John C. Schimenti

Current Institution
Cornell University
Professor of Genetics
Director, Center for Vertebrate Genomics

Scholar: 1989

Awarded Institution
Case Western Reserve University


Research Interests

The Schimenti laboratory uses the laboratory mouse as a model system to investigate the genetics of mammalian development, gametogenesis, and maintenance of genome integrity. The lab has used forward genetic screens to identify novel genes involved in these processes. With respect to gametogenesis, the focus is 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. Mutants isolated in the Schimenti lab disrupt various steps in these processes. These mutants were produced by chemical mutagenesis of embryonic stem (ES) cells and of the germline. Some of lab's advanced studies focus on mutations that are involved in recombination initiation (the formation of double strand breaks), strand exchange during recombination, sister chromatid cohesion, the formation of chiasmata, and transcriptional control of meiotic genes. In addition to this collection of meiotic mutants, the lab investigates infertility mutations that affect earlier stages of germ cell production as well as postmeiotic sperm development.

In another project, a region-specific ENU mutagenesis screen was conducted to explore the functional content of proximal mouse Chromosome 5, representing about 2% of the genome. Embryonic lethal mutations (a total of 37) were overwhelmingly the largest class of mutants recovered. The timing and phenotypes of death have been determined for most of them, which range from pre-implantation lethality to a late-gestation homeotic-like skeletal transformation. To facilitate the mapping and cloning of these mutations in a systematic manner, a collection of nested chromosomal deletions in the region was created, using an ES cell-based technology. Mice bearing some of these deletions provide a mouse model for the Wolf-Hirshhorn contiguous gene syndrome in humans.

A more recent project involves the isolation of mice having mutations causing genomic instability (GIN). GIN is a hallmark of cancer cells, but there is controversy over whether it is an early or late event or cancer progression. By isolating a collection of GIN mutants, the lab plans to address this issue and to potentially identify new cancer susceptibility genes. A mutagenesis screen was conducted for mice with GIN, using a flow cytometric screen for DNA fragmentation in blood cells. Of the two mutations that were positionally cloned, one is in the gene encoding polymerase theta (Polq), an enzyme which is involved in translesion synthesis and may be required for somatic hypermutation of immunoglobulin genes. The other mutation is in a hypomorphic allele of the DNA replication licensing gene Mcm4, causing a dramatic elevation in chromosome instability. Remarkably, these mutant mice are highly susceptible to mammary adenocarcinomas.