Glutamate Oxaloacetate Transaminase (Got) Genetics in the Mouse: Polymorphism of Got-1

We have examined a polymorphism for the soluble glutamate oxaloacetate (GOT-1) isozyme system which was found in the Asian mouse Mus castaneus. Variants of GOT-1 segregate as though they are controlled by codominant alleles for a single autosomal locus which we have designated Got-1. No close linkage of genes for soluble and mitochondrial forms of the enzyme, GOT-1 and GOT-2 respectively, was observed. Furthermore, no close linkage of Got-1 and the loci c, Gpi-1, Mod-2, Mod-1, Ld-1, Gpd-1, Pgm-1 or Gpo-1 was observed. Our results demonstrate the utility of sampling Mus from diverse populations to extend the repertoire of polymorphic loci and the genetic linkage map

Detailed Genetic Mapping of the A-raf Proto-oncogene on the Mouse X Chromosome

The transcribed murine A-raf proto-oncogene has been localized to the proximal region of the mouse X chromosome, within the context of four other active genes in this region which together constitute a conserved linkage group between mouse and man. This localization has been accomplished using species-specific restriction fragment length variation and DNAs from a previously defined informative subset of progeny representative of a set of 100 progeny from an interspecific backcross between inbred C57BL/6JRos and wild-derived Mus spretus. This new data regionally orders the mouse A-raf locus relative to the 24 X-linked markers previously examined in this backcross. We find that A-raf co-localizes with two other active genes, tissue inhibitor of metalloproteinases (Timp) and synapsin (Syn-1), 4.0 +/- 2.0 cM distal to the Otc gene at the proximal end of the mouse X chromosome, for a partial gene order in this region of: centromere-Cybb-Otc-Timp/A-raf/Syn-1-Xlr-1-Hprt

Mechanisms of X-chromosome Regulation

The mammalian X chromosome is unique in ‬its hemizygous ‬expression ‬in somatic ‬tissues. In ‬males, hemizygous expression ‬is dictated by the XY genotype, but in females, the single active X condition is a result of X-chromosome inactivation. All of the genes on an X chromosome become coordinately inactivated, and, once initiated, the inactive condition becomes a somatically heritable feature that is stably maintained within a cell lineage. The stability ‬of the inactive condition appears to differ between the embryonic and extraembryonic ‬cell ‬lineages of ‬placental mammals and between the somatic lineages ‬of placental mammals and marsupials. Moreover, the relative stability of the inactivation ‬of X-chromosome genes can be altered by changing the genomic environment of the cell in ‬interspecific ‬somatic cell hybrids or by treatment with drugs that ‬impair the DNA cytosine methylation process. In contrast to the single active-X condition of somatic tissues, both X chromosomes are functional in oocytes and in cleavage-stage female embryos. The transitions from single active X expression in primordial germ cells and oogonia to an oocyte ‬with two active X chromosomes, and from embryonic cells with two active Xs to somatic cells with a single ‬X-active, provide a major focus for the ‬interest ‬in the regulation ‬of ‬X-chromosome expression. In general, we would like to know the molecular basis for ‬these changes in X-chromosome expression and how the events that both ‬initiate and maintain inactivation or reactivation relate to the maintenance of those changes in levels of expression. This review attempts to address many of the unresolved issues associated with mammalian X-chromosome inactivation. Whether inactivation, ‬reactivation, or ‬both are active processes is, as yet, ‬unknown. Similarly, whether either condition is fundamentally stable or must be actively maintained is still a matter for speculation. The inactivation process appears to affect virtually the entire X chromosome, and the inactive condition acts as if it ‬becomes a chromosome-autonomous property that is self-perpetuating. By contrast, we know less about the reactivation process and whether active gene products are required to sustain two-X expression during oogenesis and in cleavage stage embryos. Finally, ‬we attempt to discuss X inactivation as a chromosomal process and not merely a regulatory mechanism at ‬the single gene level. The regulation of ‬X-chromosome expression has received ‬ongoing attention as a topic of experimental and speculative interest. Investigation of the role of DNA methylation relative to the inactivation process has been especially prominent in recent years. This review attempts to incorporate much of that data into the refinement of a ‬generalized scheme for regulating X-chromosome expression. Where possible, ‬we have tried to incorporate the special features of X-chromosome expression ‬into ‬a developmental framework with an evolutionary perspective. This view appears especially appropriate when one considers that reactivation occurs at the time of entry into meiotic prophase. Having both X chromosomes in an active state may facilitate pairing and recombination. Conversely, other components of constitutive heterochromatin, such as satellite DNA in rodents, are normally highly methylated in somatic tissues but become hypomethylated during gametogenesis. Thus, it is possible that X-chromosome reactivation is a secondary consequence of generalized demethylation of genomic DNA in heterochromatin during oogenesis. In view of this possibility, we examine other experimental systems that produce demethylation of cytosine in DNA in an attempt to determine the conditions necessary for X-chromosome reactivation. In recent years, the general model that has emerged of X-chromosome expression during development indicates that oocyte and cleavage stage embryos have two active X chromosomes, whereas both embryonic and extraembryonic somatic tissues beyond the initial stages of cytodifferentiation have a single X chromosome active. These aspects of X-chromosome expression have been extensively reviewed

Electrophoretic Variation for X Chromosome-Linked Hypoxanthine Phosphoribosyl Transferase (Hprt) in Wild-Derived Mice

An electrophoretic variation for hypoxanthine phosphoribosyltransferase, HPRT, has been identified in samples of Mus spretus, a field mouse from southern Europe and in M. m. castaneus, a house mouse from southeast Asia. These mice will interbreed with laboratory mice to produce viable, fertile F(1) progeny. The variation for HPRT segregates as an X chromosome gene in F(1) and backcross progeny. Linkage analysis involving the markers Pgk-1 and Ags indicated a gene order of centromere— Hprt—Pgk-1—Ags in crosses involving both stocks of wild mice

X-chromosome Linked Mutations Affecting Mosaic Expression of the Mouse X Chromosome

In eutherian females, one of the two sex chromosomes is inactive. The inactivated status is established relatively early during embryogenesis and is somatically heritable within a cell lineage throughout development. The inactivation event is generally random with respect to the parental origin of an X chromosome, such that equal numbers of cells expressing the paternal (XP) and maternal (Xm) chromosome can be seen as a mosaic mixture in adult tissues using a variety of direct and indirect measures of X chromosome gene function. Using allelic variants of ubiquitous X-linked enzymes that are separable electrophoretically, the relative contributions of XP and Xm gene product can be qualitatively identified. Deviations from the equal occurrence of cells which express and occur by either non-random inactivation or by random inactivation followed by selection for cells which express one copy of the X chromosome. We used ethyl-nitrosourea as a mutagen to ask whether we could induce X-linked mutations that alter the mosaic expression of the X chromosomes in heterozygous females as a consequence of either altering the process of inactivation itself or by inducing mutations which could cause a selective growth of cells expressing only one kind of X chromosome. In this report, we describe our initial findings of nine non-mosaic female progeny of ENU-treated male mice. Further, we demonstrate the heritability of this phenotype from two of these progeny and show that the effect is primarily limited to the blood lineages

mdx Cv3 mouse is a model for electroretinography of Duchenne/Becker muscular dystrophy

Purpose. To identify an animal model for the abnormal scotopic electroretinogram found in a majority of Duchenne and Becker muscular dystrophy patients. Methods. Ganzfeld electroretinograms were recorded in dark-adapted normal C57BL/6 mice, and two strains of mice with different X-linked muscular dystrophy mutations {mdx and mdx Cv}). Responses for the right eye were averaged and the amplitudes and implicit times of the a-wave and b-wave were measured. The electroretinogram was digitally filtered to extract the oscillatory potentials. Statistical analyses included one-way analysis of variance and the Scheffe S test. Results. While the electroretinogram in mdx was normal, in mdx Cv3 the scotopic b-wave was markedly reduced and the oscillatory potentials were delayed, similar to changes observed in Duchenne and Becker muscular dystrophy patients. Some of the mdx <J " 3 animals demonstrated negative configuration electroretinograms, with the b-wave amplitude reduced compared to that of the a-wave. Conclusions. Abnormalities found in the electroretinograms of Duchenne and Becker muscular dystrophy patients led to the identification of dystrophin in human retina and the discover