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

• 批准号: 1565844
• 负责人: Vaishali Katju
• 金额: $ 50.4万
• 依托单位: Texas A&M AgriLife Research
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1565844&HistoricalAwards=false
• 关键词: Molecular; Fitness; Consequences; Spontaneous; Mutation

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.

突变引起遗传变异。遗传变异反过来又促进了进化。对自发突变的速率和适应性效应的实验研究是进化和生物学研究的核心。突变累积（MA）实验一直有助于测量有害突变的起源率。然而，迄今为止，绝大多数MA研究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）使用维持在单一最小有效群体大小的实验品系。虽然群体遗传学理论预测了各种自发突变的适应性后果，但它们的适应性效应的分布仍然不清楚。此外，突变的丧失或固定及其对群体适应性的后果还取决于它们的个体效应和自然选择的效力，后者受群体大小的影响。 自发MA线的线虫秀丽隐杆线虫平行进化超过400代，在三个不同的有效人口规模，以操纵在不同的基因组背景的自然选择的效力。这是任何物种中最雄心勃勃的实验。在不同强度的选择和强大的高通量基因组技术的使用下的长期自发MA系的组合将使前所未有的洞察到（i）不同突变的起源率，（ii）在不同的自然选择制度下的差异积累，和（iii）一个框架，以评估突变和选择之间的相互作用在分子水平上的全基因组规模。其目的是确定所有获得的突变在线粒体和核水平上，调查他们的差异积累率在不同的人口规模，并推断其分布的健身效果。表型适应性测定将量化不同种群规模下的适应性衰减速率，并确定较大种群从突变退化中缓冲的程度。通过在遗传和表型水平上对自发突变的后果提供统一的解释，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变的力量下突变的进化动力学，以及它们的适应性效应范围。更广泛的影响实验线提供了一个前所未有的资源，研究生物进化在多个尺度上，从表型到蛋白质功能。作为这项研究的一部分而创建的实验性MA系以及在公共数据库中沉积的基因组序列代表了与科学界同事共享的巨大社区资源。除了列出的有个别目标的培训项目外，该项目还将在两个领域产生广泛影响：学术培训/指导和在代表性不足的少数群体占很大比例的环境中的公共宣传。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公众传播，以传达其进化意义并促进科学素养，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，并向他们介绍用于分析基因组序列的基本进化计算方法。新墨西哥州的大学是唯一的研究密集型大学，也是西班牙裔服务，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。这为指导本科少数民族学生，研究生和博士后提供了一个独特的机会，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赞赏。来自这个项目的研究预计将大大提高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的量化成为可能，对生物学的所有领域都有影响，包括对维持小规模种群的遗传和表型后果的理解。