Haston Christina K, Humes Daryl G, Lafleur Melanie
Meakins-Christie Laboratories and Department of Medicine, McGill University, Urbain, Montreal, Quebec, Canada.
BMC Genet. 2007 May 16;8:23. doi: 10.1186/1471-2156-8-23.
Cystic fibrosis (CF) mice, created with a genetically engineered mutation in the Cystic fibrosis transmembrane conductance regulator (Cftr) gene, may develop intestinal plugs which limit their survival past weaning. In a studied population of genetically mixed CF mice differences in allelic ratios at particular loci, between surviving CF mice and mice with the lethal intestinal defect, were used to map cystic fibrosis modifier gene one, Cfm1. Using this approach, we previously identified an X chromosome locus which may influence the survival to weaning of C57BL/6J x BALB/cJ F2 CF mice. We also detected two regions of transmission ratio distortion, independent of Cftr genotype, in a limited dataset. To investigate these findings, in this study we have genotyped 1208 three-week old F2 mice, and 186 day E15.5 embryos, derived from a congenic (C57BL/6J x BALB/cJ) F1 Cftr +/- intercross, for the putative distortion regions.
An excess of homozygous BALB genotypes, compared to Mendelian expectations, was detected on chromosomes 5 (p = 5.7 x 10-15) and X (p = 3.0 x 10-35) in three-week old female mice but transmission ratio distortion was not evident in the tested region of chromosome 3 (p = 0.39). Significant pre-weaning lethality of CF mice occurred as 11.3% (137/1208) of the three-week old offspring were identified as CF mice. X chromosome genotypes were not, however, distorted in the female CF mice (p = 0.62), thus the significant non-Mendelian inheritance of this locus was dependent on CF status. The survival of CF embryos to day E15.5 was consistent with Mendelian expectations (42/186 = 23%), demonstrating the loss of CF mice to have occurred between E15.5 and three weeks of age. The excess of X chromosome homozygous BALB genotypes was recorded in female embryos (p = 0.0048), including CF embryos, indicating the distortion to be evident at this age.
Two of three previously suggested loci of transmission ratio distortion were replicated as distorted in this mouse cross. The non-Mendelian inheritance of X chromosome genotypes implicates this region in the survival to weaning of non-CF mice.
通过对囊性纤维化跨膜传导调节因子（Cftr）基因进行基因工程突变培育出的囊性纤维化（CF）小鼠，可能会形成肠道堵塞，这限制了它们断奶后的存活。在一个基因混合的CF小鼠研究群体中，利用存活的CF小鼠与具有致命肠道缺陷的小鼠在特定基因座上等位基因比例的差异，来定位囊性纤维化修饰基因1（Cfm1）。使用这种方法，我们之前鉴定出一个X染色体基因座，它可能影响C57BL/6J×BALB/cJ F2 CF小鼠断奶后的存活。我们还在一个有限的数据集中检测到两个与Cftr基因型无关的传递率失真区域。为了研究这些发现，在本研究中，我们对来自同基因（C57BL/6J×BALB/cJ）F1 Cftr +/- 杂交后代的1208只三周龄F2小鼠和186个E15.5天胚胎进行了假定失真区域的基因分型。
在三周龄雌性小鼠的5号染色体（p = 5.7×10 -15）和X染色体（p = 3.0×10 -35）上，检测到与孟德尔预期相比过量的纯合BALB基因型，但在3号染色体的测试区域未发现明显的传递率失真（p = 0.39）。CF小鼠出现显著的断奶前致死率，因为11.3%（137/1208）的三周龄后代被鉴定为CF小鼠。然而，雌性CF小鼠的X染色体基因型没有失真（p = 0.62），因此该基因座显著的非孟德尔遗传取决于CF状态。CF胚胎存活到E15.5天符合孟德尔预期（42/186 = 23%），表明CF小鼠在E15.5天到三周龄之间出现了死亡。在包括CF胚胎在内 的雌性胚胎中记录到过量的X染色体纯合BALB基因型（p = 0.0048），表明这种失真在这个年龄段很明显。
在这个小鼠杂交实验中，之前提出的三个传递率失真基因座中的两个被重复确认为失真。X染色体基因型的非孟德尔遗传表明该区域与非CF小鼠断奶后的存活有关。
