Faculty Bibliography

Inherited single gene defects have been identified in both humans and mice that lead to loss of developmental control over the left-right asymmetry of the heart and viscera. In mice the recessively inherited mutation iv leads to such apparent loss of control over situs: 50% of iv/iv mice exhibit situs inversus and 50% exhibit normal situs. The affected gene product has not been identified in these animals. To study the normal function of iv, we have taken an approach directed to the gene itself. As a first step, we have mapped iv genetically, by examining its segregation in backcrosses with respect to markers defined by restriction fragment length polymorphisms. The iv locus lies 3 centimorgans (cM) from the immunoglobulin heavy-chain constant-region gene complex (Igh-C) on chromosome 12. A multilocus map of the region suggests the gene order centromere-Aat (alpha 1-antitrypsin gene complex)-(11 cM)-iv-(3 cM)-Igh-C-(1 cM)-Igh-V (immunoglobulin heavy-chain variable-region gene complex)

Progeny from an interspecific backcross between laboratory mice and Mus spretus were typed for inheritance of eight genetic markers on chromosome 12. Marker order determined by segregation analyses of 115 meiotic events was in good agreement with that determined previously using intraspecific laboratory strain backcrosses. Two additional markers, D12Nyu5 and Lamb-1, previously not ordered, were located in the middle of the interval between D12Nyu12 and D12Nyu1. Marker spacing was reduced in the interspecific cross relative to that observed in intraspecific crosses. Furthermore, the interspecific cross was characterized by marked deviation from 1:1 segregation in the recombinant chromosomes and very strong positive interference. These data suggest that comparisons of different mouse crosses may facilitate the understanding of underlying mechanisms that govern recombination events in complex genomes

The myc family of proto-oncogenes consists of at least three members, whose expression is tightly and co-ordinately regulated. The genes are nevertheless dispersed to three distinct chromosomal sites in humans. We have now used somatic cell genetics and the analysis of restriction fragment length polymorphisms (RFLPs) to identify and chromosomally map two mouse N-myc loci, to chromosomes 12 and 5, and two L-myc loci, provisionally to chromosomes 4 and 12. The second locus in each pair may be a pseudogene

Inheritance of restriction fragment length polymorphisms associated with four anonymous DNA markers (D12Nyu1, 2, 3 and 4), the Fos proto-oncogene, the Mtv-9 viral integration site, and the alpha 1-antitrypsin (Aat-1) and immunoglobulin heavy chain (Igh) gene families in the mouse has been followed in a backcross experiment. A Bayesian multilocus map-building strategy yielded the map: centromere-D12Nyu2-10 cM-D12Nyu1-2 cM-D12Nyu3-15 cM-Fos-1 cM-D12Nyu4-2 cM-Mtv-9-8 cM-Aat-1-17 cM-Igh-C. A map constructed from male meiotic data was substantially shorter than one constructed from female meiotic data. Significant interference was observed for the linkage group. Two groups of markers studied in recombinant inbred strains of mice could be interpolated into the map: Es-25, D12Nyu10, D12Nyu7 and Apob form a cluster proximal to D12Nyu2, and Ly-18, Ah, and D12Nyu5 form a cluster between D12Nyu2 and D12Nyu1. These data establish an unambiguously ordered linkage group including Igh and Aat-1 that spans most of chromosome 12

IL-4/B cell stimulatory factor 1 (IL-4) is a potent mediator of the growth and differentiation of cells of most hemopoietic lineages. IL-4 is one of a number of lymphokines produced by T cells after activation with Ag or mitogen. In order to map the chromosomal location of the IL-4 gene, Chinese hamster-mouse somatic cell hybrids were used in Southern blot analyses with an IL-4 cDNA probe. These results suggested that the IL-4 gene was located on chromosome 11. In contrast, the gene encoding IL-2 was localized to either chromosome 1 or 3. The identification of a strain-specific Bgl II restriction enzyme polymorphism in the IL-4 gene was used to map the IL-4 gene to a position on mouse chromosome 11 within 1 centimorgan of the gene encoding IL-3

Cyclic nucleotide phosphodiesterase (CNP) and glial fibrillary acidic protein (GFAP) are useful markers of myelin and astroglia, respectively. Two proteins with CNP activity are known to exist in brain and lymphoid tissues. They appear to be the products of several distinct but related messenger ribonucleic acid (mRNA) species. GFAP is a single protein encoded by a single mRNA. We have localized the GFAP gene to distal chromosome 11 in the mouse. There are two genetic loci identified by CNP probes, one is closely linked to the GFAP gene, and the other maps to chromosome 3

We report here the cloning of a partial cDNA for Esterase 1, the major esterase activity in mouse plasma. A 470 base pair insert was isolated from a lambda gt11 cDNA library constructed from mouse liver poly A+ RNA, and identified by hybrid selected translation. We show that the sexual dimorphism displayed in the plasma levels of this protein is caused by a difference at the level of transcription. In addition, RFLP data using mouse recombinant inbred strains mapped this clone at the Es-1 locus on mouse chromosome 8

The two myelin-associated glycoprotein (MAG) species, designated large MAG (L-MAG) and small MAG (S-MAG), are believed to be generated by differential splicing from a single RNA transcript. We have now defined the genetic locus encoding the two MAG proteins in the mouse. Analysis of a panel of interspecies somatic cell hybrids indicated that all MAG coding sequences reside on chromosome 7. Following the inheritance of a restriction fragment length polymorphism associated with MAG coding sequences allowed the locus to be positioned 0.5 centimorgans from the locus Abpa (androgen binding protein alpha) on proximal chromosome 7. These data strongly support the hypothesis that a single gene encodes the two MAG proteins, and we propose the name Mag for this locus. This localization places Mag in close proximity to the neurological mutant locus qv (quivering) and raises the possibility of a functional relationship or identity between Mag and qv. However, an analysis of the MAG gene, its RNA transcripts, and its protein products revealed no abnormalities in homozygous qv mutant mice, suggesting that this chromosomal linkage is not etiologically significant

A new murine homeo-box, called Hox-1.7, has been identified in a rare cDNA from F9 teratocarcinoma stem cells. The Hox-1.7 homeo-box is 68 and 72% homologous to the Drosophila antennapedia (Antp) and iab-7 homeo-boxes, respectively. A major 2.5-kilobase transcript and several minor transcripts were detected by Northern blot (RNA blot) analysis in adult tissues as well as in midgestational embryos. The posterior spinal cord was found to be a major site of Hox-1.7 expression in 12.5-day-old embryos. Somatic cell hybrids were used to map the Hox-1.7 gene to mouse chromosome 6. Restriction fragment length polymorphisms associated with either the Hox-1.7 gene or the previously known Hox-1 complex were identified. Their distribution patterns in recombinant inbred mouse strains were used to determine the linkage between the two loci as well as to other loci on chromosome 6. This maps Hox-1 and Hox-1.7 close to two mouse loci that affect morphogenesis, postaxial hemimelia (px) and hypodactyly (Hd)