PROVIDIED. This Core will provide genomic sequence data derived from NMDP patients and donors that will be used by other projects and cores in the design and implementation of appropriate experiments. Building on prior work sequencing MHC regions, we have determined the genomic sequence of a Killer cell Ig-like receptor (KIR) haplotype, representing a first step in deciphering haplotypic variation at KIR. Given genomic sequence data, which includes both gene content and second level allelic variation within coding and noncociing regions, it will be possible to develop detection methodologies amenable to the unique characteristics of this gene family that will allow for the direct determination of complete KIR haplotypes. With the aim of applying these developments to studies of the involvement of KIR in the outcome of marrow transplant specifically though the NMDP, and immune related genetic effects in general, in the context of this program project we propose to accomplish the following specific aims: 1) To identify and characterize new haplotypes and allelic polymorphisms in the killer cell Ig-like receptor (KIR) genomic locus. This will be accorriDlished by utilizing high-throughputgenomic sequenceanalysis of the complete KIR locus from multiple marrow donor and recipient derived cell line DNAs.
This aim will define the complete structureof sufficient numbers of KIR haplotypes to include a large majority of the relevant population. 2) To develop and define a set of reagents and technologies useful as mapping tools for the study of potential KIR-linked diseases. To accomplish this we will define and relate KIR haplotype frequencies, allelic linkage disequilibrium, recombination frequency, and location relative to existing and new genes within the NMDP population and from a spectrum of ethnic groups. This will allow us to select from the substantialKIR dataset we will build, in order to select an appropriate subset that will allow for the optimal discriminationof whole or major portions of KIR haplotypes. During the course of this grant, data will be exchanged between this core and other appropriate projects and cores in order to guide the choice of new haplotypes to be sequenced, and to direct the development and utilization of superior genotyping assays capable of moreprecisely genotyping KIR. These data will be simultaneously be made available to the interested scientific community through submissions through the database Core project.
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