Polymorphism & Transplantation Biology of Novel MHC loci

这项提案的长期目标是确定一组广泛的遗传多态性，跨越人类主要组织相容性复合体（MHC），这将是有用的，以确定MHC疾病协会，包括与无关的捐赠者骨髓移植相关的疾病。 从遗传学的角度来看，由HLA I类、II类和III类区域组成的MHC是人类基因组中研究最透彻的区域之一。 自30多年前发现以来，数十种疾病关联通过其与高度多态性的I类和II类抗原呈递基因的关联而与该区域遗传相关。 最近，I、II和III类区域的完整序列分析已经确定了220多个基因，更详细的分析已经给出了I类内另外40个新基因的初步信息。 我们将利用本基金前几年收集的基因组数据的广泛背景来开发工具和数据集，使我们能够测试MHC内但I类和II类基因座外的遗传因素可以影响和更好地预测无关供体移植的结果的假设。 因此，我们原来的主题研究新的HLA基因的多态性和移植生物学可以继续在一个逻辑和有效的方式来测试这一假设，通过实现以下具体目标：1）识别和表征新的基因在HLA I类区域。 这将通过利用现有的基于计算和表达序列标记（EST）的基因预测作为全长cDNA分离和表征的起点来实现。 2)开发和定义一组明确的SNPs，作为与MHC相关疾病相关的作图工具。 为了完成这一点，我们将定义和相关的SNP频率，连锁不平衡，重组频率，和现有的和新的基因从一个频谱的种族群体的位置，和3）进行基于SNP的分析的MHC和SNP的关系，HLA单倍型发现在骨髓移植受者，从而开辟了道路，研究SNP的潜在参与无关的骨髓移植结果。

The long term goal of this proposal is to define a broad set of genetic polymorphisms spanning the human major histocompatibility complex (MHC) that will be useful for identifying MHC disease associations, including those diseases associated with unrelated donor marrow transplants. The MHC, which is comprised of the HLA class I, II, and III regions, is, from a genetic standpoint, one of the most thoroughly perused areas of the human genome. Since its discovery over 30 years ago, dozens of disease associations have been linked genetically to this region through their associations to the highly polymorphic class I and II antigen- presenting genes. More recently, complete sequence analysis of the class I, II and III regions has defined over 220 genes, and more detailed analyses have given preliminary information on an additional 40 new genes within class I. We will utilize the extensive background of genomic data gathered in the prior years of this grant to develop tools and datasets that will allow us to test the hypothesis that genetic factors within the MHC, but outside of the class I and II loci, can effect and better predict the outcome of an unrelated donor transplant. Thus our original theme of studying the polymorphism and transplantation biology of novel HLA genes can be continued in a logical and effective manner towards testing this hypothesis, by accomplishing the following specific aims: 1) To identify and characterize new genes in the HLA class I region. This will be achieved by utilizing existing computational and expressed sequence tagged (EST)-based gene predictions as a starting point for full-length cDNA isolations and characterization. 2) To develop and define a definitive set of SNPs useful as mapping tools in the association with MHC-linked diseases. To complete this we will define and relate SNP frequencies, linkage disequilibrium, recombination frequency, and location relative to existing and new genes from a spectrum of ethnic groups, and 3) To carry out SNP-based analysis of the MHC and the relationship of SNPs to HLA haplotypes found in marrow transplant recipients, thus opening the way to study the potential involvement of SNPs in unrelated marrow transplant outcome.