Evolution and Ancestral Functions of a Human MHC Class I Pseudogene, HLA-Y

描述（由申请人提供）：主要组织相容性复合体（MHC）的基因提供了选择如何维持（或消除）自然群体中适应性重要（或有害）遗传多样性的范例。人类MHC I类区域包含6个表达的I类基因，MHC- a、B、C、E、F和g。Parham实验室意外地在黑猩猩中发现了名为Patr-AL的第7类I基因，因为它与MHC- a最相似，并且在黑猩猩（Pan troglodytes a -like）中被发现。Patr-AL基因与Patr-A（黑猩猩HLA-A的同源基因）相连，在一个独特的125kb片段中发现，仅存在于约50%的MHC单倍型中。Patr-AL编码一种22m相关蛋白，这是已知的唯一具有基本等电点的MHC I类同工异构体（8.5）。这表明，与任何已知的脊椎动物MHC I类分子不同，Patr-AL具有独特的功能。系统发育分析最近表明，人类具有MHC-AL同源物，即无活性的HLA-Y假基因。非常有限的HLA-Y测序已经确定了三个等位基因。因为这些等位基因中的每一个都包含一个独立的失活突变，这个基因座的最近祖先可能包括功能性的形式。同样区分这三种等位基因形式的是与不同现代HLA-A等位基因密切相关的片段（在外显子中）的存在，可能是通过重组获得的，部分原因是HLA-Y和HLA-A之间存在强烈的连锁不平衡。有趣的是，HLA-Y只存在于大约20%的人类中，大多数是非高加索人，MHC单倍型。这些观察结果提出了一种可能性，即HLA-Y可能是由于与疾病易感性相关的选择而失去了其独特的功能。然而，HLA-Y在人群中仍然维持在低频率的事实表明，它可能是有益的。由于HLA-Y中存在与不同现代HLA-A等位基因密切相关的片段，HLA-Y等位基因在人群中仍然保持较低的频率，这可能有助于HLA-A位点的多样性。这两种可能性并非相互排斥。因此，我建议测试这样一个假设，即尽管HLA-Y因其功能而被淘汰，但它在人群中仍然保持在低频率，因为它是一个有用的多样性储存库。实验旨在定位HLA- Y在MHC中的位置，确定是否存在任何活性形式，并检查该基因产物的功能。为了寻找祖先HLA-Y的功能，它的黑猩猩同源物parr - al也将被研究。因此，该应用程序旨在解决唯一已知的基本MHC I类基因产物的功能，并研究该基因在人类中衰变的生物学原因。本申请中提出的项目提供了一个非常独特的机会，可以一窥人体免疫系统最近的发展情况。从这项研究中获得的结果将有助于理解MHC变异对人类免疫反应和疾病抗性和易感性的影响。

DESCRIPTION (provided by applicant): Genes of the Major Histocompatibility Complex (MHC) present a paradigm for how selection can act to maintain (or eliminate) adaptively important (or detrimental) genetic diversity in natural populations. The human MHC class I region contains six expressed class I genes, MHC-A, B, C, E, F and G. The Parham lab unexpectedly discovered a seventh class I gene in chimpanzee named Patr-AL because it was most like MHC-A and was identified in the chimpanzee (Pan troglodytes A-like). The Patr-AL gene is linked to Patr-A (chimpanzee ortholog of HLA-A) and found within a unique 125kb block present on only ~50% of MHC haplotypes. Patr-AL encodes a 22m-associated protein that is the only known MHC class I isoform with a basic isoelectric point (8.5). This suggests that Patr-AL has a unique function unlike any known vertebrate MHC class I molecule. Phylogenetic analysis has recently demonstrated that humans have an MHC-AL ortholog, the inactive HLA-Y pseudogene. Very limited sequencing of HLA-Y has identified three alleles. Because each of these alleles contains an independent inactivating mutation, the recent ancestry of this locus likely includes forms that are functional. Also distinguishing the three allelic forms are the presence of segments (in exons) closely related to different modern HLA-A alleles, presumably obtained by recombination, partially due to the strong linkage disequilibrium between HLA-Y and HLA-A. Interestingly, HLA-Y is only present in about 20% of human, mostly non-Caucasian, MHC haplotypes. These observations raise the possibility that HLA-Y has been lost by selection against its unique function, possibly because of an association with disease susceptibility. The fact that HLA-Y is still maintained in the population at a low frequency, however, suggests that it might be beneficial. Because of the presence in HLA-Y of segments closely related to different modern HLA-A alleles, the low frequency of HLA-Y alleles still maintained in the population might contribute to the diversity of the HLA-A locus. These two possibilities are not mutually exclusive. I therefore propose to test the hypothesis that while HLA-Y has been selected against because of its function, it is still maintained at a low frequency in human populations because it is a useful reservoir of diversity. Experiments proposed aim to locate HLA- Y in the MHC, determine if any active forms persist and examine the function of this gene product. To search for ancestral HLA-Y functions, its chimpanzee ortholog, Patr-AL, will also be investigated. This application therefore aims to address the function of the only known basic MHC class I gene product and investigate biological reasons why this gene has decayed in humans. The project proposed in this application presents a very unique opportunity to catch a glimpse of the recent evolution of human immunity in action. Results obtained from this study will help in the understanding of the consequences of MHC variation on the human immune response and in disease resistance and susceptibility. PUBLIC HEALTH RELEVANCE: Major Histocompatibility Complex (MHC) molecules are essential components of the human immune system and have been shown to play a major role in determining disease susceptibilities. By studying these rapidly evolving immune system components in humans and closely related species of primates we will gain new insight and greater understanding of the human immune system and its contribution to human health and survival.