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Applications of network biology
Published in Karthik Raman, An Introduction to Computational Systems Biology, 2021
Barabási, Vidal, and co-workers first developed the concept of disease networks [12]. They represented the disease network as a bipartite graph, where there are two sets of nodes, corresponding to diseases (genetic disorders) and disease genes. Being a bipartite graph (see §2.3.4), edges connect only diseases and genes, with no edges between the diseases or genes themselves, as shown in Figure 4.1. The network, which they called the diseasome, contained 1,284 genetic disorders and 1,777 disease genes from the Online Mendelian Inheritance in Man (OMIM) database [13]. Figure 4.1 (centre panel) shows a small subset of these disorder–disease gene associations, with circles and rectangles representing disorders and disease genes, respectively. An edge connects a disorder to a disease gene if mutations in the gene lead to that disorder. The size of each circle is proportional to the number of genes participating in the disorder; the disease nodes themselves are coloured based on the class to which the disorder belongs.
Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Pertea et al. (2018) published the results of an investigation (entitled “Thousands of large-scale RNA sequencing experiments yield a comprehensive new human gene list and reveal extensive transcriptional noise”) leading to a new human gene database which contains 43,162 genes, of which nearly 50% (21,306) are protein-coding. According to the Online Mendelian Inheritance in Man (www.omim.org/statistics/geneMap) compendium of mutations (updated May 2019), 4,000 genes within the human have so far been linked to disease
Systems toxicology approach explores target-pathway relationship and adverse health impacts of ubiquitous environmental pollutant bisphenol A
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Manigandan Nagarajan, Gobichettipalayam Balasubramaniam Maadurshni, Jeganathan Manivannan
In case of BPA disease targets, the Online Mendelian Inheritance in Man (OMIM) diseases indicated occurrence of hypertension as evidenced by alterations in phenylethanolamine n-methyltransferase (PNMT), nitric oxide synthase 3 (NOS3) and nuclear receptor subfamily 3, group C, member 2 (NR3C2) gene polymorphism (NR3C2). Thids gene catalyzes production of nitric oxide (NO) in the endothelium and its deficiency leads to alterations in NO metabolism and pathogenesis of hypertension (Zintzaras, Kitsios, and Stefanidis 2006). In this regard, Zhang et al. (2012) observed significant associations with NOS3 variants and coronary heart disease (CHD) and heart failure associated with significant pharmacogenetic effects for stroke and all-cause mortality. Subsequently, the gene polymorphism is known to be associated with risk of gestational hypertension in Han Chinese women (Cui, Xu, and Jiang 2019). Further, a study using genetic model of hypertension reported novel molecular mechanisms involved in the dysregulation of cardiac, the terminal enzyme in the catecholamine biosynthetic pathway that is responsible for adrenaline biosynthesis (Peltsch et al. 2016).
Medical diagnosis and treatment is NP-complete
Published in Journal of Experimental & Theoretical Artificial Intelligence, 2021
Jeffrey. E. Arle, Kristen W. Carlson
Another example of diagnosis-treatment pairs would be digested from the ~8,000 known single-gene inherited disorders Online Mendelian Inheritance in Man (OMIM) (Amberger et al., 2015). The diagnosis-treatment matrix would consist of gene-by-gene alleles of the human genome and their clinical synopsis and phenotypes as the symptoms in the top row, left side, with treatments added in the right side. Bits in the row vector below each allele on the left side would indicate if the gene was implicated in the disorder and its observable symptoms, and for the prescribed tests or treatments for each disorder on the right side. The power set of all possible subsets of OMIM gene sets is on the order of 102048, but these single-allele disorders occupy only 1/102045 of the total combinatorial space (we omit |T| in these calculations as |T| << |S|). The sparseness is greater for polygenetic disorders across the entire human genome. Given 21,000 genes, there are on the order of 106031 subsets. The number of polygenic diseases and degree of polygenicity is unknown, assumed to be large, but with few dominant factors (International Common Disease Alliance, 2019). Assuming six dominant gene factors on average, n choose k, where n = 21,000 and k = 6, the resulting ~1023 combinations would occupy just 1/106008 of the genetic disease diagnosis subset space. Assuming 100 factors on average per disease boosts the number of combinations to 10274, but they would occupy just 1/105757 of the total space.
Agrochemical-mediated cardiotoxicity in zebrafish embryos/larvae: What we do and where we go
Published in Critical Reviews in Environmental Science and Technology, 2023
Yang Yang, Yue Tao, Zixu Li, Yunhe Cui, Jinzhu Zhang, Ying Zhang
Currently, approximately 82% of morbid genes in the Online Mendelian Inheritance in Man database are related to at least one zebrafish ortholog (Howe et al., 2013). Additionally, zebrafish have a short developmental cycle, low feeding costs, and high reproduction rate, unlike other model organisms. Therefore, zebrafish has been gaining prominence in multiple fields, including drug screening, clinical research, water quality testing, cosmetic efficacy evaluation, and toxicology studies (Kithcart & Macrae, 2017; Peng et al., 2018; Shao et al., 2019) (Figure 1). The developmental progression of zebrafish embryos at 28.5 °C is predictable; at around 5 h post-fertilisation (hpf), cardiac progenitor cells (atrial and ventricular progenitor cells) appear in the anterolateral plate of the mesoderm. At approximately 22 hpf, heart primordia are formed and begin to contract, and the atria and ventricles form at 28 hpf (Bakkers, 2011). Although zebrafish has only a single atrium and ventricle, its developmental mechanism, cardiac function, and pharmacodynamic response are highly similar to those in humans. With advances in CRISPR-Cas9 gene editing technology, zebrafish have become indispensable tools for studying cardiovascular development, congenital and acquired heart disease, and injury regeneration (Bowley et al., 2021; Ryan et al., 2020) (Figure 1). Moreover, its ectogenesis and embryonic transparency allow researchers to visually assess the negative effects of various environmental stresses, including the effects of agrochemicals on cardiovascular development such as atrial/ventricle malformations, cardiac rate abnormalities.