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1.
Genetic Epilepsy Model Derived from Common Inbred Mouse Strains   总被引:7,自引:0,他引:7       下载免费PDF全文
The recombinant inbred mouse strain, SWXL-4, exhibits tonic-clonic and generalized seizures similar to the commonest epilepsies in humans. In SWXL-4 animals, seizures are observed following routine handling at about 80 days of age and may be induced as early as 55 days by rhythmic gentle tossing. Seizures are accompanied by rapid, bilateral high frequency spike cortical discharges and followed by a quiescent post-ictal phase. Immunohistochemistry of the immediate early gene products c-Fos and c-Jun revealed abnormal activation within cortical and limbic structures. The seizure phenotype of SWXL-4 can be explained and replicated fully by the inheritance of susceptibility alleles from its progenitor strains, SWR/J and C57L/J. Outcrosses of SWXL-4 with most other common inbred strains result in F(1) hybrids that have seizures at least as frequently as SWXL-4 itself. Quantitative trait locus mapping reveals a seizure frequency determinant, Szf1, near the pink-eyed dilution locus on chromosome 7, accounting for up to 32% of the genetic variance in an F(2) intercross between SWXL-4 and the linkage testing strain ABP/Le. These studies demonstrate that common strains of mice such as SWR and C57L contain latent epilepsy susceptibility alleles. Although the inheritance of susceptibility may be complex, these results imply that a number of potentially important and practical, noninvasive models for this disorder can be constructred and studied in crosses between common mouse strains.  相似文献   

2.
The electroconvulsive threshold (ECT) test is used commonly in the screening of anti-epileptic drugs in rodent models, but little is known about its genetic or mechanistic basis. Thresholds for minimal clonic, maximal tonic, or psychomotor (partial) seizures were determined in 16 different inbred mouse strains in two different laboratories. A wide range of thresholds was observed, suggesting that a variety of neuroexcitability alleles exist in inbred strains. Although there was generally good cross-strain correlation between the three seizure types, several outlier strains were detected, showing that genetically encoded differences can affect the ability of a particular seizure type to spread through the brain. Furthermore, the relative seizure susceptibility of a strain was comparable between the two laboratories, suggesting that despite different test sites, instrumentation, and personnel, the ECT assay is portable and that common inbred strains can often be relied upon as calibration standards. Last, the ECT paradigm was also sensitive enough to detect single locus differences, laying the groundwork for mutation screens for new neuroexcitability models.  相似文献   

3.
Glucuronidase Phenotypes of Inbred Mouse Strains   总被引:4,自引:0,他引:4       下载免费PDF全文
  相似文献   

4.
W. R. Atchley  S. Newman    D. E. Cowley 《Genetics》1988,120(1):239-253
Genetic divergence in the form of the mandible is examined in ten inbred strains of mice. Several univariate and multivariate genetic distance estimates are given for the morphological data and these estimates are compared to measures of genealogical and molecular divergence. Highly significant divergence occurs among the ten strains in all 11 mandible traits considered individually and simultaneously. Genealogical relationship among strains is highly correlated with genetic divergence in single locus molecular traits. However, the concordance between genealogical relationship and multivariate genetic divergence in morphology is much more complex. Whether there is a significant correlation between morphological divergence and genealogy depends upon the method of analysis and the particular genetic distance statistic being employed.  相似文献   

5.
6.
State-of-the-art, genome-wide assessment of mouse genetic background uses single nucleotide polymorphism (SNP) PCR. As SNP analysis can use multiplex testing, it is amenable to high-throughput analysis and is the preferred method for shared resource facilities that offer genetic background assessment of mouse genomes. However, a typical individual SNP query yields only two alleles (A vs. B), limiting the application of this methodology to distinguishing contributions from no more than two inbred mouse strains. By contrast, simple sequence length polymorphism (SSLP) analysis yields multiple alleles but is not amenable to high-throughput testing. We sought to devise a SNP-based technique to identify donor strain origins when three distinct mouse strains potentially contribute to the genetic makeup of an individual mouse. A computational approach was used to devise a three-strain analysis (3SA) algorithm that would permit identification of three genetic backgrounds while still using a binary-output SNP platform. A panel of 15 mosaic mice with contributions from BALB/c, C57Bl/6, and DBA/2 genetic backgrounds was bred and analyzed using a genome-wide SNP panel using 1449 markers. The 3SA algorithm was applied and then validated using SSLP. The 3SA algorithm assigned 85% of 1449 SNPs as informative for the C57Bl/6, BALB/c, or DBA/2 backgrounds, respectively. Testing the panel of 15 F2 mice, the 3SA algorithm predicted donor strain origins genome-wide. Donor strain origins predicted by the 3SA algorithm correlated perfectly with results from individual SSLP markers located on five different chromosomes (n=70 tests). We have established and validated an analysis algorithm based on binary SNP data that can successfully identify the donor strain origins of chromosomal regions in mice that are bred from three distinct inbred mouse strains.  相似文献   

7.
8.
Forty-four inbred and four randombred rat strains and 20 inbred mouse strains were examined for their Ah phenotype by determining the induction of liver microsomal aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity (EC 1.14.14.1) by intraperitoneal treatment with either β-naphthoflavone or 3-methylcholanthrene. All 48 rat strains were found to be Ah-responsive. The maximally induced hydroxylase specific activities of the ALB/Pit, MNR/Pit, MR/Pit, SHR/Pit, and Sprague-Dawley strains were of the same order of magnitude as the basal hydroxylase specific activities of the ACI/Pit, F344/Pit, OKA/Pit, and MNR/N strains. Six of the 20 mouse strains were Ah-nonresponsive (i.e. lacking the normal induction response and presumably lacking detectable amounts of the Ah receptor). The basal hydroxylase specific activities of the BDL/N, NFS/N, STAR/N, and ST/JN mouse strains were more than twice as high as the maximally induced hydroxylase specific activity of the CBA/HT strain.——To date, 24 Ah-nonresponsive mouse strains have been identified, out of a total of 68 known to have been characterized. The reasons for not finding a single Ah-nonresponsive inbred rat strain—as compared with about one Ah-nonresponsive inbred mouse strain found for every three examined—remain unknown.  相似文献   

9.
We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the β-adrenergic receptor blocker atenolol or under a low and a high dose of the β-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H2>0.7) and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to β-stimulation and β-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains.  相似文献   

10.
Experimental analysis of background dependenteffects of genetic interactions can be designed usingstrains generated by introgression of small geneticregions containing identical genotypes at loci in question into different inbred strains. We usea novel multilocus paradigm, denoted conditionalintergenic functional association (CIFA), to simulatethis procedure, with the trade-off of power forconvenience that is affordable when sufficiently strongeffects are present. We analyze nine enzyme loci atthree chromosomes in groups of D. melanogasterwith different developmental rates that showed similarallelic frequencies at individual loci. Resultsobtained suggest the presence of adaptive interactionbetween particular alleles at two loci when geneticvariation at seven background loci is eliminated.Biochemical considerations show that, in the resultingdevelopmental context, strong interaction between thesegenes may emerge from shifted control of the pentosephosphate pathway, with cascading effects on theglycolysis, TCA cycle, and biosynthetic pathways: one genemay assume control of the irreversible rate-limitingstep in the pentose phosphate pathway, whereas the othergene may assume control of the NADP+ levelthat regulates the same rate-limiting step as anelectron acceptor. The newly developing functionalgenomics research and the absence of inbreeding makeCIFA directly applicable to complex human traits inlarge samples.  相似文献   

11.
目的建立近交系实验用鱼DNA检测方法,用于遗传质量控制。方法以RR-B、RW-H、BY-F三个近交系剑尾鱼的基因组DNA为主要研究对象,并以非选育剑尾鱼作对照,采用STR(short tandem repeat)引物扩增方法检测不同品系在DNA上的异同。设计10对STR引物,优化PCR电泳条件,使用相同的实验条件进行重复,以得到可靠的扩增条带,筛选出特异性引物。结果有4对引物可扩增出稳定条带,1对引物(AY204223)的PCR扩增条带在非选育群中表现多态性,在RR-B与BY-F系表型一致,与RW-H表型不同。这些STR位点能够区分剑尾鱼三个近交系品系。结论STR检测技术可望用于近交系剑尾鱼的遗传质量监测。  相似文献   

12.
昆明小鼠4个可能近交系的基因分型验证   总被引:1,自引:0,他引:1  
在我国,昆明小鼠作为一种实验动物广泛应用于药理和遗传学相关的研究领域。但由于昆明小鼠属于远交群,而且不同地区的种群间已经出现了严重分化,缺乏具有显著特征的近交系,这使得它在生物学上的应用受到了很大的限制。研究人员已经以昆明小鼠为背景培育出了几个可能的近交系,但由于缺乏可靠的遗传检测,至今未得到广泛的认可和应用。文章收集昆明小鼠的4个已经60代以上兄妹交配繁殖的可能近交系,并以两个标准近交系BALB/c和C57BL/6为参照,利用30个微卫星标记对每个品系的5只小鼠进行了微卫星基因分型,进而分析其遗传纯度。结果发现,品系A1和品系N4在本研究所用的30个位点均呈纯合状态;而T2和N2均在D15Mit16位点呈杂合状态。本研究第一次为我国昆明小鼠近交系的遗传学纯度提供了可靠的分子水平证据。今后应当加强昆明小鼠近交系的标准化,以扩大其在遗传学方面的应用。  相似文献   

13.
Mutant laboratory mice with distinctive hair phenotypes are useful for identifying genes responsible for hair diseases. The work presented here demonstrates that shotgun proteomic profiling can distinguish hair shafts from different inbred mouse strains. For this purpose, analyzing the total hair shaft provided better discrimination than analyzing the isolated solubilized and particulate (cross-linked) fractions. Over 100 proteins exhibited significant differences among the 11 strains and 5 mutant stocks across the wide spectrum of strains surveyed. Effects on the profile of single gene mutations causing hair shaft defects were profound. Since the hair shaft provides a discrete sampling of the species proteome, with constituents serving important functions in epidermal appendages and throughout the body, this work provides a foundation for non-invasive diagnosis of genetic diseases of hair and perhaps other tissues.  相似文献   

14.
The genetics of phenotypic variation in inbred mice has for nearly a century provided a primary weapon in the medical research arsenal. A catalog of the genetic variation among inbred mouse strains, however, is required to enable powerful positional cloning and association techniques. A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, yet the common use of hundreds of inbred strains in medical research motivates the need for a high-density variation map of a larger set of strains. Here we report a dense set of genotypes from 94 inbred mouse strains containing 10.77 million genotypes over 121,433 single nucleotide polymorphisms (SNPs), dispersed at 20-kb intervals on average across the genome, with an average concordance of 99.94% with previous SNP sets. Through pairwise comparisons of the strains, we identified an average of 4.70 distinct segments over 73 classical inbred strains in each region of the genome, suggesting limited genetic diversity between the strains. Combining these data with genotypes of 7570 gap-filling SNPs, we further imputed the untyped or missing genotypes of 94 strains over 8.27 million Perlegen SNPs. The imputation accuracy among classical inbred strains is estimated at 99.7% for the genotypes imputed with high confidence. We demonstrated the utility of these data in high-resolution linkage mapping through power simulations and statistical power analysis and provide guidelines for developing such studies. We also provide a resource of in silico association mapping between the complex traits deposited in the Mouse Phenome Database with our genotypes. We expect that these resources will facilitate effective designs of both human and mouse studies for dissecting the genetic basis of complex traits.PHENOTYPIC variation among inbred mouse strains exposed to a disease-causing agent (be it genetic, infectious, or environmental) provides potential insight into human disease processes that often cannot be practically achieved through direct human studies. Indeed, hundreds of phenotype measurements related to human diseases are available for dozens of inbred strains in common use over the past 50–100 years (Bogue et al. 2007; Grubb et al. 2009). As with the direct study of chronic disease in humans, key steps toward determining the genetic underpinnings of this phenotypic variation are to develop a catalog of the genetic variation among inbred mouse strains and to interpret the structure of variation patterns across the strains. Recent advances in high-throughput genotyping and DNA resequencing technologies are making it possible to rapidly uncover the genetic variation maps of many model organisms (Lindblad-Toh et al. 2005; Mackay and Anholt 2006; Borevitz et al. 2007; Frazer et al. 2007; International Hapmap Consortium 2007; Star Consortium 2008). A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, allowing researchers to infer patterns of genetic variation and to identify the ancestral origin of the genetic variation (Frazer et al. 2007; Yang et al. 2007). Yet the availability and common experimental employment of hundreds of inbred strains, including >190 stocks available from the Jackson Laboratory, motivates the need for a high-density variation map for a larger set of strains. We have assembled the Mouse HapMap, a resource consisting of a dense set of genotypes for a total of 138,980 unique biallelic single nucleotide polymorphisms (SNPs) in 94 inbred mouse strains at an average spacing of 20 kb on chromosomes 1–19 and X.This resource is ideal for performing high-resolution mapping studies under QTL peaks. We evaluate the feasibility and effectiveness of such studies by examining a typical study from the Mouse Phenome Database (MPD) (Bogue et al. 2007; Grubb et al. 2009) (http://www.jax.org/phenome) and measure the statistical power to detect genetic associations in regions of various sizes. We provide several resources to the mouse genetics community for supporting such studies and a webserver that can estimate the significance threshold, compute the statistical power of a proposed study, and perform in the fine mapping of measured phenotypes. In addition, we provide a database of associations for all phenotypes contained in the MPD. The web resources are available at http://mouse.cs.ucla.edu/.  相似文献   

15.
目的对IRM-2、ICR及615小鼠骨髓细胞体外照射后细胞损伤进行比较研究,探讨IRM-2小鼠的抗辐射损伤机制。方法用常规法进行外周血白细胞和骨髓有核细胞计数;应用化学发光法检测不同剂量γ射线对小鼠骨髓细胞活力的影响;用PA法(FITC-Annexin V和PI标记法)检测骨髓细胞凋亡。结果IRM-2小鼠骨髓细胞和外周血白细胞计数高于ICR、615小鼠,经统计学处理后差异有显著性(P〈0.01)。经1 Gy、4 Gy照射后6 h,IRM-2、ICR、615小鼠骨髓细胞相对活力分别为86.6%和79.3%,77.5%和70.4%,77.4%和68.7%,IRM-2小鼠与ICR、615小鼠比较,细胞活力有所提高,IRM-2小鼠骨髓造血细胞死亡率及凋亡率低于ICR及615小鼠。结论IRM-2小鼠有较强的免疫及造血功能,骨髓造血细胞凋亡率低于ICR及615小鼠,其抗辐射机制仍需进一步研究。  相似文献   

16.
多重PCR在几个近交系小鼠遗传检测中的应用初探   总被引:6,自引:1,他引:6  
目的 探讨多重PCR方法在小鼠微卫星检测中的应用。方法 用 34对特异性引物对AKR、BALB c、C57 BL、DBA 2、CBA、A WY、6 15、T739、BALB cJ和AKR J 10个品系的近交系小鼠用PCR方法进行遗传检测 ,并从中选用 4对引物 ,对这些品系小鼠进行二重和多重PCR检测。结果 二重PCR在与单一PCR相同的反应条件下 ,扩增出两条与预期条带相同的带 ,而三重PCR则没有得到三条预期的条带 ,出现了干扰现象。结论 通过二条条带的距离可以鉴别出不同的近交系小鼠 ,二重PCR可应用于近交系小鼠的遗传检测 ,具有方便简单、省时的优点  相似文献   

17.
Genetic variation in pathogen populations may be an important factor driving heterogeneity in disease dynamics within their host populations. However, to date, we understand poorly how genetic diversity in diseases impact on epidemiological dynamics because data and tools required to answer this questions are lacking. Here, we combine pathogen genetic data with epidemiological monitoring of disease progression, and introduce a statistical exploratory method to investigate differences among pathogen strains in their performance in the field. The method exploits epidemiological data providing a measure of disease progress in time and space, and genetic data indicating the relative spatial patterns of the sampled pathogen strains. Applying this method allows to assign ranks to the pathogen strains with respect to their contributions to natural epidemics and to assess the significance of the ranking. This method was first tested on simulated data, including data obtained from an original, stochastic, multi-strain epidemic model. It was then applied to epidemiological and genetic data collected during one natural epidemic of powdery mildew occurring in its wild host population. Based on the simulation study, we conclude that the method can achieve its aim of ranking pathogen strains if the sampling effort is sufficient. For powdery mildew data, the method indicated that one of the sampled strains tends to have a higher fitness than the four other sampled strains, highlighting the importance of strain diversity for disease dynamics. Our approach allowing the comparison of pathogen strains in natural epidemic is complementary to the classical practice of using experimental infections in controlled conditions to estimate fitness of different pathogen strains. Our statistical tool, implemented in the R package StrainRanking, is mainly based on regression and does not rely on mechanistic assumptions on the pathogen dynamics. Thus, the method can be applied to a wide range of pathogens.  相似文献   

18.
Infection with monkeypox virus (MPXV) causes disease manifestations in humans that are similar, although usually less severe, than those of smallpox. Since routine vaccination for smallpox ceased more than 30 years ago, there is concern that MPXV could be used for bioterrorism. Thus, there is a need to develop animal models to study MPXV infection. Accordingly, we screened 38 inbred mouse strains for susceptibility to MPXV. Three highly susceptible wild-derived inbred strains were identified, of which CAST/EiJ was further developed as a model. Using an intranasal route of infection with an isolate of the Congo Basin clade of MPXV, CAST/EiJ mice exhibited weight loss, morbidity, and death in a dose-dependent manner with a calculated 50% lethal dose (LD50) of 680 PFU, whereas there were no deaths of BALB/c mice at a 10,000-fold higher dose. CAST/EiJ mice exhibited greater MPXV sensitivity when infected via the intraperitoneal route, with an LD50 of 14 PFU. Both routes resulted in MPXV replication in the lung, spleen, and liver. Intranasal infection with an isolate of the less-pathogenic West African clade yielded an LD50 of 7,600 PFU. The immune competence of CAST/EiJ mice was established by immunization with vaccinia virus, which induced antigen-specific T- and B-lymphocyte responses and fully protected mice from lethal doses of MPXV. The new mouse model has the following advantages for studying pathogenesis of MPXV, as well as for evaluation of potential vaccines and therapeutics: relative sensitivity to MPXV through multiple routes, genetic homogeneity, available immunological reagents, and commercial production.Monkeypox virus (MPXV), a member of the orthopoxvirus genus of the Chordopoxvirinae subfamily of the Poxviridae, was isolated in 1958 from lesions in a cynomolgous monkey that had been imported from Africa (27). The first human infections with MPXV were reported in 1972, and since then more than two thousand cases have been recorded, most in the Democratic Republic of the Congo and lesser numbers in West African countries (reviewed by Parker et al. [18]). The mortality from human monkeypox in the Congo is estimated to be 10% of infected individuals with clinical symptoms that mimic smallpox, which is caused by another member of the orthopoxvirus genus: variola virus. However, whereas the host range of variola virus is restricted to humans, serological studies indicate that MPXV naturally infects a large number of animal species, particularly squirrels and nonhuman primates. The sporadic occurrence of human monkeypox is thought to arise from close proximity and handling of infected animals. In this respect, a self-limited outbreak in the United States was traced to a shipment of West African rodents (19). Although monkeypox is a minor public health problem when compared historically to smallpox, the potential for expansion of the MPXV host range and adaptations to enhance human transmission make it prudent to continue careful surveillance. Moreover, the potential use of MPXV for bioterrorism has led to its inclusion as a select agent in the United States (http://www.selectagents.gov).Animal models are crucial for studying virus pathogenesis, and MXPV is no exception. Ground squirrels (22, 26), black-tailed prairie dogs (9, 11, 13, 30), and African dormice (23) are highly susceptible to MPXV. However, as experimental systems, each has limitations with regard to unavailability of commercial breeding, genetic heterogeneity and absence of immunological and other reagents. Laboratory mice, including BALB/c, C57BL/6, and several other mouse strains tested, were found to be resistant to MPXV disease unless impaired in innate or acquired immunity (10, 17, 24). In the present study, we tested a large group of distinct inbred strains of mice chosen for genetic diversity, inclusion of classical and wild-derived strains, and commercial availability. Of 38 inbred mouse strains tested, three wild-derived strains were highly susceptible to MPXV. One of these, CAST/EiJ, was further characterized with regard to MPXV strain sensitivity, route of inoculation, virus dissemination, immune response, and protection by vaccination and drug treatment.  相似文献   

19.
20.

Objective

Proliferation and migration of vascular smooth muscle cells (SMCs) are central for arterial diseases including atherosclerosis and restenosis. We hypothesized that the underlying mechanisms may be modeled by carotid ligation in mice. In FVB/N inbred mice, ligation leads to abundant neointima formation with proliferating media-derived SMCs, whereas in C57BL/6 mice hardly any neointima is formed. In the present study, we aimed to identify the chromosomal location of the causative gene variants in an F2 intercross between these two mouse strains.

Methods and Results

The neointimal cross-sectional area was significantly different between FVB/N, C57BL/6 and F1 female mice 4 weeks after ligation. Carotid artery ligation and a genome scan using 800 informative SNP markers were then performed in 157 female F2 mice. Using quantitative trait loci (QTL) analysis, we identified suggestive, but no genome-wide significant, QTLs on chromosomes 7 and 12 for neointimal cross-sectional area and on chromosome 14 for media area. Further analysis of the cross revealed 4 QTLs for plasma cholesterol, which combined explained 69% of the variation among F2 mice.

Conclusions

We identified suggestive QTLs for neointima and media area after carotid ligation in an intercross of FVB/N and C57BL/6 mice, but none that reached genome-wide significance indicating a complex genetic architecture of the traits. Genome-wide significant QTLs for total cholesterol levels were identified on chromosomes 1, 3, 9, and 12.  相似文献   

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