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.

注意：此项目摘要是从父母赠款中重复的，但大胆地突出显示为 指标的研究部分是本科生托马斯·华盛顿（Thomas Washington） 根据拟议的补充剂进行研究，以促进与健康相关研究的多样性。 项目摘要 我们体内的> 20,000个蛋白质编码基因已由 突变，自然选择，遗传漂移和迁移。理解 这些力的影响，尤其是单个氨基酸变化的后果 蛋白质功能的突变是将我们的基因和蛋白质与壁橱的基因和蛋白质进行比较 亲属。这样做的选择方式（正选择，否定选择或放松 也可以推断出约束）。在过去的十年中，超过十几个高质量的灵长类动物 基因组序列已发表，允许对 使用复杂的进化作用于人类基因组和其他人类的基因组 基于种群遗传学和分子进化原理的模型。在提议中 研究，我们将通过执行定量来超越选择的计算预测 使用重组蛋白和合成胡椒的功能测定，以测量 在 人类精液。这种蛋白质经常在计算上被预测为 人类隐私之间的积极选择，净化选择和伪造 （人类和大猿）。 实验设计将包括测试人类重组蛋白的功能， Chinamzees，大猩猩和猕猴。此外，我们将创建蛋白质对应 人类和黑猩猩的最后一个共同的祖先；人类，黑猩猩和 大猩猩；以及猕猴和人类，使用祖先序列重建。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KLK3的蛋白酶活性，而 前列腺TGM4的转谷氨酰胺酶活性。此外，效率和特异性 这些酶将使用其自然底物测试第二个囊泡 表示SEMG1和SEMG2，以了解它们的协同进化。除了检查 酶活性中物种之间的差异，我们将测试物种不同的假设 源自ACPP，SEMG1和SEMG2形成淀粉样蛋白纤维的小型宠物的能力 并增强HIV感染。最后，我们将使用生物信息学方法来识别主要 进化的基因可能是由于性选择或抵抗力驱动的 性传播病毒。 这项研究将通过暴露 学生进行功绩化研究，同时显着增强了研究环境 PI的实验室，系和大学。