Correlation of centromeric heterochromatin C-band polymorphism with breeding failure in mice

The aim of the present study was to test the hypothesis about the relation between segregation of chromosomes 14 and 18 and the deterioration of mouse fertility and vitality. The analysis was possible because C-banding on chromosome 14 and chromosome 18 of the CBA/Kw and KE strains show size polymorphism. A small sized C-band on chromosome 14 is characteristic for the CBA/Kw mice, while the KE mice show small C-bands on chromosomes 18. Thus, if fertility parameters are affected in a centromere-dependent manner, we should observe non-random inheritance of both chromosome pairs in recombinant inbred (RI) strains. The results showed statistically significant preferential segregation of chromosomes 14 and 18 with small C-bands. Most of the RI strains inherited chromosome 14 from the CBA/Kw strain and chromosome 18 from the KE strain, and did not manifest a deterioration of fertility and vitality. On the contrary, RI strains that inherited chromosomes 14 and 18 from one of the parental strains, particularly the KE strain, stopped breeding or had difficulties in producing the next generation.     

Gene mapping of sperm quality parameters in recombinant inbred strains of mice

The aim of this study was to map chromosomal regions containing hypothetical genes responsible for the following parameters of mouse semen quality: (1) the percentage of sperm with abnormal head morphology, (2) the level of dead spermatozoa, (3) the percentage of sperm tails with residual cytoplasmic droplets, and (4) the percentage of sperm with impaired sperm tail membrane integrity. We also analyzed any possible correlations between these parameters. The most appropriate animal model for mapping genes controlling quantitative traits (QTL, quantitative trait locus) is a set of recombinant inbred (RI) strains. The set of RI strains used in this study was derived from crosses between two inbred mouse strains, KE and CBA/Kw, which differ significantly in fertility parameters and gamete quality. We analyzed the four parameters of sperm quality in male mice from two parental strains and from 12 RI strains. The strain distribution pattern (SDP) of 187 polymorphic microsatellite markers was prepared for 20 chromosomes of the mouse genome in 12 RI strains. We correlated the SDP of these markers with the values of sperm quality parameters, using MapManager QTX software (ver. b18). The mapping procedure indicated that the percentage of sperm with abnormal head morphology is controlled by gene(s) located in chromosomal regions 11q24, 11q31 and 6q15.6. There was also a strong correlation between male body weight and the hypothetical gene(s) in chromosomal region 18q47. A detailed analysis of the genes located in these regions enabled us to prepare a list of candidate genes. We discuss the basis of the correlation between the measured parameters.     

Cryptosporidium infections in inbred strains of mice.

Cryptosporidium, a protozoan parasite of man and animals, is an important etiological agent of diarrhea throughout the world, particularly in children and immunocompromised individuals such as AIDS patients. Unfortunately, because of the lack of both in vivo laboratory models and reliable in vitro parasite culture systems, virtually nothing is known about the immunological events occurring during disease. In order to identify reliable animal models for infection, we studied C. parvum infections in 19 different strains of mice representing 12 H-2 haplotypes: A/J, AKR/J, B10.D2/J, B10.M/J, C3H/HeJ, C57BL/65, C57BL/6J-bgJ, CBA/NJ, DBA/1J, DBA/2J, HRS/J, HTG/J, NZB/B1NJ, NZW/J, P/J, RIII/J, SJL/J, SWR/J, and WB/ReJ, and in one gerbil: Meriones unguiculatus. Fecal samples and histological sections of the intestine taken on day 7 post-Cryptosporidium inoculation indicated that only the beige mouse (C57BL/6J-bgJ) harbored significant numbers of parasites compared to the other strains. The numbers of parasites harbored in these NK cell-deficient beige mice were, however, considerably lower than those seen in neonatal mice. Adult inbred mouse strains susceptible to Cryptosporidium infections are discussed.     

Prospects for association mapping in classical inbred mouse strains

The collection of classical inbred mouse strains displays heritable variation in a large number of complex traits. Many generations of historical recombination have contributed to the panel of classical strain genomes, raising the possibility that quantitative trait loci could be located with high resolution by correlating strain genotypes and phenotypes. Although this association mapping framework has been successful in several empirical applications, its expected performance remains unclear. We used computer simulations based on a publicly available, dense single-nucleotide polymorphism (SNP) map to measure the power and false-positive rate of association mapping on a genomic scale across 30 commonly used classical inbred strains. Expected power is (i) often low for phenotypic effect sizes that are realistic for complex traits, (ii) highly variable across the genome, and (iii) correlated with linkage disequilibrium, aspects of the allele frequency distribution, and haplotype characteristics, as predicted by theory. Simulations also demonstrate clear potential for spurious associations to be generated by unequal relatedness among the strains. These findings suggest that association mapping in the classical strains is best applied in combination with other procedures, such as QTL mapping.     

Screening of inbred rat strains for electrophoretic protein polymorphisms

Nineteen inbred strains of the laboratory rat (Rattus norvegicus) were investigated for genetic differences by starch and agarose gel electrophoretic techniques. For six out of 21 loci, interstrain differences were observed: Tf, 6PGD, Es-1, Es-4, Es-5, and Svp. The variants are briefly described and the allelic distributions are tabulated. The 6GPD locus was found to be linked neither to the major histocompatibility gene region nor to the coat color genes c, a, h.This investigation was supported by the Deutsche Forschungsgemeinschaft (Be 352/10 and Gu 105).     

The segregation of C-band polymorphisms on chromosomes 1, 9, and 16.

Eleven normal families with at least four children were studied cytogenetically using the C-band technique to identify polymorphisms in the constitutive heterochromatin of chromosomes 1, 9 and 16. Thirteen individuals showed one or more variants in such chromosomes. The analysis of the segregation ratios in the 35 offspring of these 13 individuals showed that these marker chromosomes generally segregated according to the expected 50:50. However, one of these variants, chromosome no. 9 with an increased heterochromatin block in the secondary constriction, has an apparently preferential segregation, when the findings from this study are combined with those of other authors.     

Impulsive choice in inbred strains of mice

When humans or non-humans are given a choice between receiving a sooner-smaller (SS) reinforcer, or a later-larger (LL) reinforcer, the choice of a SS reinforcer represents impulsive choice whereas the choice of a LL reinforcer represents self-controlled choice. It has been suggested that both biological and genetic factors influence impulsive/self-control choice in this paradigm. In the present study, the inbred strains of BALB/c, C57BL/6, and DBA/2 mice were given a choice to press one of two levers in an operant chamber. Depending on their choice, mice received either a smaller reinforcer (one pellet delivered after 6s) sooner (SS) or a larger reinforcer (two pellets after 6, 9, 12, 18, or 30s) later (LL). Mice preference for the larger reinforcer decreased with longer delays. More importantly, the BALB/c mice chose the SS reinforcer more often than the C57BL/6 mice under the 9- and 12-s delays, and more often than the DBA/2 mice under the 9-s delay. This indicates that the choice pattern of the BALB/c strain is more "impulsive" than the other strains and suggests that specific gene configurations influence impulsive choice in mice.     

Variations in serum calcium between strains of inbred mice.

Serum calcium concentrations of C3H/Fg, C3H/HeJFg, AKR/Fg, A/Fg, and LCS/Fg mice were compared at 4 and 7 mo of age. In the C3H/Fg and A-strain mice, calcium levels did not differ significantly between the 2 strains nor between the 2 age groups. The C3H/HeJFg, LCS/Fg, and C57BL/Fg strains formed a distinct group with similar calcium levels, but at a significantly higher level than C3H/Fg and A/Fg group. Again there was no significant difference between the 4- and 7-mo groups. The AKR/Fg strain was distinct from both groups in that higher calcium levels characteristic of the second group (C3H/HeJFg, LCS/Fg, and C57BL/Fg, were seen at 4 mo of age, but lower calcium levels similar to those of the C3H/Fg and A/Fg strains were found at 7 mo of age.     

Quiet mutations in inbred strains of mice

The year 2009 is the 100th anniversary of the founding of the first inbred strain of mouse, called DBA. During the last 100 years, inbred strains have proved their value for biomedical research and the number of such strains has mushroomed to over 450, each with different genotypic and phenotypic characteristics and useful for the study of disease and normal function. However, although inbred strains are stable, they are not fixed entities and researchers need to be aware of the phenomena of new mutations and of genetic drift, which occur within all mouse colonies. If the mutations are what we term in this review 'quiet mutations', then they might result in rather unexpected and sometimes tremendously valuable results. Here, we discuss these phenomena and look at how new genomic technologies might help us to detect 'quiet mutations' and use them to our advantage.     

Identification of inbred strains of mice,Mus musculus. I. Genetic control of inbred strains of mice using starch gel electrophoresis

Fifteen biochemical markers were tested in 30 inbred strains of mice to control the genetic constitution of each strain. Discrepancies in pattern from Standardized Nomenclature for Inbred Strains of Mice are reported and discussed.This work was supported by Grant No. 512–2532 from the Danish Medical Research Council.     

Heritability, correlations and in silico mapping of locomotor behavior and neurochemistry in inbred strains of mice

The midbrain dopamine system mediates normal and pathologic behaviors related to motor activity, attention, motivation/reward and cognition. These are complex, quantitative traits whose variation among individuals is modulated by genetic, epigenetic and environmental factors. Conventional genetic methods have identified several genes important to this system, but the majority of factors contributing to the variation remain unknown. To understand these genetic and environmental factors, we initiated a study measuring 21 behavioral and neurochemical traits in 15 common inbred mouse strains. We report trait data, heritabilities and genetic and non-genetic correlations between pheno-types. In general, the behavioral traits were more heritable than neurochemical traits, and both genetic and non-genetic correlations within these trait sets were high. Surprisingly, there were few significant correlations between the behavioral and the individual neurochemical traits. However, striatal serotonin and one measure of dopamine turnover (DOPAC/DA) were highly correlated with most behavioral measures. The variable accounting for the most variation in behavior was mouse strain and not a specific neurochemical measure, suggesting that additional genetic factors remain to be determined to account for these behavioral differences. We also report the prospective use of the in silico method of quantitative trait loci (QTL) analysis and demonstrate difficulties in the use of this method, which failed to detect significant QTLs for the majority of these traits. These data serve as a framework for further studies of correlations between different midbrain dopamine traits and as a guide for experimental cross designs to identify QTLs and genes that contribute to these traits.     

Multiple single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase and its truncated pseudogene of 23 inbred strains of mice

Reduced 5,10-methylenetetrahydrofolate reductase (MTHFR) results in a number of human diseases. To find a model mouse sensitive to these diseases, we analyzed single-nucleotide polymorphisms (SNPs) of the mouse Mthfr using 23 phylogenetically distant strains of mouse. We found five SNPs: two nonsynonymous and three synonymous. The CAST/Ei strain has the nonsynonymous SNP L350V and five strains (NMRI, KJR, SWN2, MSM, and JF1) have the nonsynonymous SNP S22G. The MTHFR activity of CAST/Ei and MSM showed no significant difference in activity or thermostability compared with that of C57BL/6J. We also found a pseudogene segment of the mouse Mthfr that was not present in human and was more frequently variable than the functional gene. These results suggest a possibility that the truncated pseudogene may buffer variations of the mouse Mthfr functional gene, and the mouse has evolved fewer variations of the gene than human.     

Trichinella spiralis: anaphylactic antibody formation and susceptibility in strains of inbred mice.

The anaphylactic antibody response of various strains of inbred mice of different H-2 specificities was investigated using the passive cutaneous anaphylactic technique (PCA) for the detection of the antibody response. Neither IgC₁ nor reaginic antibody were detected in serum samples obtained at the end of the first week of infection with Trichinella spiralis. Subsequently, all animals had detectable IgG₁ antibodies, although in some strains the titers were very low. Reaginic antibody was detected in relatively high titers in C57L, A, and DBA/1 mice. Two other strains were very poor responders (SJL and AKR). In most strains, reagin and IgG₁ remained detectable for 14 wk or longer. The pattern of response of all strains was very reproducible, indicating genetic control of the anaphylactic antibody production to the infection. In F₁ hybrids obtained from crosses between good and poor anaphylactic antibody responders, intermediate levels of both antibody classes were detected.Adult worm recovery rates were established at various points during the intestinal phase of infection, and no correlation between worm numbers and reaginic antibody titers in the various strains of mice could be demonstrated. There were noticeable differences in larval yields obtained after muscle digestion of mice belonging to the different inbred strains. In fact, we generally observed an inverse relationship between the number of larvae recovered from a given strain and their reaginic antibody titer.The intravenous injection of newborn larvae (NBL), obtained upon in vitro incubation of adult worms, produced detectable antibodies only in mice of the DBA/1 strain. These antibodies were consistently of low titer and became detectable only after the administration of two additional injections of NBL. This contrasted with the results observed after “per os” infection of DBA/1 mice, where high titers of these antibodies were always obtained, in spite of comparable ratios of muscle larval yield.     

Brugia malayi: establishment in inbred and outbred strains of mice

Immunocompetent mouse model for human filarial parasite Brugia malayi is urgently required in view of the paucity of commercial reagents for other susceptible rodent viz. mastomys and gerbil. Genes within the major histocompatibility complex have been reported to influence the susceptibility of mouse to helminth parasites. Attempts have therefore been made in the present investigation to experimentally infect various inbred strains of mice viz. NZB/BINJ, BALB/c, AKR, C(3)H, and SJL/J with H-2 haplotype (H-2: d, d, k, k, s, respectively) and outbred strains of mice viz. Parks and Swiss. Findings indicate that susceptibility of mice to B. malayi is strain associated. This is the first report on the successful completion of full developmental cycle of subperiodic B. malayi in NZB/BINJ, an immunocompetent mouse strain. In some of the other strains, partial development or low degree of establishment of worms was observed.     

Egg production of Clonorchis sinensis in different strains of inbred mice.

In order to compare the intraspecific variation in host-parasite relationship of Clonorchis sinensis, six strains of inbred mice, ICR, DDY, GPC, BALB/c, nude and DS, were infected orally with 20 metacercariae of C. sinensis. The biologic incubation period of C. sinensis was the shortest in DDY mice, 21.2 days in average, followed by GPC 21.4, BALB/c and DS 23.2, ICR and nude 23.4 days, respectively. The fertile period of the fluke was also the longest in the DDY strain, 164 days on average, followed by GPC 132, BALB/c 97, nude 37, DS 32 and ICR 28 days. The egg-laying capacity of the fluke in DDY and GPC was relatively high and stable compared with the other four strains of mice. It was found that there are intraspecific variations in biologic incubation period, fertile period, and fecundity of C. sinensis. The DDY mouse is likely to be the most suitable experimental animal among the six strains of the mice tested.