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The Molecular and Fitness Consequences of Spontaneous Mutation Accumulation Under Varying Intensities of Natural Selection

不同自然选择强度下自发突变积累的分子和适应性后果

基本信息

批准号：
1330245
负责人：
Vaishali Katju
金额：
$ 75万
依托单位：
University of New Mexico
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2015-11-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1330245&HistoricalAwards=false
关键词：
Molecular Fitness Consequences Spontaneous Mutation

项目摘要

Mutation induces genetic variation. Genetic variation, in turn, fuels evolutionary change. Experimental investigations into the rate and fitness effects of spontaneous mutations are central to the study of evolution and biology. Mutation accumulation (MA) experiments have been instrumental in measuring the rate of origin of deleterious mutations. However, the vast majority of MA studies to date are compromised by two major limitations: (i) the use of phenotypic data to indirectly estimate key mutational parameters, and (ii) the use of experimental lines maintained at a single, minimum effective population size. Although population-genetics theory predicts a wide range of fitness consequences for all classes of spontaneous mutations, their distribution of fitness effects remains obscure. Furthermore, the loss or fixation of mutations and their consequences for population fitness additionally depend upon their individual effect and the efficacy of natural selection, the latter being influenced by the population size. Spontaneous MA lines of the nematode Caenorhabditis elegans were evolved in parallel over 400 generations at three varying effective population sizes to manipulate the efficacy of natural selection in different genomic backgrounds. This represents the most ambitious experiment of its kind within any species. The combination of long-term spontaneous MA lines under varying intensities of selection and use of powerful high-throughput genomic techniques will enable unprecedented insights into (i) the rates of origin of diverse mutations, (ii) their differential accumulation under varying regimes of natural selection, and (iii) a framework to assess the interaction between mutation and selection at the molecular level on a genome-wide scale. The aims are to identify all acquired mutations at the mitochondrial and nuclear level, investigate their differential rates of accumulation under varying population sizes and infer their distribution of fitness effects. Phenotypic fitness-assays will quantify the rate of fitness decay at different population sizes and determine the extent to which larger populations are buffered from mutational degradation. By providing a unified account of the consequences of spontaneous mutations at the genetic and phenotypic levels, this research will yield significant insights into the evolutionary process for several different topics, including the genetic basis of variation, the evolutionary dynamics of mutations under the forces of natural selection and genetic drift, and their range of fitness effects. Broader ImpactsThe experimental lines provide an unprecedented resource to study biological evolution at multiple scales, from phenotype to protein function. The experimental MA lines created as part of this research and the deposition of genome sequences in public databases represent an enormous community resource to be shared with colleagues in the scientific community. In addition to the training projects listed with individual aims, this project will have broad impacts in two areas: academic training/mentorship and public outreach in an environment with a large fraction of underrepresented minorities. Data generated by the research will be (i) disseminated to high school students and the general public via seminars and interactive panel discussions to communicate its evolutionary implications and promote scientific literacy, and (ii) employed in the creation of data sets and mini tutorials for high school students to demystify molecular evolution and introduce them to basic evolutionary computational methods for analyses of genomic sequences. The University of New Mexico is the only research-intensive University that is also Hispanic serving, with two extensive underrepresented student populations comprising Hispanics and Native Americans. This provides a unique opportunity to mentor undergraduate minority students, graduate students and postdocs, and instill in them an appreciation for interdisciplinary research in population-genomics and bioinformatics. Research stemming from this project is expected to greatly enhance our fundamental understanding of the evolutionary process and enable the quantification of several key rate parameters in biology, with implications for all spheres of biology including an understanding of the genetic and phenotypic consequences of maintaining populations at small sizes.

突变会导致基因变异。基因变异反过来又推动了进化的变化。对自发突变的速率和适合度效应的实验研究是进化论和生物学研究的核心。突变累积(MA)实验有助于测量有害突变的起源率。然而，到目前为止，绝大多数MA研究都受到两个主要限制的影响：(I)使用表型数据间接估计关键突变参数，以及(Ii)使用保持在单个最小有效种群大小的实验系。尽管群体遗传学理论预测了所有类别的自发突变的适应度结果，但它们的适应度效应的分布仍然不清楚。此外，突变的丢失或固定及其对种群适合性的影响还取决于它们的个体效应和自然选择的有效性，后者受种群大小的影响。秀丽线虫的自发MA系在三个不同的有效种群规模下平行进化了400多代，以操纵不同基因组背景下的自然选择的效果。这是同类实验中最雄心勃勃的一次。不同选择强度下的长期自发MA系的组合和强大的高通量基因组技术的使用将使人们能够前所未有地深入了解(I)各种突变的起始率，(Ii)它们在不同自然选择制度下的差异积累，以及(Iii)在全基因组范围内在分子水平上评估突变和选择之间的相互作用的框架。其目的是在线粒体和核水平上识别所有获得性突变，调查它们在不同种群规模下的不同累积速度，并推断它们的适应度效应的分布。表型适合度分析将量化不同种群规模下的适合度衰减率，并确定较大种群免受突变退化的缓冲程度。通过在遗传和表型水平上对自发突变的后果提供统一的描述，这项研究将对几个不同主题的进化过程产生重要的见解，包括变异的遗传基础，在自然选择和遗传漂移的力量下突变的进化动力学，以及它们的适合度影响范围。更广泛的影响这些实验品系为研究从表型到蛋白质功能的多个尺度的生物进化提供了前所未有的资源。作为这项研究的一部分创建的实验MA线以及在公共数据库中存储的基因组序列代表着一个巨大的社区资源，将与科学界的同事共享。除了列出有个人目标的培训项目外，该项目还将在两个领域产生广泛影响：学术培训/辅导和在少数族裔人数较少的环境中进行公众宣传。研究产生的数据将(I)通过研讨会和互动小组讨论向高中生和普通公众传播，以传达其进化含义并促进科学素养，以及(Ii)用于为高中生创建数据集和迷你教程，以揭开分子进化的神秘面纱，并向他们介绍用于基因组序列分析的基本进化计算方法。新墨西哥大学是唯一一所也提供拉美裔服务的研究密集型大学，有两个广泛的代表性不足的学生群体，包括西班牙裔和美洲原住民。这为指导本科生、研究生和博士后提供了独特的机会，并向他们灌输对人口基因组学和生物信息学跨学科研究的欣赏。该项目的研究有望极大地加强我们对进化过程的基本理解，并使生物学中的几个关键速率参数得以量化，这将对生物学的所有领域产生影响，包括理解维持小种群的遗传和表型后果。