Linda D. Siracusa

The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia

Mutations in the APC gene are responsible for various familial and sporadic colorectal cancers. Min mice carry a dominant mutation in the homolog of the Apc gene and develop multiple adenomas throughout their small and large intestine. Quantitative trait loci studies have identified a locus, Mom1, which maps to the distal region of chromosome 4, that dramatically modifies Min-induced tumor number. We report here the identification of a candidate gene for Mom1. The gene for secretory type II phospholipase A2 (Pla2s) maps to the same region that contains Mom1 and displays 100% concordance between allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1 susceptible strains are most likely null for Pla2s activity. Our results indicate that Pla2s acts as a novel gene that modifies polyp number by altering the cellular microenvironment within the intestinal crypt.

The nature and identification of quantitative trait loci: a community’s view

This white paper by eighty members of the Complex Trait Consortium presents a communitys view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Mammalian microRNAs: a small world for fine-tuning gene expression

The basis of eukaryotic complexity is an intricate genetic architecture where parallel systems are involved in tuning gene expression, via RNA-DNA, RNA-RNA, RNA-protein, and DNA-protein interactions. In higher organisms, about 97% of the transcriptional output is represented by noncoding RNA (ncRNA) encompassing not only rRNA, tRNA, introns, 5′ and 3′ untranslated regions, transposable elements, and intergenic regions, but also a large, rapidly emerging family named microRNAs. MicroRNAs are short 20-22-nucleotide RNA molecules that have been shown to regulate the expression of other genes in a variety of eukaryotic systems. MicroRNAs are formed from larger transcripts that fold to produce hairpin structures and serve as substrates for the cytoplasmic Dicer, a member of the RNase III enzyme family. A recent analysis of the genomic location of human microRNA genes suggested that 50% of microRNA genes are located in cancer-associated genomic regions or in fragile sites. This review focuses on the possible implications of microRNAs in post-transcriptional gene regulation in mammalian diseases, with particular focus on cancer. We argue that developing mouse models for deleted and/or overexpressed microRNAs will be of invaluable interest to decipher the regulatory networks where microRNAs are involved.

The agouti gene: turned on to yellow

The agouti locus was first identified as a result of its effects on the type and temporal deposition of coat color pigments in mammals. Many mutations at the murine agouti locus have now been found, some of which not only affect coat color, but also interfere with diverse biological processes leading to diabetes, obesity, tumor susceptibility and embryonic lethality. Correlations between the genotype and phenotype of agouti mutants, as well as reasons for the pleiotropy of effects caused by agouti mutations, have begun to unfold with the molecular cloning of the agouti gene and its surrounding genomic region.

Chromosomal localization of seven members of the murine TGF-β superfamily suggests close linkage to several morphogenetic mutant loci

Chromosomal locations have been assigned to seven members of the TGF-beta superfamily using an interspecific mouse backcross. Probes for the Tgfb-1, -2, and -3, Bmp-2a and -3, and Vgr-1 genes recognized only single loci, whereas the Bmp-2b probe recognized two independently segregating loci (designated Bmp-2b1 and Bmp-2b2). The results show that the seven members of the TGF-beta superfamily map to eight different chromosomes, indicating that the TGF-beta family has become widely dispersed during evolution. Five of the eight loci (Tgfb-1, Bmp-2a, Bmp-2b1, Bmp-2b2, Vgr-1) mapped near mutant loci associated with connective tissue and skeletal disorders, raising the possibility that at least some of these mutations result from defects in TGF-beta-related genes.

Mouse chromosome 2

mKimmel Cancer Center, Jefferson Medical College, Department of Microbiology and Immunology, 233 South 10th Street, Philadelphia, Pennsylvania 19107-5541, USA 2Human Genetics Unit, Molecular Medicine Center, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK 3The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA 4Departrnent of Animal Science, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908, USA SMRC Mammalian Genetics Unit, Harwell, Didcot Oxon OX 11 ORD, UK

A molecular genetic linkage map of mouse chromosome 4 including the localization of several proto-oncogenes

We have constructed a 64-cM molecular genetic linkage map of mouse chromosome 4 using interspecific backcross animals derived from mating C57BL/6J and Mus spretus mice. Several proto-oncogenes and common sites of viral integration have been assigned regional locations on chromosome 4 including Mos, Lyn, Jun, Lmyc, Lck, Fgr, and Dsi-1. Additional loci mapped in this study to chromosome 4 were Tsha, Mup-1, Rrm2-ps1, Ifa, and Anf. A comparison of our mapping data with inbred strain mapping data did not show any evidence for inversions or deletions on chromosome 4. New regions of synteny were defined between mouse chromosome 4 and human chromosomes 1 and 8; a region of homology was found between mouse chromosome 4 and human chromosome 6. This linkage map will provide a framework for identifying homologous genes in mice and humans that may be involved in various disease processes.

Hepatitis B virus transgenic mouse model of chronic liver disease

A model for hepatitis B virus-associated chronic liver disease has been made using cloned hepatitis B virus DNA as a transgene in a severe combined immunodeficient host. These mice consistently support virus gene expression and replication. After adoptive transfer of unprimed, syngeneic splenocytes, these mice cleared virus from liver and serum, and developed chronic liver disease. This model will permit identification of the host and virus contributions to chronic liver disease in the absence of tolerance.

A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice.

Stratifin (Sfn, also called 14-3-3σ) is highly expressed in differentiating epidermis and mediates cell cycle arrest. Sfn is repressed in cancer, but its function during development is uncharacterized. We identified an insertion mutation in the gene Sfn in repeated epilation (Er) mutant mice by positional cloning. Er/+ mice expressed a truncated Sfn protein, which probably contributes to the defects in Er/Er and Er/+ epidermis and to cancer development in Er/+ mice.

A molecular genetic linkage map of mouse chromosome 2

Interspecific backcross mice were used to create a molecular genetic linkage map of chromosome 2. Genomic DNAs from N2 progeny were subjected to Southern blot analysis using molecular probes that identified the Abl, Acra, Ass, C5, Cas-1, Fshb, Gcg, Hox-5.1, Jgf-1, Kras-3, Ltk, Pax-1, Prn-p, and Spna-2 loci; these loci were added to the 11 loci previously mapped to the distal region of chromosome 2 in the same interspecific backcross to generate a composite multilocus linkage map. Several loci mapped near, and may be the same as, known mutations. Comparisons between the mouse and the human genomes indicate that mouse chromosome 2 contains regions homologous to at least six human chromosomes. Mouse models for human diseases are discussed.