Molecular basis of adaptation of seminal proteins of humans and other primates

人类和其他灵长类动物精蛋白适应的分子基础

• 批准号: 10117794
• 负责人: Michael Ignatius Jensen-Seaman
• 金额: $ 0.67万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117794
• 关键词: Affect; Alleles; Amino Acid Substitution; Amino Acids; Amyloid Fibrils; Bioinformatics; Biological Assay; Brain; Code; Complex; Computational Technique; Conflict (Psychology); Data; Data Analyses; Disease; Environment; Enzymes; Evolution; Experimental Designs; Extracellular Protein; Fertilization; Frequencies; Gene Proteins; Genes; Genetic Drift; Genome; Genomics; Genotype; Goals; Gorilla gorilla; HIV; HIV Infections; Health; Hominidae; Human; Human Biology; Human Genome; Immune system; In Vitro; Individual; Investigation; KLK3 gene; Knowledge; Laboratories; Macaca; Measures; Medicine; Mentors; Modeling; Molecular; Molecular Evolution; Mutation; Natural Selections; Orthologous Gene; Pan Genus; Partner in relationship; Pattern; Peptide Fragments; Peptide Hydrolases; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Pongidae; Population Genetics; Preparation; Primates; Process; Prostate; Prostatic; Proteins; Publications; Publishing; Recombinant Proteins; Recording of previous events; Relaxation; Reproduction; Research; Resistance; SIV; Science; Seminal; Seminal Vesicles; Seminal fluid; Sexual Transmission; Specificity; Students; Substrate Specificity; System; Taxonomy; Testing; Transglutaminases; Universities; Viral; Virus Diseases; Washington; base; career preparation; doctoral student; driving force; enzyme activity; extracellular; genetic evolution; improved; male; migration; parent grant; pathogen; pressure; prostatic fraction Acid phosphatase isoenzyme; protein function; reconstruction; reproductive; response; sexually transmitted virus; species difference; sperm cell; synthetic peptide; tool; undergraduate education; undergraduate student

Note: This Project Summary is repeated from the parent grant, but with bold highlighting to indicate the portion of the research the undergraduate student, Thomas Washington, will be working on under the proposed Supplement to Promote Diversity in Health-related Research. Project Summary The >20,000 protein-coding genes in our body have been shaped by the combined forces of mutation, natural selection, genetic drift, and migration. An essential way to understand the effects of these forces, especially the consequences of individual amino acid-changing mutations on protein function, is to compare our genes and proteins to those of our closest relatives. In doing so, the mode of selection (positive selection, negative selection, or relaxation of constraint) can also be inferred. Over the last decade, over a dozen high-quality primate genome sequences have been published, allowing for detailed investigation of the forces of evolution acting on the human genome and the genomes of other hominids, using complex models based on the principles of population genetics and molecular evolution. In the proposed research, we will go beyond computational predictions of selection by performing quantitative functional assays using recombinant proteins and synthetic peptides to measure differences in catalytic efficiency and substrate specificity of high-abundant extracellular proteins found in human semen. Such proteins have often been predicted computationally to be the targets of positive selection, purifying selection, and pseudogenization among the hominid primates (humans and the great apes). The experimental design will include testing the function of recombinant proteins from humans, chimpanzees, gorillas, and macaques. Furthermore, we will create the proteins corresponding to the last common ancestors of humans and chimpanzees; of humans, chimpanzees, and gorillas; and of macaques and the hominids, using ancestral sequence reconstruction. For each of these species, we will measure the phosphatase and peptidase activity of the prostatic acid phosphatase ACPP, the protease activity of the prostate expressed KLK3, and the transglutaminase activity of prostatic TGM4. Furthermore, the efficiency and specificity each of these enzymes will be tested using their natural substrates, the seminal vesicle expressed SEMG1 and SEMG2, to understand their coevolution. In addition to examining differences among species in enzyme activity, we will test the hypothesis that species differ in the ability of small peptides derived from ACPP, SEMG1, and SEMG2 to form amyloid fibrils and enhance HIV infection. Finally, we will use bioinformatics approaches to identify primate genes whose evolution may have been driven by either sexual selection or resistance to sexually transmitted viruses. This research will improve undergraduate education at Duquesne University by exposing students to meritorious research while significantly enhancing the research environment of the PI’s laboratory, department, and university.

注：本项目摘要与母基金重复，但以粗体突出显示， 指出本科生托马斯华盛顿将参与的研究部分 根据拟议的《促进卫生相关研究多样性补编》开展工作。 项目摘要 我们体内超过20，000个蛋白质编码基因是由以下因素共同作用形成的： 突变、自然选择、遗传漂变和迁移。了解这一点的一个基本方法是 这些力量的影响，特别是个别氨基酸变化的后果， 基因突变对蛋白质功能的影响，是将我们的基因和蛋白质与我们最接近的基因和蛋白质进行比较， 亲戚在这样做的时候，选择的模式（积极选择，消极选择，或放松 也可以推断出（）。在过去的十年里，超过12种高质量的灵长类动物 基因组序列已经公布，允许详细调查的力量， 进化作用于人类基因组和其他原始人的基因组，使用复杂的 基于群体遗传学和分子进化原理的模型。拟议 研究，我们将超越计算预测的选择，通过执行定量 使用重组蛋白和合成肽的功能测定， 高丰度胞外蛋白的催化效率和底物特异性， 人类精液这些蛋白质经常被预测为计算的目标， 原始灵长类的正选择、纯化选择和假生殖 （人类和类人猿）。 实验设计将包括测试来自人类的重组蛋白的功能， 黑猩猩大猩猩和猕猴此外，我们将创建相应的蛋白质 人类和黑猩猩最后的共同祖先;人类，黑猩猩， 大猩猩;猕猴和原始人类，使用祖先序列重建。为每个 在这些物种中，我们将测量前列腺酸的磷酸酶和肽酶活性， 磷酸酶ACPP、前列腺表达的KLK 3的蛋白酶活性和前列腺表达的KLK 3的蛋白酶活性。 前列腺TGM 4的转氨酶活性。此外，效率和特异性各自 这些酶将测试使用其天然底物，精囊 表达SEMG 1和SEMG 2，以了解它们的共同进化。除了审查 物种间酶活性的差异，我们将测试的假设，物种不同， 来源于ACPP、SEMG 1和SEMG 2的小肽形成淀粉样纤维的能力 并增加艾滋病毒感染。最后，我们将使用生物信息学方法来识别灵长类动物 这些基因的进化可能是由性选择或抵抗性选择驱动的。 性传播病毒 这项研究将通过揭露和分析，改善迪克讷大学的本科教育， 学生有功的研究，同时大大提高了研究环境的 PI的实验室，部门和大学。