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Schimenti, John C.

Professor
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My laboratory uses the mouse as a model system to investigate the genetics of mammalian development, gametogenesis, and cancer. We have used forward and reverse genetic technologies to mutagenize the mouse genome and identify novel genes involved in these processes.

In one project, we conducted a forward genetic screen for mice carrying mutations that cause chromosome instability (CIN). CIN is a hallmark of cancer cells, and in some cases, may be a causative defect leading to cancers. One of the mutations we recovered caused a 20 fold elevation in CIN. Positional cloning revealed that the mutation is a hypomorphic allele of an essential and highly conserved DNA replication gene called Mcm4. Whereas null mutations are lethal, our allele, called Chaos3, encodes a single amino acid change in an absolutely conserved residue, allowing the mice to be viable. However, female mice with this mutation are highly susceptible to mammary tumors exclusively; about 80% get aggressive mammary adenocarcinomas by 1 year of age. This mouse is a uniquenon-transgenic model of breast cancer, and suggests that variants in DNA replication genes may constitute a previously unrecognized basis for certain cancers. We are investigate the molecular genetic pathways leading to cancer in Chaos3 mice, exploring the cause for the mammary specificity, and investigating the potential roles of other DNA replication genes in cancer.

With respect to gametogenesis, we concentrate on the process of meiosis. During meiosis, DNA is replicated, homologous chromosomes pair, recombination occurs, and two rounds of divisions follow to create haploid gametes. We have isolated several mutants that disrupt these steps, using both forward and reverse genetic strategies. Among the novel genes we are studying are : Mei1, a vertebrate-specific gene required for initation of meiotic recombination; Mei4, which is responsible for crossing over; and Trip13, a gene that is specifically required for noncrossover recombination. We are exploiting our collection of mutants to understand the “checkpoints” that monitor the fidelity of meiotic chromosome behavior. Finally, with my colleagues Mary Ann Handel and John Eppig at The Jackson Laboratory, we have established a “Reprogenomics” program (reprogenomics.jax.org) that has generated the world’s most extensive collection of mouse infertility mutants that we and others are studying.

The final major project in the lab addresses the functional genomic content of proximal mouse Chromosome 5, representing about 2% of the genome. A region-specific ENU mutagenesis screen was conducted, yielding 37 embryonic lethal mutations. We have determined the timing and phenotypes of death for most of them, which range from pre-implantation lethality to a late-gestation homeotic-like skeletal transformation, and have been identifying the underlying genes. This project is yielding insight into the functional elements in a representative portion of the mouse genome.

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