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.

专注于阐明分子和种群遗传学的进化机制 级别，该项目涉及理论发展和实验工作的整合 以系统发育比较方式进行。分子/细胞水平的重点是 通过DNA复制，mRNA转录和蛋白质翻译的误差率在〜50中 细菌和真核生物。这项工作旨在检验漂移级式假设，这是 假设自然选择可以通过任何特征实现的精致水平有限 通过随机漂移的力量，与有效的人口规模成反比。 复制效果的度量来自长期串行集中突变积累 瓶颈重复线，然后进行全基因组测序。新开发的方法 将产生不适当核糖核苷酸的速率的平行估计值 出现在mRNA中，错误的氨基酸被掺入蛋白质中，从而允许评估 在这两个级别的错误传播之间是否存在负相关。 人口遗传机制的进化机制将通过一个项目来阐明 序列5000基因组来自该模型的地理广泛分离株 Microcrustacean花花公子pulex以及较少数量的关键外群物种。 结合有关重组精细刻度模式的信息，本研究将揭示 〜60种人群中漂移，突变和重组的相对大小，A 对任何其他物种的调查远远超出了这一点。这将使能够检验以下假设 基因结构和基因组结构水平的变化直接由局部驱动 人口遗传环境。 D. Pulex系统还具有获得的独特功能 对进化遗传学两个主要未解决的奥秘的见解：起源和长期 内含子在蛋白质编码基因中的影响，以及丧失的原因和后果 减数分裂重组。 与人类健康有关。因为突变是所有变化的来源 自然选择行为，为病原体的出现提供燃料，是最终的 遗传疾病和癌症的原因，我们在复制忠诚方面的工作对 多样化的人类健康问题。因为转录和翻译误差导致细胞 毒性和蛋白质聚集，在这些水平上的工作也具有显着的应用。 最后，第一次，5000个基因组项目将揭示人口进化如何 特征由漂移，突变和重组的相对功能定义，产生洞察力 进入推动所有物种对自然作出反应的效率和机制的因素 选择。阐明分子/细胞机制，减数分裂的产生 需要施肥的单倍体卵转化为二倍体卵的未生产的卵 理想的是，它可以打开各种物种克隆传播的可能性。