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

人类 MHC I 类假基因 (HLA-Y) 的进化和祖先功能

• 批准号: 8325793
• 负责人: Ana S Goyos
• 金额: $ 5.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325793
• 关键词: Address; Alleles; Binding; Biological; Charge; Data; Disease Resistance; Disease susceptibility; Evolution; Exons; Frequencies; Future Generations; Genes; Genetic Drift; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Genomics; Goals; HLA-A gene; Haplotypes; Health; Human; Immune response; Immune system; Immunity; Isoelectric Point; Link; Linkage Disequilibrium; MHC Class I Genes; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Modification; Mutation; Names; Natural regeneration; Nature; Orthologous Gene; Pan Genus; Pan troglodytes; Peptides; Phylogenetic Analysis; Play; Point Mutation; Population; Primates; Protein Isoforms; Proteins; Pseudogenes; Role; Testing; Variant; assault; design; gene discovery; insight; instrument; pathogen; research study; response

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.

描述（由申请人提供）：主要组织相容性复合体（MHC）的基因为选择如何在自然群体中保持（或消除）适应性重要（或有害）的遗传多样性提供了一个范例。人MHC I类区含有六个表达的I类基因，MHC-A、B、C、E、F和G。帕勒姆实验室意外地在黑猩猩中发现了第七个I类基因，命名为Patr-AL，因为它最像MHC-A，并在黑猩猩中被鉴定出来（Pan troglodytes A-like）。Patr-AL基因与Patr-A（黑猩猩HLA-A的直系同源物）连锁，并且在仅约50%的MHC单倍型上存在的独特的125 kb区块内发现。Patr-AL编码一种22 m相关蛋白，是唯一已知的具有碱性等电点（8.5）的MHC I类同种型。这表明Patr-AL具有不同于任何已知脊椎动物MHC I类分子的独特功能。最近的系统发育分析表明，人类有一个MHC-AL直系同源物，失活的HLA-Y假基因。HLA-Y的非常有限的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，所以这个基因座的最近祖先可能包括功能性的形式。这三种等位基因形式的区别还在于存在与不同的现代HLA-A等位基因密切相关的片段（在外显子中），推测是通过重组获得的，部分原因是HLA-Y和HLA-A之间的强连锁不平衡。有趣的是，HLA-Y仅存在于约20%的人类（主要是非高加索人）MHC单倍型中。这些观察结果提出了HLA-Y因其独特功能的选择而丢失的可能性，可能是因为与疾病易感性有关。然而，HLA-Y在人群中仍然保持低频率的事实表明，它可能是有益的。由于HLA-Y中存在与不同的现代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低频率可能有助于HLA-A基因座的多样性。这两种可能性并不相互排斥。因此，我建议测试的假设，虽然HLA-Y已被选择，因为它的功能，它仍然保持在一个低频率在人群中，因为它是一个有用的水库的多样性。提出的实验旨在定位MHC中的HLA-Y，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功能，还将研究其黑猩猩直系同源物Patr-AL。因此，本申请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，可以瞥见人类免疫力的最新演变。从这项研究中获得的结果将有助于了解MHC变异对人类免疫反应和疾病抵抗力和易感性的后果。