Polymorphism & Transplantation Biology of Novel MHC loci

这项提案的长期目标是定义一组跨越人类主要组织相容性复合体(MHC)的广泛遗传多态，这将有助于识别MHC疾病的相关性，包括那些与无关供者骨髓移植相关的疾病。MHC由HLAI、II和III类区域组成，从遗传学的角度来看，它是人类基因组中最彻底研究的区域之一。自30多年前发现以来，已有数十个疾病关联通过它们与高度多态的I类和II类抗原提呈基因的关联而与该地区遗传相关。最近，对I类、II类和III类区域的完整序列分析已经定义了220多个基因，更详细的分析已经提供了关于I类中另外40个新基因的初步信息。我们将利用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，使我们能够检验这一假设，即MHC内但I类和II类基因座之外的遗传因素可以影响和更好地预测无关供者移植的结果。因此，我们最初研究新的人类白细胞抗原基因的多态性和移植生物学的主题可以通过实现以下特定目的来逻辑和有效地检验这一假说：1)在人类白细胞抗原I类区域中鉴定和鉴定新的基因。这将通过利用现有的基于计算和表达序列标签(EST)的基因预测作为全长cDNA分离和表征的起点来实现。2)开发和定义一套确定的SNPs，作为与MHC相关疾病相关的图谱工具。为了完成这项工作，我们将定义和关联SNP频率、连锁不平衡、重组频率和相对于现有基因和来自不同种族群体的新基因的位置，以及3)基于SNP的MHC分析以及SNP与骨髓移植受者发现的人类白细胞抗原单倍型的关系，从而为研究SNPs在无关骨髓移植结果中的潜在参与开辟了道路。

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.