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The Case for Single Gene Effects on Human Obesity
Published in Claude Bouchard, The Genetics of Obesity, 2020
Animal models also demonstrate some of the complications that are likely to exist for human obesity. First, expression of single obesity-predisposing genes commonly depends on background genotype. This phenomenon has been demonstrated in the case of differences in insulin resistance when the ob and db mutations in mouse and the/a mutation in rats are expressed in different congenic strains.2,17 Given these differences in gene expression between closely related strains of the same species, it is to be expected that homologous human genes may be expressed very differently than in rodents. Another complication is that diet mediates gene expression in both mutant and wild-type animal strains as well as in humans. Finally, there has been some recent evidence that strain differences in weight gain on high-fat diets may be mediated in part by major gene differences among some strains.18 Such findings in animal species are consistent with evidence for similar genetically mediated susceptibility to weight gain on high-fat diets noted in human studies (see, for instance, Reference 19).
Analyzing Complex Polygenic Traits
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Bernard R. Lauwerys, Edward K. Wakeland
Other candidate genes have been identified in the subcongenic intervals and the effects of SNPs on their expression and function are being thoroughly evaluated. Again, these differences do not constitute definitive evidence for involvement in disease pathogenesis. Final demonstration for establishing the pathogenic role of a candidate gene requires that its correction results in suppression of the compound phenotype present in the congenic strains. This can be achieved in transgenic approaches, using either conventional or BAC transgenes. While conventional transgenesis induces dramatic overexpression of the gene, BAC transgenes contain much larger segments of genomic DNA, also including normal regulatory sequences, thereby resulting in physiological levels of protein expression (for review, see ref. 77).
Hormonal and Nonhormonal Mechanisms of Sexual Differentiation of the Zebra Finch Brain: Embracing the Null Hypothesis
Published in Akira Matsumoto, Sexual Differentiation of the Brain, 2017
Some experiments have manipulated the composition of genes on the Y chromosome in order to examine their effects on behavior. For example, aggressive behavior in mice differs across strains. Maxson and co-workers89–91 have produced inbred congenic strains that differ in their Y chromosome but otherwise have the same autosomal background. Males of these congenic strains show different levels of aggressive behavior, a result that indicates that some Y genes influence aggression. These Y genes are candidates for direct genetic influences on aggressive behavior, which is a sexually dimorphic trait. However, the between-strain differences are also potentially attributable to Y effects on the level of androgens or the sensitivity of neural circuits to gonadal hormones. In the end, one can only determine if a specific action of a gene has a direct, nonhormonal effect on neural development by identifying the gene and establishing its molecular and cellular mechanism of action. If the gene is expressed in brain in appropriate places and at appropriate times of development, and manipulation of the gene product alters the course of sexual differentiation, one can build a case for a nonhormonal mechanism of action.
Intratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect
Published in OncoImmunology, 2022
Kef K Prasit, Laura Ferrer-Font, Olivia K Burn, Regan J Anderson, Benjamin J Compton, Alfonso J Schmidt, Johannes U Mayer, Chun-Jen J Chen, Nathaniel Dasyam, David S Ritchie, Dale I Godfrey, Stephen R Mattarollo, P Rod Dunbar, Gavin F Painter, Ian F Hermans
Female and male mice were bred and housed by the Biomedical Research Unit at the Malaghan Institute of Medical Research. All animal experiments were performed in accordance with relevant guidelines and regulations and were approved by Victoria University of Wellington animal ethics committee. Animals used included: C57BL/6J (originally from The Jackson Laboratory, Bar Harbor, ME, USA) and the CD45.1 congenic strain B6.SJL-Ptprca Pepcb/BoyJ (from Ozgene Pty, Bentley, WA, Australia), BALB/cJ mice (The Jackson Laboratory), Cd1d−/− mice33 and Traj18−/− mice (B6(Cg)-Traj18tm1.1Kro/J; The Jackson Laboratory).34Ifnar1flox/flox mice35 were crossed with CD11c-cre mice (Tg(Itgax-cre,-EGFP)4097Ach), and then an F2 cross performed to give cre-positive Ifnar1ΔCD11c mice and cre-negative littermates used as controls (Ifnar1+/+). Experiments in Clec9a-DTR mice, which express the human diphtheria toxin (DT) receptor under the control of the Clec9a promoter,36 and Siglec-H-DTR mice which express the human DT receptor under the control of the Siglec-H promoter,36 were conducted in F1 crosses with C57BL/6J mice. Both were supplied by Nanyang Technological Unit, Singapore.
Pathophysiological significance of Stim1 mutation in sympathetic response to stress and cardiovascular phenotypes in SHRSP/Izm: In vivo evaluation by creation of a novel gene knock-in rat using CRISPR/Cas9
Published in Clinical and Experimental Hypertension, 2021
Batbayar Odongoo, Hiroki Ohara, Davis Ngarashi, Takehito Kaneko, Yayoi Kunihiro, Tomoji Mashimo, Toru Nabika
Quantitative trait locus (QTL) analysis and construction of congenic strains have been widely used as a set of genetic approaches for identifying genes associated with cardiovascular traits in hypertensive rats (15). We previously showed that a major BP QTL existed in rat chromosome (chr) 1 through a genome-wide linkage analysis using F2 generation cross derived from SHRSP and normotensive Wistar-Kyoto (WKY) rats (16). Then, we created reciprocal congenic lines between SHRSP and WKY for the BP QTL on chr1 and revealed that the chr1 QTL was implicated in the pathophysiology of exaggerated sympathetic response to stress in SHRSP (17–19) with possible involvement of hyperactivity of the RVLM (20). Subcongenic analysis successfully narrowed down the candidate region to a 1.2 Mbp fragment on the chr1 QTL, finally, stromal interaction molecule 1 (Stim1) was identified as the most promising candidate gene responsible for the sympatho-excitation to stress in SHRSP according to the existence of a nonsense mutation (c.1918 C > T, p.Arg640X) in this gene resulting in the truncated STIM1 expression in SHRSP (21).
Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy
Published in Expert Opinion on Therapeutic Targets, 2018
Alexander V. Kulikov, Raul R. Gainetdinov, Evgeni Ponimaskin, Allan V. Kalueff, Vladimir S. Naumenko, Nina K. Popova
TPH2 is the key enzyme of 5-HT synthesis in the brain and, therefore, its gene may be a likely candidate gene for SSRIs resistance. There are three currently available mouse models of genetically defined TPH2 deficiency: (1) several TPH2 gene knockout strains [47–49,114], (2) the R439H knockin strain [116], and (3) ‘natural’ C1473G polymorphism [122,123]. The TPH2 knockout markedly reduces 5-HT level in the mouse brain without altering 5-HT neuron formation and migration [47–49], but causes delayed development and early postnatal growth retardation [49,130]. The R439H knockin is a homologous model of human R441H polymorphism, resulting in 80% reduction of the mouse TPH2 activity as well as 5-HT and 5-HIAA levels in the brain [116]. C1473G polymorphism in the TPH2 gene results in about 50% reduction of the enzyme activity in the brain [119,120,122,123]. Recently, the G allele has been transferred from the Balb/c [121] or CC57BR [119,120] to the C57BL/6 genetic background, and two congenic strains (B6-1473C and B6-1473G mice) with high and low TPH2 activity have been generated. While these strains show about 50% difference in the rate of 5-HT synthesis, they do not differ in 5-HT and 5-HIAA levels in the brain [121,131,132].