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BMC Bioinformatics Apr 2022Epistasis is the interaction between different genes when expressing a certain phenotype. If epistasis involves more than two loci it is called high-order epistasis....
BACKGROUND
Epistasis is the interaction between different genes when expressing a certain phenotype. If epistasis involves more than two loci it is called high-order epistasis. High-order epistasis is an area under active research because it could be the cause of many complex traits. The most common way to specify an epistasis interaction is through a penetrance table.
RESULTS
This paper presents PyToxo, a Python tool for generating penetrance tables from any-order epistasis models. Unlike other tools available in the bibliography, PyToxo is able to work with high-order models and realistic penetrance and heritability values, achieving high-precision results in a short time. In addition, PyToxo is distributed as open-source software and includes several interfaces to ease its use.
CONCLUSIONS
PyToxo provides the scientific community with a useful tool to evaluate algorithms and methods that can detect high-order epistasis to continue advancing in the discovery of the causes behind complex diseases.
Topics: Epistasis, Genetic; Models, Genetic; Penetrance; Phenotype; Software
PubMed: 35366804
DOI: 10.1186/s12859-022-04645-7 -
Human Genetics Oct 2013Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known... (Review)
Review
Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.
Topics: Alleles; DNA Copy Number Variations; Epigenesis, Genetic; Gene Frequency; Genes, Modifier; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetics, Population; Genome, Human; Genotype; Humans; Mutation, Missense; Penetrance; Phenotype
PubMed: 23820649
DOI: 10.1007/s00439-013-1331-2 -
Annals of Clinical and Translational... May 2023To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
OBJECTIVE
To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
METHODS
Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers.
RESULTS
PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older.
INTERPRETATION
PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.
Topics: Humans; Aged; Aged, 80 and over; Alzheimer Disease; Penetrance; Bayes Theorem; Risk Factors; Apolipoproteins E
PubMed: 36946865
DOI: 10.1002/acn3.51757 -
Cellular and Molecular Life Sciences :... Mar 2012Mouse models of DNA repair deficiency are useful tools for determining susceptibility to disease. Cancer predisposition and premature aging are commonly impacted by... (Review)
Review
Mouse models of DNA repair deficiency are useful tools for determining susceptibility to disease. Cancer predisposition and premature aging are commonly impacted by deficiencies in DNA repair, presumably as a function of reduced genomic fitness. In this review, a comprehensive analysis of all DNA repair mutant mouse models has been completed in order to assess the importance of haploinsufficiency for these genes. This analysis brings to light a clear role for haploinsufficiency in disease predisposition. Unfortunately, much of the data on heterozygous models are buried or underinvestigated. In light of a better understanding that the role of DNA repair haploinsufficiency may play in penetrance of other oncogenic or disease causing factors, it may be in the interest of human health and disease prevention to further investigate the phenotypes in many of these mouse models.
Topics: Animals; DNA Repair; DNA Repair-Deficiency Disorders; Genetic Predisposition to Disease; Haploinsufficiency; Humans; Models, Animal; Penetrance
PubMed: 21952828
DOI: 10.1007/s00018-011-0839-7 -
Pest Management Science Jul 2022Thelytokous Wolbachia-infected Trichogramma wasps are superior to bisexual uninfected wasps regarding biological control programs. However, continuous oviposition...
Penetrance during Wolbachia-mediated parthenogenesis of Trichogramma wasps is reduced by continuous oviposition, associated with exhaustion of Wolbachia titers in ovary and offspring eggs.
BACKGROUND
Thelytokous Wolbachia-infected Trichogramma wasps are superior to bisexual uninfected wasps regarding biological control programs. However, continuous oviposition weakens the parthenogenesis-inducing (PI) strength of Wolbachia. Whether this reduced PI strength relates to decreases in the titer of Wolbachia in the ovary and offspring eggs of Trichogramma remains unclear. Here, using fluorescence in situ hybridization (FISH) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) methods, we investigated how the penetrance of Wolbachia-mediated parthenogenesis, Wolbachia density, and distributions of two Wolbachia-infected Trichogramma species, T. pretiosum (TP) and T. dendrolimi (TD), were influenced by different host access treatments [newly-emerged virgin females (NE), 7-day-old females without access to host eggs (NAH), and 7-day-old virgin females with access to host eggs (AH)].
RESULTS
Continuous oviposition decreased Wolbachia PI strength and titers in TP and TD. Continuous oviposition in AH decreased Wolbachia titers in abdomen and offspring eggs of TP and TD females, compared with NAH and NE; NAH had a lower thorax Wolbachia titer than NE. The numbers of parasitized host eggs and offspring wasps, and emergence rates of offspring deposited by AH were lower than those of NE and NAH, for either species.
CONCLUSION
Weakened PI strength, driven by continuous oviposition in Trichogramma wasps, is associated with Wolbachia titer exhaustion in ovary and offspring eggs. Wolbachia density is dependent on PI strength in Trichogramma wasps, highlighting the side effects of continuous oviposition regarding thelytokous Wolbachia-infected Trichogramma in biological control programs. © 2022 Society of Chemical Industry.
Topics: Animals; Female; In Situ Hybridization, Fluorescence; Ovary; Oviposition; Parthenogenesis; Penetrance; Wasps; Wolbachia
PubMed: 35437949
DOI: 10.1002/ps.6934 -
Human Mutation Apr 2016In 2008, the International Agency for Research on Cancer (IARC) proposed a system for classifying sequence variants in highly penetrant breast and colon cancer... (Review)
Review
In 2008, the International Agency for Research on Cancer (IARC) proposed a system for classifying sequence variants in highly penetrant breast and colon cancer susceptibility genes, linked to clinical actions. This system uses a multifactorial likelihood model to calculate the posterior probability that an altered DNA sequence is pathogenic. Variants between 5%-94.9% (class 3) are categorized as variants of uncertain significance (VUS). This interval is wide and might include variants with a substantial difference in pathogenicity at either end of the spectrum. We think that carriers of class 3 variants would benefit from a fine-tuning of this classification. Classification of VUS to a category with a defined clinical significance is very important because for carriers of a pathogenic mutation full surveillance and risk-reducing surgery can reduce cancer incidence. Counselees who are not carriers of a pathogenic mutation can be discharged from intensive follow-up and avoid unnecessary risk-reducing surgery. By means of examples, we show how, in selected cases, additional data can lead to reclassification of some variants to a different class with different recommendations for surveillance and therapy. To improve the clinical utility of this classification system, we suggest a pragmatic adaptation to clinical practice.
Topics: Disease Management; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Humans; Models, Statistical; Mutation; Neoplasms; Penetrance; Practice Guidelines as Topic; Uncertainty
PubMed: 26777316
DOI: 10.1002/humu.22956 -
Genetics in Medicine : Official Journal... Mar 2023The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias....
PURPOSE
The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.
METHODS
We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.
RESULTS
Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.
CONCLUSIONS
Bayesian penetrance estimates provide a continuous framework for variant interpretation.
Topics: Humans; KCNQ1 Potassium Channel; Mutation; Penetrance; Bayes Theorem; Channelopathies; Arrhythmias, Cardiac
PubMed: 36496179
DOI: 10.1016/j.gim.2022.12.002 -
Circulation. Genomic and Precision... May 2018
Topics: Brugada Syndrome; Humans; NAV1.5 Voltage-Gated Sodium Channel; Penetrance
PubMed: 29728398
DOI: 10.1161/CIRCGEN.118.002166 -
JAMA Oncology Apr 2018
Topics: Bias; Breast Neoplasms; Humans; Pedigree; Penetrance
PubMed: 29285541
DOI: 10.1001/jamaoncol.2017.4573 -
Philosophical Transactions of the Royal... Apr 2024Incomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the... (Review)
Review
Incomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the combination of incomplete penetrance for each of multiple independent clinical features. Within genetically identical individuals, such as isogenic model organisms, stochastic variation at molecular and cellular levels is the primary cause of incomplete penetrance according to a genetic threshold model. By defining specific probability distributions of causal biological readouts and genetic liability values, stochasticity and incomplete penetrance provide information about threshold values in biological systems. Ascertainment of threshold values has been achieved by simultaneous scoring of relatively simple phenotypes and quantitation of molecular readouts at the level of single cells. However, this is much more challenging for complex morphological phenotypes using experimental and reductionist approaches alone, where cause and effect are separated temporally and across multiple biological modes and scales. Here I consider how causal inference, which integrates observational data with high confidence causal models, might be used to quantify the relative contribution of different sources of stochastic variation to phenotypic diversity. Collectively, these approaches could inform disease mechanisms, improve predictions of clinical outcomes and prioritize gene therapy targets across modes and scales of gene function. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
Topics: Humans; Penetrance; Stochastic Processes; Causality; Phenotype; Biological Variation, Population
PubMed: 38432317
DOI: 10.1098/rstb.2023.0045