Analyzing Complex Polygenic Traits
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
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).
Chronic Ulcerative Dermatitis in Black Mice
John P. Sundberg in Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
Black laboratory mice are commonly used in biomedical research. These usually involve the C57BL/6 and C57BL/10 inbred strains, congenic, recombinant inbred, and partner strains. These mice can be obtained from a variety of sources. Chronic ulcerative dermatitis develops in many black strains, sometimes causing severe infection of underlying muscle and connective tissue secondary to opportunistic organisms. This disease is of particular importance to researchers studying the biology of the skin who may use these mice for their studies. Furthermore, many of the skin and hair mutations have been transferred to these black strains, which potentially interferes with interpretation of the mutant phenotype. It is likely that this is a polygenic trait that is exacerbated by environmental conditions.
Serology and Genetics of Human Ia-Antigens*
Soldano Ferrone, Chella S. David in Ia Antigens: Man and Other Species, 1982
One of the problems of the use of monoclonal antibodies in HLA serology is that many antibodies do not bind complement and are therefore not cytotoxic in the regular microlymphocytotoxicity technique. Such antibodies may nevertheless be quite valuable if a binding assay is used. It is, however, much preferable to have monoclonal antibodies which work in the regular microcytotoxicity assay, because it is possible to investigate the fine specificity of such antibodies on a large panel (N=200). Non cytotoxic antibodies are usually screened in a binding assay on a relatively small panel of cell-lines, which is rather unsatisfactory for determination of specificity. Some investigators tend to overlook the fact that human cell-lines, even if they are homozygous for some HLA antigens, are not at all comparable with congenic strains.
Animal models of systemic lupus erythematosus and their applications in drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Yue Xin, Bo Zhang, Junpeng Zhao, Qianmei Liu, Haoyuan Yin, Qianjin Lu
Based on the polygenic mechanism of SLE, several murine models have been constructed through the modification of the specific genes in wild-type mice, usually B6. Two main categories of genetically modified models have been developed: knockout or transgenic models and spontaneous mouse-derived congenic models. In the knockout or transgenic model, tolerance is disrupted by modifying some critical immunological processes, including enhancing the immunogenicity of apoptotic debris (C1qa−/−, DNase I−/−, and Tlr7 Tg, Tir8−/−), altering lymphocyte signaling (Fcgr2b−/−, Cd22−/−, Cd19 Tg, Lyn−/−), or prolonging the lifespan of autoreactive lymphocytes (Bim−/−, Bcl-2 Tg, and Ctla-4−/−), in which the B6.Tlr7.Tg and B6.Fcgr2b−/− mice are the mostly commonly used [66–68]. For the congenic model, the gene fragments containing one or a cluster of susceptible loci, which are derived from the lupus-prone strain, are integrated into the nonlupus-prone strain to induce a lupus-like disease. As mentioned above, these loci include NZB-derived Nba2 and Nba5, NZM 2410-derived Sle123, NZM 2328-derived Cgnz1 and Agnz1, MRL/lpr-derived Mag and Lmb3, and BXSB-derived Bxs 1–6 loci [69].
Comparative Expression Analysis of Stress-Inducible Genes in Murine Immune Cells
Published in Immunological Investigations, 2020
Madoka Koyanagi, Yutaka Arimura
To our knowledge, there are reportedly several stress-related genes such as Rtp801 (also known as Redd1 and Ddit4), Gilz, Mkp-1 (Mitogen-activated protein kinase phosphatase 1, also known as Dusp1), Bnip3 (BCL2/adenovirus E1B 19 kDa-interacting protein 3), and Trp53inp1 (Transformation-related protein 53 inducible nuclear protein 1, also known as Tp53inp1). The expression levels of these genes increase in immune cells upon either stress or exposure to the glucocorticoid synthetic dexamethasone (Dex) (Bruscoli et al. 2010; Cari et al. 2015; D’Adamio et al. 1997; Murata et al. 2005; Yin et al. 2006) . However, there has yet to be a comparative analysis of the expression patterns of these genes in the immune cells between C57BL/6 and BALB/c mice. Therefore, in this study, we investigated the effects of in vivo stress on these genes in immune cells using C57BL/6, BALB/c, GR congenic, and CRH deficient mice. Then, we discuss the relationship among the types of stress, stress strength, stress signaling pathways, and inducible genes that are potential indicators of stress in immune cells.
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).
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