The Cancer Project:     Personnel: Andy Castillo, Alex George, Kathryn Hentges Keith Weis and Sujatha Yarlagadda The AKXD recombinant inbred strains of mice develop B-cell leukemias and lymphomas due to the insertion of endogenous retroviruses into somatic cells.We have used viral insertion site amplification (VISA), to identify sequence tags flanking all of the retroviral insertions in the AKXD B-cell tumors.The genetic profile of insertion sites identifies pathways that lead to the development of B-cell leukemia, while they define important events in B-cell differentiation.One site, called Lvis1,is altered by proviral insertion in 22% of the B-cell tumors. We are testing the hypothesis that two genes at Lvis1, the hematopoietic expressed homeobox gene Hex and the kinesin related spindle protein Eg5, may cause leukemias when misexpressed. The Mouse Mutagenesis Projects:     Mouse Chr11 and Developmental Defects     Personnel: Maritess Alviento, Teminit Agasedom,Neil Box, Amander Clark, Chris Dinh, Karen Firozi, Kathryn Hentges, , Anita Holdsworth, Charles Hubbard, Colleen Kaiser, Ben Kile, Bin Liu, Amy Lossie, Jackie Maffucci, Cammy Mason-GarrisonSuzanne Moncrief, Mary Patterson, Matthew Ross, Andrew Salinger, Darlene Skapura, and Jeannie Zhong The chemical N-ethyl-N-nitrosourea (ENU) is a powerful mouse mutagen for phenotype-driven screens.Large-scale screens for developmental phenotypes must take into account the ease of recovering and maintaining mutations that are detrimental to the organism. Chromosome engineering techniques pioneered by our collaborator Allan Bradley, can be used to design balancer chromosomes that suppress recombination and are marked with a dominant coat color, which are ideal to isolate and maintain detrimental mutations. We are using balancer chromosomes in screens designed to define gene functions on mouse Chr 11, which shows linkage conservation with human Chr 17. The new ENU-induced mutations include recessive mutations mapping to mouse Chr 11, as well as those segregating genome-wide, demonstrating the dual benefits of this genetic strategy for large-scale mutation isolation. The phenotypes are relevant to human disease, causing early embryonic and postpartum death, infertility, as well as skeletal, hematopoietic,neurological, urogenital, skin/coat and metabolic defects. Surprisingly, nearly 2/3 of the new mutations mapping to mouse Chr 11 cause early death or infertility, phenotypes that would be difficult to manage without the use of a balancer. As a part of the new NIH-funded Mouse Mutagenesis and Phenotyping Center for Developmental Defects, we are generating additional balancer chromosomes that will cover 25% of the mouse genome.New mutants from all mutagenesis projects, physical maps, and engineered chromosome rearrangements are described at www.mouse-genome.bcm.tmc.edu.     The brown project     Personnel: Anita Holdsworth and Charles Hubbard with visiting scientist Ian Smythe Through funding from the Burroughs Wellcome Foundation, we are also carrying out saturation mutagenesis in the brown (Tyrp1) region on mouse Chr 4. In collaboration with Dr. Ian Jackson of the MRC-Human Genetics Unit and Dr. Steve Brown of the MRC-Mammalian Genetics unit, we are developing a functional and sequence map of this region.     Allele series at Odz4 and quaking     Personnel: Diego Lorenzetti, Amy Lossie, Hisashi Nakamura, Jennifer Northrop, and Lihua Zheng Allele series can dissect protein domain and isoform-specific function. My lab studies two important allele series: the Odz4 series on mouse Chr 7, and the quaking allele series on mouse Chr 17. Through mutagenesis, we have discovered novel functions for these loci, including a maternal effect for Odz4, and a role for quaking in blood vessel development.     Bioinformatics project     Personnel: Bin Liu, Jeannie Zhong and NhuHuu Tran The bioinformatics group supports all the projects in the Bradley and Justice labs. They are involved in maintaining the website, developing tools for data analysis, developing databases for the proviral insertion site tags and mouse phenotype information, as well as developing and instituting a mouse colony management program using a barcode system.