Structure and Distribution of Endogenous Nonecotropic Murine Leukemia Viruses in Wild Mice

Virtually all of our present understanding of endogenous murine leukemia viruses (MLVs) is based on studies with inbred mice. To develop a better understanding of the interaction between endogenous retroviruses and their hosts, we have carried out a systematic investigation of endogenous nonecotropic MLVs in wild mice. Species studied included four major subspecies of Mus musculus (M. m. castaneus, M. m. musculus, M. m. molossinus, and M. m. domesticus) as well as four common inbred laboratory strains (AKR/J, HRS/J, C3H/HeJ, and C57BL/6J). We determined the detailed distribution of nonecotropic proviruses in the mice by using both env- and long terminal repeat (LTR)-derived oligonucleotide probes specific for the three different groups of endogenous MLVs. The analysis indicated that proviruses that react with all of the specific probes are present in most wild mouse DNAs tested, in numbers varying from 1 or 2 to more than 50. Although in common inbred laboratory strains the linkage of group-specific sequences in env and the LTR of the proviruses is strict, proviruses which combine env and the LTR sequences from different groups were commonly observed in the wild-mouse subspecies. The “recombinant” nonecotropic proviruses in the mouse genomes were amplified by PCR, and their genetic and recombinant natures were determined. These proviruses showed extended genetic variation and provide a valuable probe for study of the evolutionary relationship between MLVs and the murine hosts.     

Physical performance and soleus muscle fiber composition in wild-derived and laboratory inbred mouse strains.

We compared four inbred mouse strains in their physical performance, measured as a maximal treadmill running time, characteristics of soleus muscle, anatomic character, and growth. The strains used were Mus musculus domesticus [C57BL/6 (B6) and BALB/c], Mus musculus molossinus (MSM/Ms), and Mus spretus. Maximal running time was significantly different among these four mouse strains. Running time until exhaustion was highest in MSM/Ms and lowest in M. spretus. Maximal times for the laboratory mouse strains were nearly identical. Soleus muscle fiber type and cross-sectional area also differed significantly among the species. In particular, M. spretus was significantly different from the other inbred mouse strains. Growth in the wild-derived inbred mice appeared to be complete earlier than in the laboratory mice, and the body size of the wild strains was about half that of the laboratory strains. From these results, we propose that wild-derived inbred mouse strains are useful models for enhancing phenotypic variation in physical performance and adaptability.     

Analysis of wild-derived mice for Fv-1 and Fv-2 murine leukemia virus restriction loci: a novel wild mouse Fv-1 allele responsible for lack of host range restriction.

Wild-derived mice originally obtained from Asia, Africa, North America, and Europe were typed for in vitro sensitivity to ecotropic murine leukemia viruses and for susceptibility to Friend virus-induced disease. Cell cultures established from some wild mouse populations were generally less sensitive to exogenous virus than were cell cultures from laboratory mice. Wild mice also differed from inbred strains in their in vitro sensitivity to the host range subgroups defined by restriction at the Fv-1 locus. None of the wild mice showed the Fv-1n or Fv-1b restriction patterns characteristic of most inbred strains, several mice resembled the few inbred strains carrying Fv-1nr, and most differed from laboratory mice in that they did not restrict either N- or B-tropic murine leukemia viruses. Analysis of genetic crosses of Mus spretus and Mus musculus praetextus demonstrated that the nonrestrictive phenotype is controlled by a novel allele at the Fv-1 locus, designated Fv-10. The wild mice were also tested for sensitivity to Friend virus complex-induced erythroblastosis to type for Fv-2. Only M. spretus was resistant to virus-induced splenomegaly and did not restrict replication of Friend virus helper murine leukemia virus. Genetic studies confirmed that this mouse carries the resistance allele at Fv-2.     

Sperm Morphology in Two House Mouse Subspecies: Do Wild-Derived Strains and Wild Mice Tell the Same Story?

Being subject to intense post-copulatory selection, sperm size is a principal determining component of male fitness. Although previous studies have presented comparative sperm size data at higher taxonomic levels, information on the evolution of sperm size within species is generally lacking. Here, we studied two house mouse subspecies, Mus musculus musculus and Mus musculus domesticus, which undergo incipient speciation. We measured four sperm dimensions from cauda epididymis smears of 28 wild-caught mice of both subspecies. As inbred mouse strains are frequently used as proxies for exploring evolutionary processes, we further studied four wild-derived inbred strains from each subspecies. The subspecies differed significantly in terms of sperm head length and midpiece length, and these differences were consistent for wild mice and wild-derived strains pooled over genomes. When the inbred strains were analyzed individually, however, their strain-specific values were in some cases significantly shifted from subspecies-specific values derived from wild mice. We conclude that: (1) the size of sperm components differ in the two house mouse subspecies studied, and that (2) wild-derived strains reflect this natural polymorphism, serving as a potential tool to identify the genetic variation driving these evolutionary processes. Nevertheless, we suggest that more strains should be used in future experiments to account for natural variation and to avoid confounding results due to reduced variability and/or founder effect in the individual strains.     

The phenotypic distribution of quantitative traits in a wild mouse F1 population

The human complex diseases such as hypertension, precocious puberty, and diabetes have their own diagnostic thresholds, which are usually estimated from the epidemiological data of nature populations. In the mouse models, numerous phenotypic data of complex traits have been accumulated; however, knowledge of the phenotypic distribution of the natural mouse populations remains quite limited. In order to investigate the distribution of quantitative traits of wild mice, 170 F1 progeny aged 8-10?weeks and derived from wild mice collected from eight spots in the suburbs of Shanghai were tested for their values of anatomic, blood chemical, and blood hematological parameters. All the wild mice breeders were of Mus. m. musculus and Mus. m. castaneus maternal origin according to the single nucleotide polymorphism (SNP) markers of the mitochondrial DNA. The results showed that phenotypes in wild mice had a normal distribution with four to six times the standard deviation. For the majority of the traits, the wild outbred mice and laboratory inbred mice have significantly different ranges and mean values, whereas the wild mice did not necessarily show more phenotypic diversity than the inbred ones. Our data also showed that natural populations may have some unique phenotypes related to sugar and protein metabolism, as the mean value of wild mice differ dramatically from the inbred mice in the levels of blood glucose, BUN (blood urea nitrogen), and total blood protein. The epidemiological information of the complex traits in the nature population from our study provided valuable reference for the application of mouse models in those complex disease studies.     

DNA segments mapped by reciprocal use of microsatellite primers between mouse and rat

Rat microsatellite primers were used for detection of homologous DNA segments in the mouse species (Mus laboratorius, Mus musculus musculus, and Mus spretus). Twenty five (16.3%) of 153 rat primer pairs amplified specific DNA segments, when genomic DNA of mice was used as a template in the polymerase chain reaction (PCR). Size variation among inbred strains of mice was found for 13 DNA segments (8.5%). Eight out of the 13 polymorphic DNA segments were mapped to a particular chromosome with two sets of recombinant inbred strains, AKXL or BXD. Similarly, mouse microsatellite primers were used for detection of homologous DNA segments in rats (Rattus norvegicus). Twenty (12.0%) of 166 primer pairs amplified specific DNA segments from rat genome. Size variation among inbred strains of rats was found for seven DNA segments (4.2%). Eleven of these 20 DNA segments were mapped with a rat x mouse somatic cell hybrid clone panel and/or linkage analysis by use of backcross progeny. Our results suggest that the mapped DNA segments are really homologs between mouse and rat. These polymorphic DNA segments are useful genetic markers.     

小家鼠和实验小鼠遗传特性的比较研究

本文用同工酶电泳法、微量细胞毒法和免疫双向扩散法对我国4个动物地理区的6个采集点的156个小家鼠(Mus musculus)进行了遗传特性的调查。结果发现:在全部被测的13个位点中,小家鼠在7个位点上存在着多种实验小鼠中罕见的基因组成;而不同动物地理区和亚区的小家鼠的遗传特性又各不相同。从而指出将小家鼠的特有基因导入实验小鼠,培育新品系的重大意义。     

Phylogenetic relationships and genetic polymorphisms in wild Indian mice

Randomly amplified polymorphic DNA (RAPD) analysis was used to examine the extent of variability in 11 Indian wild derived commensal house mice (Mus musculus) populations and compared with inbred strains of musculus and domesticus subspecies as well as commonly used laboratory inbred strains C57BL/6J and DBA/2J. Arbitrary designed 10 mer oligonucleotide primers with 60-70% (G+C) content were used to amplify DNA template. Out of 52 primers screened initially on the laboratory strains, 20 were selected for analysis on the basis of amplification product in the size range of 200-1400 bp. Among 353 total polymorphic bands, 220 bands (64%) were found to be polymorphic in Indian wild mice, 85 bands (25%) in wild derived inbred strains and 37 bands (11%) in laboratory mice strains. The amplification patterns produced by primers were statistically analysed by Jaccard's similarity coefficient the value of which ranged from 0.56 to 0.80. High level of genetic diversity was seen in the Indian wild mice populations as compared to the controls. The UPGMA phenogram grouped mice population into two major clusters except Bikaner [BIK], Bilaspur [BIL] and Ranikhet [RK] populations which were placed outside the close-knit clusters. Inspite of low values of bootstrap estimates obtained by Wagner and Dollo parsimony analysis, the results were comparable with UPGMA phenogram when constitution of the populations in the major cluster was considered. Indian mice populations appeared to be diverse from laboratory inbred mice strains.     

Common inbred strains of the laboratory mouse that are susceptible to infection by mouse xenotropic gammaretroviruses and the human-derived retrovirus XMRV

Laboratory mouse strains carry endogenous copies of the xenotropic mouse leukemia viruses (X-MLVs), named for their inability to infect cells of the laboratory mouse. This resistance to exogenous infection is due to a nonpermissive variant of the XPR1 gammaretrovirus receptor, a resistance that also limits in vivo expression of germ line X-MLV proviruses capable of producing infectious virus. Because laboratory mice vary widely in their proviral contents and in their virus expression patterns, we screened inbred strains for sequence and functional variants of the XPR1 receptor. We also typed inbred strains and wild mouse species for an endogenous provirus, Bxv1, that is capable of producing infectious X-MLV and that also contributes to the generation of pathogenic recombinant MLVs. We identified the active Bxv1 provirus in many common inbred strains and in some Japanese Mus molossinus mice but in none of the other wild mouse species that carry X-MLVs. Our screening for Xpr1 variants identified the permissive Xpr1(sxv) allele in 7 strains of laboratory mice, including a Bxv1-positive strain, F/St, which is characterized by lifelong X-MLV viremia. Cells from three strains carrying Xpr1(sxv), namely, SWR, SJL, and SIM.R, were shown to be infectable by X-MLV and XMRV; these strains carry different alleles at Fv1 and vary in their sensitivities to specific X/P-MLV isolates and XMRV. Several strains with Xpr1(sxv) lack the active Bxv1 provirus or other endogenous X-MLVs and may provide a useful model system to evaluate the in vivo spread of these gammaretroviruses and their disease potential in their natural host.     

Nucleotide variation in wild and inbred mice

The house mouse is a well-established model organism, particularly for studying the genetics of complex traits. However, most studies of mice use classical inbred strains, whose genomes derive from multiple species. Relatively little is known about the distribution of genetic variation among these species or how variation among strains relates to variation in the wild. We sequenced intronic regions of five X-linked loci in large samples of wild Mus domesticus and M. musculus, and we found low levels of nucleotide diversity in both species. We compared these data to published data from short portions of six X-linked and 18 autosomal loci in wild mice. We estimate that M. domesticus and M. musculus diverged <500,000 years ago. Consistent with this recent divergence, some gene genealogies were reciprocally monophyletic between these species, while others were paraphyletic or polyphyletic. In general, the X chromosome was more differentiated than the autosomes. We resequenced classical inbred strains for all 29 loci and found that inbred strains contain only a small amount of the genetic variation seen in wild mice. Notably, the X chromosome contains proportionately less variation among inbred strains than do the autosomes. Moreover, variation among inbred strains derives from differences between species as well as from differences within species, and these proportions differ in different genomic regions. Wild mice thus provide a reservoir of additional genetic variation that may be useful for mapping studies. Together these results suggest that wild mice will be a valuable complement to laboratory strains for studying the genetics of complex traits.     

Wild Mice As Bountiful Resources of Novel Genetic Variants for Quantitative Traits

Most traits of biological importance, including traits for human complex diseases (e.g., obesity and diabetes), are continuously distributed. These complex or quantitative traits are controlled by multiple genetic loci called QTLs (quantitative trait loci), environments and their interactions. The laboratory mouse has long been used as a pilot animal model for understanding the genetic architecture of quantitative traits. Next-generation sequencing analyses and genome-wide SNP (single nucleotide polymorphism) analyses of mouse genomes have revealed that classical inbred strains commonly used throughout the world are derived from a few fancy mice with limited and non-randomly distributed genetic diversity that occurs in nature and also indicated that their genomes are predominantly Mus musculus domesticus in origin. Many QTLs for a huge variety of traits have so far been discovered from a very limited gene pool of classical inbred strains. However, wild M. musculus mice consisting of five subspecies widely inhabit areas all over the world, and hence a number of novel QTLs may still lie undiscovered in gene pools of the wild mice. Some of the QTLs are expected to improve our understanding of human complex diseases. Using wild M. musculus subspecies in Asia as examples, this review illustrates that wild mice are untapped natural resources for valuable QTL discovery.     

Haemoglobin variants in mice.

Haemoglobin variants were studied in wild and laboratory house mice (Mus musculus), including standard and new inbred strains, using starch-gel electrophoretic technique. Single (Hbbs) or diffuse (Hbbd) types of haemoglobin were found in all of them. The embryonic haemoglobin pattern was different from although similar to that of the adult in all the strains. The haemoglobins revealed monomorphism in the inbred strains, while polymorphism was observed in non-inbred laboratory and wild mice.     

Polymorphism of Unique Noncoding DNA Sequences in Wild and Laboratory Mice

Two DNA probes, D17Tu1 and D17Tu2, were isolated from a genomic DNA library containing only two mouse chromosomes, one of which is chromosome 17, carrying the major histocompatibility complex (H-2), as well as the t complex genes. The D17Tu1 probe was mapped to the centromeric region of chromosome 17 and the D17Tu2 probe to the S region of the H-2 complex. Neither of the two probes appeared to detect any genes, but both contained unique, nonrepetitive sequences. Typing of DNA obtained from a large panel of mice revealed the presence of four D17Tu1 patterns in inbred mouse strains, one very common, one less common, and two present in one strain each. The two common patterns could not be detected in appreciable frequencies in the European wild mice tested (one of the two patterns was, however, found in Australian wild mice). Conversely, the patterns found frequently in European wild mice are absent in the laboratory mice. We therefore conclude that wild mice from the sampled regions of Europe could not have provided the ancestral stocks from which inbred strains were derived. Only one D17Tu1 pattern was found in all the populations of Mus musculus tested, while eight patterns were found in Mus domesticus, with virtually all the populations being polymorphic. We suggest that this difference reflects different modes in which the two species colonized Europe. The distribution of the D17Tu2 patterns in inbred strains correlates with the distribution of H-2 haplotypes.     

Diversity of mammary tumor viral genes within the genus Mus, the species Mus musculus, and the strain C3H.

Proviral sequences complementary to the C3H mouse mammary tumor virus RNA genome are present in the DNA of early occurring mammary tumors of C3H/HeN mice and are absent from apparently normal C3H/HeN tissues; these sequences are non-germ line transmitted in C3H/HeN mice and have been termed tumor-associated sequences; (W. Drohan et al., J. Virol. 21:986-995, 1977). We report here that tumor-associated sequences are present in the DNA of spontaneous mammary tumors that occur early in the life of several inbred, high-tumor-incidence mouse strains but are absent in mammary tumors that occur later in life in low- and moderate-tumor-incidence strains. These sequences are also absent in apparently normal organs tested from numerous laboratory mouse strains, feral mice, Mus musculus subspecies, and other Mus species. Sequences represented in tumor-associated sequence RNA, however, are present as endogenous provirus in GR mice (at approximately four copies per haploid genome) and in two of five substrains of C3H mice tested (at approximately one copy per haploid genome). The two substrains of C3H mice positive for endogenous tumor-associated sequence provirus were recently (circa 1930) separated from the negative substrains of C3H mice. The results may be explained by the unlikely chance segregation of proviral sequences or by the recent integration of viral genes (within the last few decades). Whereas radioactively labeled mouse mammary tumor virus 60-70S RNA or complementary DNA detected mouse mammary tumor virus-related proviral information in all laboratory mouse strains, feral mice, subspecies of M. musculus, and other species of Mus, the use of tumor-associated sequence RNA clearly revealed the genetic diversity that may exist between different colonies or substrains of "inbred" laboratory mice commonly used in cancer research.     

Multi-phenotype behavioral characterization of inbred strains derived from wild stocks of Mus musculus

Many aspects of mouse behavior have been studied by using only a relatively small sample of available laboratory strains. These laboratory mice were derived from the so-called ``fancy mouse' and in most cases underwent extensive domestication before inbreeding. Thus, the behavioral repertoire of the laboratory mouse may be very different from that exhibited by stocks that have not been deliberately domesticated. Another inherent problem in analyzing mouse behavior is that genetic diversity is limited among currently available strains. In this respect, the use of strains that are derived from a variety of wild mice should provide a means to identifying novel behavioral phenotypes. We have investigated several behavioral phenotypes, using females of a number of mouse strains derived from wild mice of different subspecies, BFM/2, NJL, BLG2, HMI, CAST/Ei, KJR, SWN and MSM; a strain derived from fancy mice, JF1; and two laboratory strains, C57BL/6 and DBA/1. In this report, tests for locomotor activity, light-dark transitions, passive and active avoidance, and nociception were conducted. The results show great diversity of behavioral patterns between strains in contrast to less within-strain variability. We also found that two strains, KJR and SWN, both have good learning ability, whereas BLG2 mice exhibit impairment in both passive and active avoidance learning. Received: 11 January 2000 / Accepted: 27 March 2000     

Clonal and atypical Toxoplasma strain differences in virulence vary with mouse sub-species

The severe virulence of Toxoplasma gondii in classical laboratory inbred mouse strains contradicts the hypothesis that house mice (Mus musculus) are the most important intermediate hosts for its transmission and evolution because death of the mouse before parasite transmission equals death of the parasite. However, the classical laboratory inbred mouse strains (Mus musculus domesticus), commonly used to test Toxoplasma strain differences in virulence, do not capture the genetic diversity within Mus musculus. Thus, it is possible that Toxoplasma strains that are severely virulent in laboratory inbred mice are avirulent in some other mouse sub-species. Here, we present insight into the responses of individual mouse strains, representing strains of the genetically divergent Mus musculus musculus, Mus musculus castaneus and Mus musculus domesticus, to infection with individual clonal and atypical Toxoplasma strains. We observed that, unlike M. m. domesticus, M. m. musculus and M. m. castaneus are resistant to the clonal Toxoplasma strains. For M. m. musculus, we show that this is due to a locus on chromosome 11 that includes the genes that encode the interferon gamma (IFNG)-inducible immunity-related GTPases (Irgs) that can kill the parasite by localising and subsequently vesiculating the parasitophorous vacuole membrane. However, despite the localization of known effector Irgs to the Toxoplasma parasitophorous vacuole membrane, we observed that some atypical Toxoplasma strains are virulent in all the mouse strains tested. The virulence of these atypical strains in M. m. musculus could not be attributed to individual rhoptry protein 5 (ROP5) alleles, a secreted parasite pseudokinase that antagonises the canonical effector Irgs and is indispensable for parasite virulence in laboratory inbred mice (M. m. domesticus). We conclude that murine resistance to Toxoplasma is modulated by complex interactions between host and parasite genotypes and may be independent of known effector Irgs on murine chromosome 11.     

Distribution of the C1473G polymorphism in tryptophan hydroxylase 2 gene in laboratory and wild mice

The neurotransmitter serotonin is implicated in the regulation of various forms of behavior, including aggression, sexual behavior and stress response. The rate of brain serotonin synthesis is determined by the activity of neuronal‐specific enzyme tryptophan hydroxylase 2. The missense C1473G substitution in mouse tryptophan hydroxylase 2 gene has been shown to lower the enzyme activity and brain serotonin level. Here, the C1473G polymorphism was investigated in 84 common laboratory inbred strains, 39 inbred and semi‐inbred strains derived from wild ancestors (mostly from Eurasia) and in 75 wild mice trapped in different locations in Russia and Armenia. Among all the classical inbred strains studied, only substrains of BALB/c, A and DBA, as well as the IITES/Nga and NZW/NSlc strains were homozygous for the 1473G allele. In contrast to laboratory strains, the 1473G allele was not present in any of the samples from wild and wild‐derived mice, although the wild mice varied substantially in the C1477T neutral substitution closely linked to the C1473G polymorphism. According to these results, the frequency of the 1473G allele in natural populations does not exceed 0.5%, and the C1473G polymorphism is in fact a rare mutation that is possibly eliminated by the forces of natural selection.     

野生TW近交系小鼠主要生理指标

目的建立野生来源TW（Tianjin Wild,TW）近交系小鼠的主要生理、血常规等指标。方法分别选用F28和F29代TW近交系成年雄性小鼠25只,雌性小鼠31只,检测动物的主要生理、血常规指标。结果TW小鼠体重雌雄差异无显著性,脏器指标中雌雄性比较仅肾脏重量、肾脏系数差异有显著性（P〈0.05）;血常规检测指标中,雌雄小鼠在WBC、MCV、MCH、PLT、MONO等5项指标的均值比较差异具有显著性,其他各项均无差别。与ICR、KM、NIH及BALB/c等通用实验小鼠指标比较,TW小鼠的脾脏、脾脏系数和血小板均高于或多倍高于这些通用小鼠品系。结论TW小鼠在一些主要生理指标上与通用实验小鼠品系不同,呈现自身特点。     

Conservation of the immunoglobulin C lambda 5 gene in the Mus gene.

A gene encoding the lambda 5 light chain constant region was isolated from a genomic library from the SPE mouse strain (C lambda 5S). SPE is an inbred wild mouse strain belonging to the Mus 3 or Mus spretus group that has been genetically isolated from Mus 1 (the group to which laboratory mice belong) for a period of 1-3 million years. The sequence of the C lambda 5S gene shows strong homology to C lambda 5 of (C57BL/6J x DBA/2)F1 both in the coding region (98% identity) and in the 5'- and 3'-flanking regions (98 and 95% identity, respectively). Sequence comparison of C lambda 5 genes with C lambda 1 of BALB/c shows only few substitutions in the C lambda 5 coding regions and suggests that the three genes have a common ancestor. These data indicate that the C lambda 5 gene has evolved under strong selective pressure and probably encodes a functional gene product. The conservation of the C lambda 5 gene in various Mus species was observed by high stringency Southern blot analyses using a C lambda 5S probe on DNA sample from members of four different groups of wild mice. All the laboratory and wild mouse strains tested, including those with amplified sets of C lambda 1 and C lambda 2 hybridizing sequences, showed only single C lambda 5 hybridizing fragments. Little variation in size of restriction fragments detected with the C lambda 5 probe was seen in the different Mus species suggesting a high degree of conservation.(ABSTRACT TRUNCATED AT 250 WORDS)     

α-Hydroxyacid Oxidase Genetics in the Mouse: Evidence for Two Genetic Loci and a Tetrameric Subunit Structure for the Liver Isozyme

We have examined a polymorphism for liver GOX in inbred strains of the mouse Mus musculus. Genetic studies demonstrated that the two phenotypes for this enzyme present in BALB/C and NZC parental strains segregated as though they were controlled by codominant alleles at a single autosomal locus (GOX) which mapped closely to the agouti locus in linkage group V. Kidney HAOX activity is invariant in these inbred strains and is encoded by a separate genetic locus designated HAOX. BALB/C x NZC F(1) hybrid mice exhibited three intermediate forms of liver GOX activity, in addition to the parental enzymes, which is consistent with a tetrameric subunit structure.