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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

基本信息

批准号：
9305458
负责人：
Michael Ignatius Jensen-Seaman
金额：
$ 42.83万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305458
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 Doctor of Philosophy 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 Specificity Students Substrate Specificity System Taxonomy Testing Transglutaminases Universities Viral Virus Virus Diseases base career preparation driving force enzyme activity extracellular genetic evolution improved male migration pathogen pressure prostatic fraction Acid phosphatase isoenzyme protein function reconstruction reproductive response species difference sperm cell synthetic peptide tool undergraduate education undergraduate student

项目摘要

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.

项目总结