Faculty Bibliography

Laboratory strains of mice are thought to be derived from wild populations of Mus domesticus. Many instances of non-domesticus genetic information fixed in these strains have been described, however, and the amount of strain-to-strain genetic variation exceeds that found in wild domesticus populations. In order to estimate the extent of the non-domesticus contribution to laboratory mouse genomes, and to determine whether it could account for observed variation, we have used computer simulations to investigate the properties of genetically marked chromosomal segments and the distribution of residual allogenicity at various times during inbreeding. A locus or chromosomal segment is allogenic if it is unfixed within a lineage at a given time. The odds of fixation of a foreign chromosome segment are predicted to be an exponentially decreasing function of its length. The median segment length is predicted to be 17 centimorgans. Available data for markers of chromosomes 1, 9 and 12 in recombinant inbred strain sets conform to these predictions. Together, the results suggest that introgression of non-domesticus chromosomes and segregation of residual allogenicity are sufficient to account for the genetic diversity observed among inbred mouse strains and substrains

The MH-3 gene, which contains a homeo box that is expressed specifically in the adult testis, was identified and mapped to mouse chromosome 6. By means of in situ hybridization with adult testis sections and Northern blot hybridization with testis RNA from prepuberal mice and from Sl/Sld mutant mice, it was demonstrated that this gene is expressed in male germ cells during late meiosis. In the embryo, MH-3 transcripts were present at day 11.5 post coitum, a stage in mouse development when gonadal differentiation has not yet occurred. The MH-3 gene may have functions in spermatogenesis and embryogenesis

DNAs from rat nasal and mouse skin carcinomas and fibrosarcomas induced by the alkylating agents methylmethane sulfonate (MMS), beta-propiolactone (BPL), and dimethylcarbamyl chloride (DMCC) were tested for their ability to transform NIH3T3 cells by DNA transfection. Each of eight MMS-induced rat nasal carcinomas and two of five BPL-induced mouse skin tumors were positive in the transfection assay while all of four fibrosarcomas and six carcinomas induced by DMCC were negative. Anchorage independent growth, tumorigenicity in nude mice, and secondary transfection confirmed the transformed phenotype of the positive transfectants. The transfectants from MMS-induced tumor DNAs did not contain restriction fragments homologous to rat H-, K- or N-ras oncogenes although exogenous (rat) tumor-derived DNA sequences were detected in transfectant genomes by Southern analysis. In contrast a BPL-induced mouse skin tumor showed evidence of containing activated H-ras. These results suggest specificity among causal chemical carcinogens for activation of transforming genes in experimental tumors

We have created an insertional mutation that leads to a severe defect in the pattern of limb formation in the developing mouse. The novel recessive mutation is phenotypically identical and non-complementary to two previously encountered limb deformity mutations, and is closely linked to a dominant mutation that gives rise to a related limb dysmorphism. The inserted element thus provides a molecular genetic link with the control of pattern formation in the mammalian embryo

The gene encoding the neural cell adhesion molecule, N-CAM, has been localized on mouse chromosome 9. A BALB/cJ mouse genomic library prepared in lambda bacteriophage EMBL4 was screened by using a cDNA probe, pEC204, that corresponds to the coding region of the chicken N-CAM gene. Four weakly reactive and one strongly reactive recombinant phage were isolated. A region of the latter that was strongly homologous to pEC204 was subcloned to yield a new probe, pEC501. RNA transfer blots and nucleotide sequencing indicated that pEC501 encoded part of the mouse N-CAM gene. This probe defined a unique genetic locus, Ncam, associated with a restriction fragment length polymorphism that allowed the definition of two alleles. The locus could be provisionally assigned either to chromosome 9 or to chromosome 10 by correlating the presence or absence of mouse-specific DNA fragments reactive with the probe in a panel of somatic hybrid cell lines with the presence or absence of the various mouse chromosomes. Analysis of the inheritance of the Ncam-associated DNA polymorphism in recombinant inbred strains of mice revealed close linkage between Ncam and the Lap-1, Sep-1, and Thy-1 loci on chromosome 9. This result suggests an additional linkage between Ncam and the locus for the cerebellar mutation staggerer (sg). The Ncam locus provides an important reference point for mapping the genes for additional cell adhesion molecules as well as genes for other molecules involved in neural development and function

The striking number of human and murine immunodeficiency disorders which map to the X chromosome suggests that genes localized on this chromosome must have important roles in lymphocyte development. At least seven distinct disorders in the human and two in the mouse disrupt lymphocyte maturation, particularly that of B cells, at characteristic stages. As functional genes mapping to the X chromosome in one mammal are found on the X chromosome in all other mammals, the same genes regulating lymphocyte development are expected to be found on the X chromosome in mouse and man. Investigations into the possible mechanisms of these X-linked disorders have been hampered by the lack of molecular probes for the genes or gene products affected; because of this, and the possibility of correlating one or more of the several hundred B- or T-cell-specific genes with a specific mutation, we surveyed 15 different B- and T-cell-specific cDNA clones for localization to the X chromosome. We report here the characterization of one of these murine cDNA clones, which hybridizes with a large, X-linked gene family, designated XLR (X-linked, lymphocyte-regulated). We show that the XLR gene family is closely linked to the X-linked immunodeficiency described in the CBA/N mouse strain (xid), by restriction fragment length polymorphism (RFLP) analysis of DNA from mice congeneic for xid. This finding, together with data on the expression of the XLR locus in B cells, indicates that this gene family either includes the locus defined by the xid mutation or is adjacent to it in a gene complex which may be important in lymphocyte differentiation

Treatment of mice with the carcinogen N-methylnitrosourea results in the development of thymic lymphomas with frequent involvement of the N-ras oncogene. The activated mouse N-ras gene was isolated from one of these lymphomas and, by transformation in concert with restriction digestion, a map of the gene was prepared and its approximate boundaries were determined. By means of somatic cell hybrids the normal N-ras gene was found to be unlinked to other members of the ras gene family

Southern blot analysis of somatic cell hybrid lines indicates that the beta chain of the T cell receptor for antigen maps to chromosome 6 of the mouse. An experiment testing hybridization of the constant region of this gene to DNA from a hybrid cell line containing a translocation of chromosome 6 supports the localization of this gene to the proximal (centromeric) one-third of chromosome 6, in the same general region as the immunoglobulin kappa chain locus. This may be another indication of the shared evolutionary origins of the genes encoding both T and B cell antigen recognition

Mouse chromosome 12 encodes the heavy chains of immunoglobulins (Igh), a family of T cell surface molecules, and a tumor antigen that may be homologous to immunoglobulins. To refine and extend the genetic map of this chromosome, a procedure has been developed to isolate chromosome 12-specific DNA fragments from a somatic cell hybrid carrying the chromosome on a Chinese hamster background. Five fragments have been isolated and characterized in detail. All are polymorphic, defining loci D12-1, 2, 3, 4, and 5. Using recombinant inbred mouse strains, a tentative linkage map of chromosome 12 has been worked out that incorporates these markers, the c-fos oncogene, Igh, and Pre-1/alpha 1 antitrypsin. This strategy should be applicable to any mouse chromosome or chromosomal region that can be isolated in a somatic cell hybrid

DNA sequences homologous to adult alpha-globin genes are dispersed in the mouse. Two functional genes are tightly linked on chromosome 11. Pseudogenes have been assigned to chromosomes 15 and 17 by analysis of interspecies somatic cell hybrids. We have now further characterized the second of these pseudogenes, Hba-a4. The gene is highly polymorphic, with three forms occurring in a panel of 15 inbred strains and a fourth occurring in an inbred strain derived from M. m. molossinus. Analysis of Hba-a4 alleles in CXB, BXH, and AKXL recombinant inbred strains placed Hba-a4 6.60 +/- 3.14 cM centromeric to H-2. Analysis of congenic mouse strains confirmed the linkage and the gene order. Hba-a4 is the first mammalian dispersed pseudogene to be localized in a linkage map, and should provide a useful marker for the region of chromosome 17 proximal to H-2