Comparative molecular genetic analysis of lymphomas from six inbred mouse strains.

Previous studies of 21 highly lymphomatous AKXD recombinant inbred mouse strains demonstrated correlations between lymphoma type, the somatic proviral DNA content of the lymphoma, and the frequency of virally induced rearrangements in eight common sites of viral integration (Myc, Pim-i, Pvt-1, Mlvi-1, Mlvi-2, Fis-1, Myb, and Evi-1). In this study we analyzed lymphomas from six inbred mouse strains, AKR/J, C58/J, HRS/J (hr/hr and hr/+), SJL/J, SEA/GnJ, and CWD/LeAgl, to determine whether these correlations are also evident in these strains. Mice of the AKR/J, C58/J, and HRS/J strains died exclusively of T-cell lymphomas. In contrast to earlier studies which showed a great disparity in the rate and incidence of lymphomas in HRS/J hr/hr and HRS/J hr/+ mice, we found a high incidence of T-cell lymphomas and the same mean age of onset of disease in both strains. SJL/J mice died primarily of pre-B-cell lymphomas, whereas CWD/LeAgl and SEA/GnJ mice died primarily of B-cell lymphomas. Somatically acquired mink cell focus-forming proviruses were detected only in T-cell lymphomas, whereas ecotropic proviruses were found in lymphomas from all hematopoietic cell lineages. No rearrangements were detected in the Fis-1, Mlvi-2, and Myb loci, whereas rearrangements were detected in the Mlvi-1, Myc, Pim-1, Pvt-1, and Evi-1 loci. Most rearrangements were found in T-cell lymphomas, and many were virally induced. These results are similar to those we obtained previously for lymphomas of 21 highly lymphomatous AKXD recombinant inbred mouse strains.     

The molecular and genetic control of ovule development

A genetic approach has resulted in an extensive framework for the methodical analysis of ovule development. The most recent progress was accomplished in the areas of primordium formation and integument morphogenesis. Furthermore, systematic screens have identified a number of gametophytic mutations disrupting several distinct steps of embryo sac ontogenesis.     

The molecular basis of genetic disease.

The pace of localization and characterization of genes affected in human genetic disorders is quickening. Many important genes were localized or characterized recently: genes for in cystic fibrosis, NF-2, Marfan's syndrome and xeroderma pigmentosum, to name a few. Also, in the past 15 months, the CFTR gene affected in cystic fibrosis has been isolated, the first disease gene to be isolated without use of previous cytogenetic clues, such as deletions or translocations in sporadic cases. Other examples should follow, although we have been disappointed to date by the difficulties encountered in the isolation of Huntington's disease gene which was localized a number of years ago to distal chromosome 4p. It is still very difficult to isolate a disease gene without critical cytogenetic information. New improved techniques for finding the desired expressed sequences in a large cloned segment of human DNA are needed. Our ability to find mutant alleles of a given sequence has expanded greatly with the recent technical advances in denaturing gradient gel electrophoresis, chemical cleavage, and single-stranded conformational electrophoresis. One would predict that information derived from the human genome project will have a major impact upon the isolation of further disease genes. As whole regions of human chromosomes or indeed entire chromosomes are physically mapped and cloned as continuous, overlapping YACs (yeast artificial chromosomes), isolation of disease genes will become easier and easier.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recent genetic studies of mouse kidney development

Recent functional studies in mouse further illustrate the importance of the epithelial-mesenchymal interaction between the ureteric bud epithelium and the metanephric mesenchyme in kidney formation. Genetic ablation of Gdf11, Six1, Slit2/Robo2 reveal a role of these genes in regulating the outgrowth of a single ureteric bud from the Wolffian duct. Studies of Wnt11 and Fras1/Grip1, all expressed in the ureteric bud, show a role for these genes in regulating events in the adjacent metanephric mesenchyme. Furthermore, various approaches were used to address the function of Pod1, Pbx1, the Notch pathway and Brn1 in nephron formation.     

A molecular genetic linkage map of mouse chromosome 7

The homology between mouse chromosome 7 and human chromosomes 11, 15, and 19 was examined using interspecific backcross animals derived from mating C3H/HeJ-gld/gld and Mus spretus mice. In an earlier study, we reported on the linkage relationships of 16 loci on mouse chromosome 7 and the homologous relationship between this chromosome and the myotonic dystrophy gene region on human chromosome 19. Segregation analyses were used to extend the gene linkage relationships on mouse chromosome 7 by an additional 21 loci. Seven of these genes (Cyp2a, D19F11S1h, Myod-1, Otf-2, Rnu1p70, Rnu2pa, and Xrcc-1) were previously unmapped in the mouse. Several potential mouse chromosome 7 genes (Mel, Hkr-1, Icam-1, Pvs) did not segregate with chromosome 7 markers, and provisional chromosomal assignments were made. This study establishes a detailed molecular genetic linkage map of mouse chromosome 7 that will be useful as a framework for determining linkage relationships of additional molecular markers and for identifying homologous disease genes in mice and humans.     

The genetic structure of mouse ornithine transcarbamylase.

The gene encoding the mouse urea cycle enzyme, ornithine transcarbamylase has been isolated on five partially overlapping bacteriophage lambda clones. We have characterized the gene and found that it is split between ten exons distributed over approximately 70 kb of the X chromosome. The introns range in size from 88 bases to the relatively unusual size of approximately 26 kilobases, while the splice donor/splice acceptor sequences conform to the consensus established for other eukaryotic genes.     

New mouse genetic models for human contraceptive development

Genetic strategies for the post-genomic sequence age will be designed to provide information about gene function in a myriad of physiological processes. Here an ENU mutagenesis program (http://reprogenomics.jax.org) is described that is generating a large resource of mutant mouse models of infertility; male and female mutants with defects in a wide range of reproductive processes are being recovered. Identification of the genes responsible for these defects, and the pathways in which these genes function, will advance the fields of reproduction research and medicine. Importantly, this program has potential to reveal novel human contraceptive targets.     

The multipoint genetic mapping of mouse chromosome 16.

Utilizing a Mus spretus/Mus domesticus (C57BL/10) interspecific backcross, we have constructed a multipoint genetic map of mouse chromosome 16 that extends 43.2 cM from the proximal Prm-1 locus to the distal Ets-2 locus. The genetic map incorporates three new markers: D16Smh6, a random genomic clone; Pgk-1ps1, a phosphoglycerate kinase pseudogene; and the growth-associated protein Gap43. The map position of Gap43 indicates the presence, on mouse chromosome 16, of a significant-size conserved linkage group with human chromosome 3.     

Development and applications of a molecular genetic linkage map of the mouse genome

Interspecific mouse backcrosses provide almost limitless genetic variation for gene mapping. We have used interspecific backcrosses to develop the first comprehensive molecular genetic linkage map of the mouse genome. More than 600 loci have been positioned on the map; the current average map resolution is less than 3 cM. Since all loci were mapped using a single backcross panel, gene order can be determined unambiguously. With this level of resolution, it is now possible to position any new locus on the linkage map with virtually 100% certainty. In this article, we review how interspecific linkage maps are constructed, the salient features of our linkage map, and some of the many applications of interspecific linkage maps, in general, for future research.     

Cloning and molecular genetic analysis of Drosopbila melanogaster interband DNA

Interband DNA of Drosophila melanogaster polytene chromosomes was studied using a novel approach based on the electron microscopic (EM) analysis of chromosome regions carrying DNA fragements of known molecular genetic composition, inserted by P element-mediated transformation. Insertion of such fragments predominantly into interbands makes it possible to clone interband DNA by constructing genomic libraries from transformed strains and probing them with the insert DNA. The transformed strain P[H-sp70:Adh](61C) has insertion in the 61 C7-8 interband on the left arm of chromosome 3. This DNA consists of part of the hsp70 gene promoter fused to the coding region of the Adh gene, and is flanked on either side by P element sequences. We constructed a genomic library from DNA of this strain and isolated a clone containing the insert and the interband DNA. Subsequently the genomic library of wild-type strain was probed with a subclone composed of interband DNA only. We have thus isolated a clone containing the entire native interband. 1289 by of interband DNA was sequenced and found to be AT-rich (53.4%) with numerous regions of overlapping direct and inverted repeats, regulatory sites, and two overlapping open reading frames (ORFs).     

Genetic and molecular analysis of light-regulated plant development

Light regulates many physiological and developmental events in plants through the action of multiple sensory pigment systems. Although our understanding of the regulatory photoreceptors, including phytochromes (that principally absorb red and far-red energy) and blue light receptors, has advanced considerably in the recent past, the mechanisms of light signal transduction in higher plants are poorly understood. To unravel the molecular events associated with light-regulated plant development, a large number of photomorphogenic mutants have been isolated in several different plant species, including Arabidopsis, cucumber, tomato, pea, Brassica and Sorghum, which are either impaired in normal perception of light signal (photoreceptor mutants) or are affected in some specific or a sub-set of phenotypic traits (signal transduction mutants). Their physiological and molecular analysis is proving to be valuable in (1) assigning specific function to discrete phytochrome species, (2) elucidation of elements that constitute the transduction pathway downstream of signal perception, and (3) determining how different photosensory systems regulate many diverse responses. The progress made in the analysis of photomorphogenic mutants, as reviewed in this article, clearly indicates that multiple photoreceptors, either of the same or different class, interact through an intricate network of signal transduction pathways to finally determine the light-dependent phenotype of both monocots and dicots.     

A genetic analysis of visual system development in Drosophilia melanogaster.

The eyes and optic lobes of adult Drosophila melanogaster comprise a highly organized system of interconnected neurons. The eye and optic lobe primordia are physically separate during the embryonic and larval stages of development, and these tissues do not come into contact until the third larval instar, as a consequence of axons growing from the receptor cells of the developing eyes to the primordial optic lobes. After this contact, the axons of the eyes arrange themselves into their complex and orderly adult pattern. Simultaneously, the optic lobe cells begin elaborating axons which organize into their precise adult array. One question posed by this system is: Does cellular pattern formation in either the eyes or optic lobes depend on eye-brain interactions, or do the two tissues organize autonomously? To answer this question, mutations were found which cause abnormal ommatidial array in the eyes and which also perturb the normal adult axon array in the optic lobes. By means of X ray-induced somatic recombination and by genetically controlled mitotic chromosome loss (gynandromorph formation), flies mosaic for genotypically mutant and normal tissue were constructed. Analysis of the neuronal array in mosaic flies in which eye and optic lobe tissue differed genotypically showed that the axon array phenotype of the optic lobe depends on the genotype of the eye tissue innervating that lobe, while the eye phenotype does not depend on optic lobe genotype. Thus, the axonal organization of the D. melanogaster optic lobe has been shown to depend on the transmission of information from the eyes to the optic lobes.     

Quiet as a mouse: dissecting the molecular and genetic basis of hearing

Mouse genetics has made crucial contributions to the understanding of the molecular mechanisms of hearing. With the help of a plethora of mouse mutants, many of the key genes that are involved in the development and functioning of the auditory system have been elucidated. Mouse mutants continue to shed light on the genetic and physiological bases of human hearing impairment, including both early- and late-onset deafness. A combination of genetic and physiological studies of mouse mutant lines, allied to investigations into the protein networks of the stereocilia bundle in the inner ear, are identifying key complexes that are crucial for auditory function and for providing profound insights into the underlying causes of hearing loss.     

The molecular underpinnings of genetic phenomena

Epiphenomena are those processes that ostensibly have no precedent at lower levels of scientific organization. In this review, it is argued that many genetic processes, including ploidy, dominance, heritability, pleiotropy, epistasis, mutational load and recombination, all are at least analogous to biochemical events that were requisite features of the RNA world. Most, if not all, of these features of contemporary whole organisms and populations may have their ultimate evolutionary roots in the chemical repertoire of catalytic RNAs. Some of these phenomena will eventually prove to be not only analogous but homologous to ribozyme activities.