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Inbred Laboratory Mice as Animal Models and Biomedical Tools: General Concepts
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
These concepts are based on the assumption that a particular human disease is monomorphic and well defined. This is a mistake since humans, domestic animals, and wild animals are outbred or linebred animals in most cases. This implies thal there are many genetic and epigenetic (environmental-genetic interactions) factors that vary between individuals with the same disease, thereby causing variation in the clinical presentation. Inbred laboratory mice, maintained in a controlled environment, provide a uniquely different population. Genetic diseases, response to infectious or irritating agents, etc. will result in similar responses within a strain that can be dramatically different between strains. For example, the flaky skin mouse mutation (fsn) produces an inflammatory-based hyperproliferative skin disease in mice. On the original A/J background, the skin had marked acanthosis and orthokeratosis with focal parakeratosis. The stratum granulosum was not evident. When the mutant gene was transferred onto the BALB/cByJ background, hyperplasia of the stratum granulosum became a very prominent feature. Flaky skin on the C57BL/6J background is a juvenile lethal (Sundberg, Shultz, and Beamer, unpublished data).
Knowledge is power
Published in Brendan Curran, A Terrible Beauty is Born, 2020
We have already seen that there is a strong genetic component to many of the commonest diseases, including heart conditions, diabetes, mental disorders and cancer. We have also seen that their complex inheritance patterns arise because they are under the influence of several genes and there is also a large environmental input. Nevertheless, the web of genetic interactions conveying a predisposition to contracting the diseases is rapidly being identified (Table 7.1) and screening programmes will soon be in place capable of identifying individuals with a genetic predisposition to various types of illness. In fact, sequencing technology is developing so rapidly that, in the not-too-dístant future, each individual will be able to possess their total genetic profile.
William Bateson (1861–1926)
Published in Krishna Dronamraju, A Century of Geneticists, 2018
Bateson codiscovered genetic linkage with Reginald Punnett and Edith Saunders, and he and Punnett founded the Journal of Genetics in 1910. Bateson also coined the term “epistasis” to describe the genetic interaction of two independent loci (Bateson and Saunders 1902; Bateson and Punnett 1908).
Past, present, and future of FGFR inhibitors in cholangiocarcinoma: from biological mechanisms to clinical applications
Published in Expert Review of Clinical Pharmacology, 2023
Elisabeth Amadeo, Federico Rossari, Francesco Vitiello, Valentina Burgio, Mara Persano, Stefano Cascinu, Andrea Casadei-Gardini, Margherita Rimini
FGFR2 has a fusion point with the partner gene at C-terminal (Figure 2). Most partner genes, BCC1 being the most common, fuse at a consistent breakpoint within the FGFR2 gene on chromosome 10 in intron 17 or 18 and, indeed, both laboratory and clinical experimentations presented good therapeutic potential in suppressing these [20,27,28]. They are mutually exclusive with KRAS and BRAF [27], and ERBB2/BRAF/NRAS aberrations [25]. In addition, in pre-clinical studies, mutations in BAP1, a chromatin-remodeling gene, were discovered frequently co-altered with FGFR2 fusions, creating a synergic inhibitory effect on iCCA [27]. The implications of these genetic interactions on a clinical basis, however, are still under investigation.
The Kendall interaction filter for variable interaction screening in high dimensional classification problems
Published in Journal of Applied Statistics, 2023
Youssef Anzarmou, Abdallah Mkhadri, Karim Oualkacha
As stated earlier, most existing SIS-type feature screening methods process predictors to capture marginal main effects, ignoring features' interplay impact on the outcome. Accounting for important interaction effects can substantially contribute to explaining the outcome total variation and might help improve the prediction of many statistical learning models. In the genetics field, for instance, the study of gene-gene (i.e. epistasis) and gene-environment interactions has been a focus of research for several years [5,33]; such genetic interactions play a crucial role in the etiology, prognosis and response to treatment of many complex human diseases beyond the main effects [29]. Yet, with the emergence of Multi-omics data collection (genomics, epigenomics, trancriptomics, metabolomics), the interplay between DNA methylation (epigenomics marks) and near-by SNPs (genomics markers) in influencing the patterns of gene expression (transcriptomics profiles) is a focus of many recent pharmacogenomics applications to contribute to ‘precision medicine’ and treatment plans tailored to the genetic makeup of patients.
The safety evaluation of food flavoring substances: the role of genotoxicity studies
Published in Critical Reviews in Toxicology, 2020
Nigel J. Gooderham, Samuel M. Cohen, Gerhard Eisenbrand, Shoji Fukushima, F. Peter Guengerich, Stephen S. Hecht, Ivonne M. C. M. Rietjens, Thomas J. Rosol, Maria Bastaki, Matthew J. Linman, Sean V. Taylor
Genotoxicity testing, as with other toxicity testing, can provide information relevant to the hazard potential of the tested substance. For the FEMA Expert Panel, a genotoxic risk to the consumer is determined not purely by an inherent ability of a substance to interact with DNA under testing conditions (i.e. identification of a potential hazard) but also by evaluating the likelihood that such an event is manifested in an in vivo functional phenotype and whether that is likely to be a human-relevant risk. Theoretically, genetic damage poses a safety concern only if (a) interaction with genetic material is likely to occur in vivo; (b) the genetic interaction, which is a stochastic event, occurs at a relevant genetic locus in a coding or otherwise functional DNA sequence (rather than as a silent DNA modification); (c) repair is insufficient (DNA repair capacity is exceeded); and (d) the phenotype of the genetic damage has biological consequences (i.e. leads to cancer, germ cell damage, or other cell/tissue disruption) (Vogelstein et al. 2013; Klapacz et al. 2016; Liu et al. 2016; Basu 2018).