Causes and Population-genetic Consequences of Molecular Variation

分子变异的原因和群体遗传后果

• 批准号: 9914301
• 负责人: Michael R LYNCH
• 金额: $ 105.77万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 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/9914301
• 关键词: Amino Acids; Architecture; Automobile Driving; Code; Collection; DNA; DNA biosynthesis; Daphnia; Development; Diploidy; Environment; Evaluation; Evolution; Fertilization; Gene Structure; Genes; Genetic; Genetic Diseases; Genetic Recombination; Genetic Transcription; Genome; Geography; Haploidy; Health; Heritability; Human; Introns; Lead; Long-Term Effects; Malignant Neoplasms; Measures; Meiosis; Meiotic Recombination; Messenger RNA; Methods; Modeling; Molecular; Molecular Genetics; Mutation; Natural Selections; Pattern; Phylogenetic Analysis; Population; Population Genetics; Population Sizes; Production; Proteins; RNA; Research; Ribonucleotides; Source; Surveys; System; Testing; Time; Toxic effect; Translations; Variant; Work; comparative; egg; fitness; genome sequencing; insight; pathogen; protein aggregation; structural genomics; theories; trait; whole genome

Focused on elucidating the mechanisms of evolution at the molecular and population-genetic levels, this project involves an integration of theory development and experimental work performed in a phylogenetic comparative manner. The molecular/cellular level focus is on the rate of error production via DNA replication, mRNA transcription, and protein translation in ~50 bacterial and eukaryotic species. This work seeks to test the drift-barrier hypothesis, which postulates that the level of refinement that natural selection can achieve with any trait is limited by the power of random drift and inversely proportional to the effective population size. Measures of replication-fidelity derive from mutation accumulation in long-term sets of serially bottlenecked replicate lines followed by whole-genome sequencing. Newly developed methods will yield parallel estimates of the much higher rates at which inappropriate ribonucleotides appear in mRNAs and erroneous amino acids are incorporated into proteins, allowing evaluation of whether negative associations exist between error propagation at these two levels. The population-genetic mechanisms of evolution will be clarified via a project to sequence 5000 genomes from geographically widespread isolates of the model microcrustacean Daphnia pulex, as well as from smaller numbers of key outgroup species. Combined with information on the fine-scaled pattern of recombination, this study will reveal the relative magnitudes of drift, mutation, and recombination in a collection of ~60 populations, a survey far beyond that for any other species. This will enable a test of the hypothesis that variation at the level of gene structure and genomic architecture is directly driven by the local population-genetic environment. The D. pulex system also has unique features for gaining insights into two major unsolved mysteries in evolutionary genetics: the origin and long-term effects of introns in protein-coding genes, and the causes and consequences of the loss of meiotic recombination. Relevance to human health. Because mutation is the source of all variation upon which natural selection acts, provides the fuel for the emergence of pathogens, and is the ultimate cause of genetic disorders and cancer, our work on replication fidelity has broad significance for diverse human-health issues. Because transcription and translation errors lead to cellular toxicity and protein aggregation, work at these levels also has significant applied implications. Finally, for the first time, the 5000 Genomes Project will reveal how population evolutionary features are defined by the relative power of drift, mutation and recombination, yielding insight into the factors driving the efficiencies and mechanisms by which all species respond to natural selection. Elucidation of the molecular/cellular mechanisms by which meiotic production of haploid eggs requiring fertilization is converted to ameiotic production of diploid eggs is highly desirable as it would open up possibilities of clonal propagation in diverse species.

着重从分子和群体遗传学角度阐明进化机制 该项目涉及理论发展和实验工作的整合 以系统发育比较的方式进行。分子/细胞水平的重点是 通过DNA复制、mRNA转录和蛋白质翻译产生的错误率约为50 细菌和真核生物物种。这项工作旨在测试漂移障碍假说， 假设自然选择对任何性状所能达到的改良水平是有限的 由随机漂移的力量和成反比的有效人口规模。 复制保真度的度量来自于长期序列中的突变积累。 重复检测系，然后进行全基因组测序。新开发的方法 将产生平行的估计，在不适当的核糖核苷酸 出现在mRNA中，错误的氨基酸被掺入蛋白质中， 在这两个级别上的错误传播之间是否存在负关联。 将通过一个项目澄清进化的群体遗传机制， 从该模型的地理分布广泛的分离株中测序5000个基因组 此外，还从小型甲壳动物蚤状水蚤以及数量较少的关键外群物种中获得了一些新的证据。 结合重组精细模式的信息，本研究将揭示 在一个收集了约60个群体的漂移、突变和重组的相对幅度， 远远超过其他物种的调查。这将使一个假设的测试， 基因结构和基因组结构水平上的变异直接由局部基因驱动。 种群遗传环境。地方pulex系统还具有获得 深入了解两个主要的未解之谜在进化遗传学：起源和长期 内含子在蛋白质编码基因中的作用，以及内含子丢失的原因和后果。 减数分裂重组 与人类健康的相关性。因为突变是所有变异的来源， 自然选择起作用，为病原体的出现提供燃料，是最终的选择。 遗传性疾病和癌症的原因，我们在复制保真度方面的工作具有广泛的意义， 各种人类健康问题。因为转录和翻译错误导致细胞 毒性和蛋白质聚集，在这些水平上的工作也具有重要的应用意义。 最后，5000个基因组计划将首次揭示人口进化的方式。 特征是由漂移、突变和重组的相对力量定义的， 研究推动所有物种对自然环境做出反应的效率和机制的因素 选择.阐明减数分裂产生的分子/细胞机制， 需要受精的单倍体卵子转化为非减数分裂的二倍体卵子的生产是非常困难的。 因为它将为不同物种的克隆繁殖开辟可能性。