and their interpretation in variation effect analysis
- 2012
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Ingår i: BMC Genomics. - 1471-2164. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prediction methods are increasingly used in biosciences to forecast diverse features and characteristics. Binary two-state classifiers are the most common applications. They are usually based on machine learning approaches. For the end user it is often problematic to evaluate the true performance and applicability of computational tools as some knowledge about computer science and statistics would be needed. Results: Instructions are given on how to interpret and compare method evaluation results. For systematic method performance analysis is needed established benchmark datasets which contain cases with known outcome, and suitable evaluation measures. The criteria for benchmark datasets are discussed along with their implementation in VariBench, benchmark database for variations. There is no single measure that alone could describe all the aspects of method performance. Predictions of genetic variation effects on DNA, RNA and protein level are important as information about variants can be produced much faster than their disease relevance can be experimentally verified. Therefore numerous prediction tools have been developed, however, systematic analyses of their performance and comparison have just started to emerge. Conclusions: The end users of prediction tools should be able to understand how evaluation is done and how to interpret the results. Six main performance evaluation measures are introduced. These include sensitivity, specificity, positive predictive value, negative predictive value, accuracy and Matthews correlation coefficient. Together with receiver operating characteristics (ROC) analysis they provide a good picture about the performance of methods and allow their objective and quantitative comparison. A checklist of items to look at is provided. Comparisons of methods for missense variant tolerance, protein stability changes due to amino acid substitutions, and effects of variations on mRNA splicing are presented.
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| 67. |
- Vihinen, Mauno, et al.
(författare)
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Human Variome Project Quality Assessment Criteria for Variation Databases.
- 2016
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 37:6, s. 549-549
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Tidskriftsartikel (refereegranskat)abstract
- Numerous databases containing information about DNA, RNA and protein variations are available. Gene-specific variant databases (locus specific variation databases, LSDBs) are typically curated and maintained for single genes or groups of genes for a certain disease(s). These databases are widely considered as the most reliable information source for a particular gene/protein/disease, but it should also be made clear they may have widely varying contents, infrastructure, and quality. Quality is very important to evaluate because these databases may affect health decision-making, research and clinical practice. The Human Variome Project (HVP) established a Working Group for Variant Database Quality Assessment. The basic principle was to develop a simple system that nevertheless provides a good overview of the quality of a database. The HVP quality evaluation criteria that resulted are divided into four main components: data quality, technical quality, accessibility, and timeliness. This report elaborates on the developed quality criteria and how implementation of the quality scheme can be achieved. Examples are provided for the current status of the quality items in two different databases, BTKbase, an LSDB, and ClinVar, a central archive of submissions about variants and their clinical significance. This article is protected by copyright. All rights reserved.
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| 68. |
- Vihinen, Mauno
(författare)
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Individual Genetic Heterogeneity
- 2022
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 13:9
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Forskningsöversikt (refereegranskat)abstract
- Genetic variation has been widely covered in literature, however, not from the perspective of an individual in any species. Here, a synthesis of genetic concepts and variations relevant for individual genetic constitution is provided. All the different levels of genetic information and variation are covered, ranging from whether an organism is unmixed or hybrid, has variations in genome, chromosomes, and more locally in DNA regions, to epigenetic variants or alterations in selfish genetic elements. Genetic constitution and heterogeneity of microbiota are highly relevant for health and wellbeing of an individual. Mutation rates vary widely for variation types, e.g., due to the sequence context. Genetic information guides numerous aspects in organisms. Types of inheritance, whether Mendelian or non-Mendelian, zygosity, sexual reproduction, and sex determination are covered. Functions of DNA and functional effects of variations are introduced, along with mechanism that reduce and modulate functional effects, including TARAR countermeasures and intraindividual genetic conflict. TARAR countermeasures for tolerance, avoidance, repair, attenuation, and resistance are essential for life, integrity of genetic information, and gene expression. The genetic composition, effects of variations, and their expression are considered also in diseases and personalized medicine. The text synthesizes knowledge and insight on individual genetic heterogeneity and organizes and systematizes the central concepts.
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| 69. |
- Vihinen, Mauno
(författare)
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Majority Vote and Other Problems when using Computational Tools.
- 2014
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 35:8, s. 912-914
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Tidskriftsartikel (refereegranskat)abstract
- Computational tools are essential for most of our research. To use these tools, one needs to know how they work. Problems in application of computational methods to variation analysis can appear at several stages and affect, for example, the interpretation of results. Such cases are discussed along with suggestions how to avoid them. The applications include incomplete reporting of methods, especially about the use of prediction tools; method selection on unscientific grounds and without consulting independent method performance assessments; extending application area of methods outside their intended purpose; use of the same data several times for obtaining majority vote; and filtering of datasets so that variants of interest are excluded. All these issues can be avoided by discontinuing the use software tools as black boxes.
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| 70. |
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