Functional genomic approaches to duplicate gene evolution

复制基因进化的功能基因组方法

• 批准号: 7665280
• 负责人: JIANZHI ZHANG
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665280
• 关键词: Address; Biodiversity; Biological; Biological Assay; Biological Models; Biological Process; Code; Copy Number Polymorphism; Custom; Data; Data Set; Evolution; Financial compensation; Gene Dosage; Gene Duplication; Gene Expression; Gene Family; Genes; Genetic; Genome; Genomics; Grant; Health; Hereditary Disease; Human; Individual; Kluyveromyces; Laboratories; Mammals; Measures; Modeling; Molecular; Mus; Mutation; Organism; Pancreatic ribonuclease; Pattern; Prevalence; Process; Production; Proteins; Relative (related person); Ribonucleases; Saccharomyces cerevisiae; Saccharomycetales; Severities; Source; Technology; Testing; Time; Two-Hybrid System Techniques; Uncertainty; Variant; Yeasts; base; cost; disorder prevention; duplicate genes; experience; fitness; functional genomics; gene function; genome-wide; human data; human disease; improved; innovation; insight; novel; paralogous gene; protein function; protein protein interaction; public health relevance; research study; sample fixation; theories; wasting; Address; Biodiversity; Biological; Biological Assay; Biological Models; Biological Process; Code; Copy Number Polymorphism; Custom; Data; Data Set; Evolution; Financial compensation; Gene Dosage; Gene Duplication; Gene Expression; Gene Family; Genes; Genetic; Genome; Genomics; Grant; Health; Hereditary Disease; Human; Individual; Kluyveromyces; Laboratories; Mammals; Measures; Modeling; Molecular; Mus; Mutation; Organism; Pancreatic ribonuclease; Pattern; Prevalence; Process; Production; Proteins; Relative (related person); Ribonucleases; Saccharomyces cerevisiae; Saccharomycetales; Severities; Source; Technology; Testing; Time; Two-Hybrid System Techniques; Uncertainty; Variant; Yeasts; base; cost; disorder prevention; duplicate genes; experience; fitness; functional genomics; gene function; genome-wide; human data; human disease; improved; innovation; insight; novel; paralogous gene; protein function; protein protein interaction; public health relevance; research study; sample fixation; theories; wasting

DESCRIPTION (provided by applicant): The long-term objective of my laboratory is to understand how new genes with novel functions originate and how these molecular innovations contribute to the survival, adaptation, and evolution of organisms. Gene duplication is wildly regarded as the primary source of new genes, but the general patterns and mechanisms of functional divergence of duplicate genes are not well understood. Taking advantage of high-throughput genomic technologies and unprecedented amount of functional genomic data, we propose experimental and computational functional genomic approaches to duplicate gene evolution, with four specific aims. First, using protein-protein interaction (PPI) as a measure of protein function, we plan to study the rate of protein functional change in duplicated and unduplicated genes between the budding yeast Saccharomyces cerevisiae and its relative Kluyveromyces waltii. The S. cerevisiae lineage experienced a whole-genome duplication (WGD) shortly after its separation from K. waltii and has retained ~450 pairs of WGD-duplicates. PPI information from S. cerevisiae is publicly available, while the corresponding PPIs in K. waltii will be experimentally tested. Second, we propose to make custom gene expression microarrays of K. waltii and compare its genome- wide gene expression pattern with that of S. cerevisiae to study how expression patterns of unduplicated and duplicated genes change in evolution. A similar analysis will also be conducted on the publicly available high-quality microarray data of the human and mouse. Third, competing hypotheses exist on whether gene duplication in an individual organism causes an immediate fitness gain by providing extra protein products, an immediate fitness loss by wasting energy for making extra products that are not needed, or no fitness change. Using publicly available functional genomic data of yeast and mammals, we will examine these hypotheses computationally. We will then experimentally measure in yeast the fitness cost of protein production at various levels, using foreign proteins that are not needed in yeast. Fourth, it is controversial as whether a gene can functionally compensate the loss of its duplicate copy. We propose a critical examination of this compensation hypothesis by a yeast experiment in which we measure the fitness change caused by replacing the coding region of a gene with that of its paralog. Complete protein compensation predicts no fitness change whereas an absence of compensation leads to fitness reduction. Together, these studies are expected to improve significantly our understanding of the patterns and mechanisms of duplicate gene evolution. PUBLIC HEALTH RELEVANCE: Our projects will increase understanding of mechanisms of gene evolution and aid many studies of how new biological functions arise. Our study is of human health relevance, because many gene copy number variations, generated by gene duplication, are involved in human diseases. Furthermore, different functional relationships among duplicate genes (e.g., completely redundant, partially overlapping, or distinctly different) would predict different consequences of mutations to the likelihood and severity of genetic diseases. A clear understanding of these relationships helps clarify the exact molecular basis of human diseases, a necessary step in the treatment and prevention of these diseases.

描述（由申请人提供）：我实验室的长期目标是了解具有新功能的新基因是如何产生的，以及这些分子创新如何促进生物体的生存，适应和进化。基因重复被疯狂地视为新基因的主要来源，但是重复基因功能差异的一般模式和机制尚不清楚。利用高通量基因组技术和前所未有的功能基因组数据，我们提出了实验和计算功能基因组方法，以复制基因演变，并具有四个特定的目标。首先，使用蛋白质 - 蛋白质相互作用（PPI）作为蛋白质功能的量度，我们计划研究酿酒酵母及其相对kluyveromyces waltii之间重复和未叠加基因中蛋白质功能变化的速率。 S. cerevisiae谱系与K. waltii分离后不久就经历了全基因组重复（WGD），并保留了约450对WGD duplicate。酿酒酵母的PPI信息公开可用，而K. waltii中的相应PPI将进行实验测试。其次，我们建议将K. waltii的自定义基因表达微阵列进行比较，并将其广泛的基因表达模式与酿酒酵母的基因组表达模式进行比较，以研究未塑性和重复基因的表达模式如何变化。还将对人和老鼠的公共高质量微阵列数据进行类似的分析。第三，存在相互竞争的假设，即单个生物体中的基因重复是通过提供额外的蛋白质产品而引起的立即适应性增长，即通过浪费能量来制造不需要的额外产品或不改变健身的能量来立即丧失。使用酵母和哺乳动物的公开功能基因组数据，我们将在计算上检查这些假设。然后，我们将使用酵母中不需要的异物蛋白质在酵母中测量蛋白质产生的适应性成本。第四，这是有争议的，因为一个基因是否可以在功能上补偿其重复副本的损失。我们通过酵母实验提出了对该补偿假说的批判性检查，在该实验中，我们通过用其旁系同源物替换基因的编码区域所引起的适应性变化。完整的蛋白质补偿预测没有适应性变化，而没有补偿会导致健身降低。总之，这些研究有望显着改善我们对重复基因进化的模式和机制的理解。 公共卫生相关性：我们的项目将增加对基因进化机制的理解，并帮助许多研究新的生物学功能。我们的研究是人类健康相关性的，因为许多基因拷贝数变异是由基因重复产生的，涉及人类疾病。此外，重复基因之间的不同功能关系（例如，完全冗余，部分重叠或明显不同）将预测突变对遗传疾病的可能性和严重性的不同后果。对这些关系的明确理解有助于阐明人类疾病的确切分子基础，这是治疗和预防这些疾病的必要步骤。