The overall goal of the Cooperative Human Linkage Center is the construction of a highly informative, readily utilizable, high resolution (2.5 cM sex-averaged) comprehensive human genetic map that is rich in gene based polymorphic markers. Major emphasis is placed on providing a resource to the scientific community to facilitate the use of the genetic map for the study of human diseases. This specific project will contribute to the construction of the genetic map by developing 2500 short tandem repeat polymorphisms (STRPs) with a heterozygosity of 0.7 or greater during the five year course of this project.
This aim will be accomplished using genomic and cDNA clones greatly enriched for short tandem repeat sequences obtained by a novel strategy termed """"""""marker selection"""""""" described in detail in Project 1. In addition, in collaboration with Project 3 we will use denaturing gradient gel electrophoresis and single strand conformation polymorphism analysis to identify sequence polymorphisms in 500 gene sequences each year. These polymorphisms will be assayable by PCR based technology and will allow the incorporation of the associated genes into the genetic map. The heterozygosity frequency will be determined for all polymorphic markers developed in this project. Furthermore, each marker will be assigned to a chromosome using a somatic cell hybrid mapping panel. Furthermore, each marker will be assigned to a chromosome using a somatic cell hybrid mapping panel. The STRPs and gene based polymorphisms identified in this project will be used to construct the high resolution comprehensive human genetic map in Projects 3, 4, and 5. We will also develop, and continue to update and improve, a core set of primary index STRPs (spaced at 1015 cM) which are assayable by standardized PCR conditions. This set of primary index markers will consist of approximately 300 markers selected for their high heterozygosity, ease of use and interpretation, and ability to be multiplexed. These markers will be a valuable resource to the scientific community for primary linkage studies. Finally, we will aid other investigators working on specific genetic diseases in the search for polymorphisms and/or mutations in candidate genes. This will serve to facilitate the studies of other investigators and to provide a mechanism for technology transfer from the Cooperative Human Linkage Center to other laboratories.
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