Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain
Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain
复制标题
DOI：
10.1007/s003359900098
复制
发表时间：
1996-05-01
期刊：
影响因子：
2.5
通讯作者：
Wakeland, EK
中科院分区：
文献类型：
--
作者：
Morel, L;Yu, Y;Wakeland, EK
系统性红斑狼疮是一种复杂的多基因遗传特征。先前在NZM 2410小鼠模型中通过区间作图确定了包含主要SLE易感性位点的四个基因组区间。在本文中，我们利用一个标记辅助选择协议，以产生四个同源小鼠品系，每个携带NZM 2410衍生的SLE易感性区间的C57 BL/6抗性背景。每个菌株只携带一个易感性等位基因，来自这个多基因模型，因此可以用来表征特定的组成部分表型由个人SLE易感基因。我们用我们的同类菌株B6.NZMH2（z）的表型数据说明了这种方法的有效性。我们的研究结果表明，来自NZM 2410的染色体（Chr）17的这一单基因组间隔可以介导染色质特异性IgG自身抗体水平的增加，并且与我们最初的遗传杂交中获得的结果相似，B6.NZMH2（z/B）杂合子比B6.NZMH2（z）纯合子更倾向于发展对核抗原的体液自身免疫。这些结果说明了使用同源菌株来剖析介导多基因SLE的复杂致病机制的可行性。这些同源菌株将是SLE易感性遗传分析的有用工具。在未来的研究中，这些同源株将杂交产生双和三同源株，以评估遗传相互作用的作用，在表达的特定组成部分的SLE发病机制。它们也将有助于通过产生同源重组体定位克隆和鉴定SLE易感性基因。
Systemic lupus erythematosus is inherited as a complex polygenic trait. Four genomic intervals containing major SLE-susceptibility loci were previously identified by interval mapping in the NZM2410 mouse model. In this paper, we utilized a marker-assisted selection protocol to produce four congenic mouse strains, each carrying an NZM2410-derived SLE-susceptibility interval on a C57BL/6-resistant background. Each strain carries only one susceptibility allele derived from this polygenic model and consequently can be used to characterize the specific component phenotypes contributed by individual SLE-susceptibility genes. We illustrate the efficacy of this approach with phenotypic data for one of our congenic strains, B6.NZMH2(z). Our results indicate that this single genomic interval from Chromosome (Chr) 17 of NZM2410 can mediate increased levels of IgG autoantibodies specific for chromatin and that, similar to results obtained in our original genetic cross, B6.NZMH2(z/b) heterozygotes are more prone than B6.NZMH2(z) homozygotes to the development of humoral autoimmunity to nuclear antigens. These results illustrate the feasibility of using congenic strains to dissect the complex pathogenic mechanisms that mediate polygenic SLE. These congenic strains will be valuable tools in the genetic analysis of SLE susceptibility. In future studies, these congenic strains will be interbred to produce bi- and tri-congenic strains in order to assess the role of genetic interactions in the expression of specific components of SLE pathogenesis. They will also be instrumental to the positional cloning and identification of the genes responsible for SLE susceptibility, via the production of congenic recombinants.