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Definition of an allergen (immunobiology)
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
The atopic immune response is a complex reaction involving genetic as well as environmental factors (Figure 3.2). The evidence for genetic factors influencing the different phenotypes of atopy have consisted of familial disease clustering, increased prevalence in first-degree relatives, and increased concordance in monozygotic twins compared to dizygotic twins [1,54–56]. Genetic investigations to determine where the genes are located have used many approaches including forward genetics, candidate genes, genome screens, fine mapping, and functional genomics using statistical linkage and association analysis. The candidate gene studies are hypothesis driven, and the results are easy to interpret. Although they can detect genes with modest effect size, they are limited to what we know and cannot discover novel genes or pathways and require linkage dissociation (LD) between markers and causal variants. They are selected for a particular gene or set of genes based on its biological plausibility or suspected role in the phenotype of interest. More than 1000 papers have been published with candidate genes studies examining asthma and related phenotypes, identifying more than 100 genes reviewed elsewhere [57]. Genome-wide linkage studies can discover novel genes and pathways. They require relatively few genetic markers, do not rely on LD between markers and causal variants, and can detect genes harboring rare risk variants. Disadvantages include the requirement of families, poor resolution, and low power to detect genes with modest effects.
Molecular Biology Tools to Boost the Production of Natural Products
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Luzia Valentina Modolo, Samuel Chaves-Silva, Thamara Ferreira da Silva, Cristiane Jovelina da-Silva
The biosynthesis of secondary metabolites in plants is a complex process controlled by genetics and environment (Kessler and Kalske, 2018). The identification of genes involved in a pathway is the very first step to rationally modulate plant secondary metabolism (Yang et al., 2014). Prior to the advent of whole genome sequencing, forward genetics was predominantly used to identify the molecular basis associated with a trait of interest (Tierney and Lamour, 2005). From the observation of a particular phenotype originating from a naturally occurring mutation, one can identify the genes involved in that trait. This approach is based on “phenotype to gene” determinations. The observable variation (phenotype) may also be purposely induced in cells or an organism using a DNA mutagen. The investigator eventually ends up sequencing the gene or genes thought to be involved in a certain biosynthetic pathway related to the observable trait (Figure 4.1). The main strategies used in forward genetics are map-based cloning and mutational breeding. The former consists of mapping of a biparental population based on recombination frequency during meiosis and identifies the underlying genetic cause of a mutant phenotype. Mutational breeding, on the other hand, induces mutation to generate various phenotypes to identify candidate genes. This technique is used to obtain new genetic combinations, without changing the major total genetic setup of an organism (Abbai et al., 2017). Both techniques are widely used in the study of medicinal plants: recognizing there is the disadvantage that only one trait can be analyzed at a time, some genes may be missed in the screening and the procedure is feasible only in plants that are amenable to Agrobacterium transformation. Examples of mutagens used in forward genetics include X-rays and ethylmethanesulfonate (EMS), in which the former may generate large deletions in the chromosomes or chromosomes rearrangements (it induces point mutation while the latter causes point mutation – changes at a single nucleotide position).
Definition of an Allergen (Immunobiology)
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2014
Malcolm N. Blumenthal, Lauren Fine
The atopic immune response is a complex condition involving genetic as well as environmental factors (Figure 2.2). The evidence for genetic factors influencing the different phenotypes of atopy has consisted of familial disease clustering, increased prevalence in first-degree relatives, and increased concordance in monozygotic twins compared with dizygotic twins [1,41–43]. Genetic investigations to determine where the genes are located have used many approaches including forward genetics, candidate genes, genome screens, fine mapping, and functional genomics using statistical linkage and association analysis. There are many approaches for gene discovery including the candidate gene association studies, genome-wide linkage studies, and genome-wide association studies (GWAS) and resequencing studies in genes. The candidate gene studies are hypothesis driven and the results are easy to interpret. Although they can detect genes with modest effect size, they are limited to what we know and cannot discover novel genes or pathways and require linkage disequilibrium (LD) between markers and causal variants. They are selected for a particular gene or a set of genes based on their biological plausibility or suspected role in the phenotype of interest. More than 1000 papers have been published with candidate genes studies examining asthma and related phenotypes, identifying more than 100 genes reviewed elsewhere. Genome-wide linkage studies can discover novel genes and pathways. They require relatively few genetic markers, do not rely on LD between markers and causal variants, and can detect genes harboring rare risk variants. Disadvantages include the requirement of families, poor resolution, and low power to detect genes with modest effects. Approximately 20 genome-wide linkage screens have been reported in different populations investigating chromosomal regions that are linked to asthma and atopy or related phenotypes. Regions identified include the cytokine cluster on chromosome 5q, FCER1B on 11q, EFNG and STAT6 on 12.q, and IL4L on 16q. Linkage studies followed by position cloning approaches have resulted in the identification of some novel asthma susceptibility genes such as CYFIP2, DPP10, HLAG, HF11, GPRA, and ADAM33. The GWAS can discover novel genes and pathways and provide excellent resolution. They can detect loci with modest effect size. The disadvantages involve the need for dense marker typing and very large sample size. They also required LD between markers and causal variants limited to common variants. The GWAS identified two genes in the region of ORMDL3 and GSDML for asthma. Six GWAS have been reported using intermediate phenotypes and quantitative traits rather than asthma [41,42].
Structure-activity relationships of Toxoplasma gondii cytochrome bc 1 inhibitors
Published in Expert Opinion on Drug Discovery, 2022
P. Holland Alday, Aaron Nilsen, J. Stone Doggett
Much progress has been made in establishing SAR through iterative medicinal chemistry and forward genetics. However, the identification of unique structural features of the apicomplexan cyt b that can be exploited for drug design has been limited by the lack of an apicomplexan crystal or cryo-EM structure. For the most part, cocrystallization of inhibitors bound to cyt bc1 have used Bos taurus, Gallus gallus, S. cerevisiae, or Rhodobacter sphaeroides. These studies have been crucial for understanding cyt bc1 structure, function, and its inhibitors; however, they have not provided a model that is fully tractable for structural optimization of inhibitors. Improved transmembrane protein capture and purification techniques, and improvements that have been made in cryo-EM methods may facilitate apicomplexan co-crystallization studies. This structural information would aid in the design of highly selective T. gondii cyt bc1 inhibitors. Forward genetic approaches of selecting drug-resistant parasites have identified key residues for atovaquone, HDQ, and ELQ binding in T. gondii. More could be learned from selecting for resistance to T. gondii cyt bc1 inhibitors that do not have significant cross resistance with current mutants. However, a limitation of the forward genetic approach is the low likelihood of identifying secondary targets and the confounder that some targets may be more prone to single nucleotide variations than others.
Generation and characterization of fruitless P1 promoter mutant in Drosophila melanogaster
Published in Journal of Neurogenetics, 2021
Megan C. Neville, Alexander Eastwood, Aaron M. Allen, Ammerins de Haan, Tetsuya Nojima, Stephen F. Goodwin
While forward genetic screens remain one of the most powerful tools to study biological pathways in Drosophila, the development of reverse genetic approaches, like homologous recombination, permitted the generation or rescue of mutations in genes for which a DNA clone or sequence was available (Rong & Golic, 2000). In 2005, the Dickson lab used homologous recombination to introduce mutations in the fru locus which altered the ability of fru P1 transcripts to be sex-specifically spliced, forcing FruM expression in females; these females had been masculinized by FruM and were able to display many male pre-copulatory courtship behaviors (Demir & Dickson, 2005). Such reverse genetic approaches became more accessible with the advent of CRISPR/Cas-9 technologies, enabling genomic engineering of precise mutations in D. melanogaster with relative ease (Bassett, Tibbit, Ponting, & Liu, 2013; Gratz et al., 2013; Yu et al., 2013).
Pharmacogenomics in the era of next generation sequencing – from byte to bedside
Published in Drug Metabolism Reviews, 2021
Laura E. Russell, Yitian Zhou, Ahmed A. Almousa, Jasleen K. Sodhi, Chukwunonso K. Nwabufo, Volker M. Lauschke
Early successes of pharmacogenomics were made possible using forward genetics, in which studies aimed to identify genetic differences that might explain a given phenotype. However, this approach proves difficult for rare phenotypes and for complex genetic associations that comprise a multitude of variants with individually small effect sizes. Recent advances in sequencing technologies have opened new possibilities for reverse genetics, in which large-scale genetic data forms the basis for functional studies. In this review, we provide an updated overview of current pharmacogenetic biomarkers of clinical relevance, highlight the advantages and limitations of emerging sequencing methods, and discuss how the resulting genomic datasets can facilitate precision medicine in clinical care and drug development.