The human genome project is entering a sequencing intensive stage. However, it is the premise of this proposal that high resolution gene and EST based map construction still has a role to play in 1) providing additional infrastructure for these efforts and 2) to facilitate the utilization of the emerging genome resources in a wide variety of investigations into genetic disease. Computational algorithms will be used to identify mouse ESTs/genes that are the orthologues of mapped human ESTs/genes. To further develop a high density gene rich map of the mouse genome the investigators will map 600 of these mouse ESTs/genes using their well-characterized interspecific backcross (containing 1200 markers). The mouse ESTs selected for mapping will be based on the human chromosomal location of the orthologous human unigenes. Although homology relationships have been rapidly identified at low resolution the borders of conserved genomic segments as well as intra-segment rearrangement events remain largely ambiguous. The current proposal will allow a higher resolution definition of these mouse/human homology relationships by this selective mapping of ESTs and genes in a single gene dense mouse map. The integration of microsatellite markers in the high-density genetic map will also be a component of these efforts. Approximately 500 microsatellite markers will be chosen to provide an integration of these maps. These studies will facilitate contig construction in the mouse as well as gene hunting studies in both mouse and human. The proposal will provide an additional framework for future biological studies as well as the tools necessary to verify and extend the definitive characterization of the mouse genome and completion of contig construction. An on-line database that provides access to the human/mouse homologies (http:/www3.ncbi.nlm.nih.gov/Homology/) will be maintained and updated as part of this project. This database will provide a simple interface between human and mouse coding sequences as well as nongenic STS markers. The database will be integrated with the online Gene Map of the Human Genome and will be annotated to include unmapped mouse orthologues of human unigenes and their putative chromosomal location.
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