Collaborative Research: Fitness effects of loss-of-function mutations in duplicate genes

这个项目的目标是了解基因复制时突变的影响。DNA的突变可以导致复制，即DNA序列的一段被复制。在这种情况下，只有当两个基因都通过进化出不同的功能来为个体的适应性做出贡献时，两个基因拷贝才会被保留下来。因此，预计一个基因拷贝的突变会消除其功能，从而降低适应度。与这种预期相反，这种突变的影响似乎表明，重复的基因共享相同的功能。这个项目将通过观察模式植物拟南芥中重复基因突变的影响来探索这种矛盾。这些突变的适应度效应将被测量，并与现有数据相结合，以预测重复基因之间的冗余程度。最终，这些知识对于破译重复基因如何导致疾病以及在医学、农业和产生新物种方面很重要的新特征至关重要。该项目还将培训几名本科生和研究生，并向公众提供服务。由于对基因冗余的过高估计是理解重复基因保留的主要挑战，因此有必要对重复基因之间的基因冗余进行更准确的测量。在本提案中，将在生长室内和田间比较240对拟楠重复基因的单突变体（每个副本都有突变）、双突变体（两个副本都有突变）和野生型植物之间的终生适应度差异。由此产生的适应度数据将与大规模分子功能研究数据、比较基因组数据和现有表型信息相结合，建立可以预测任何重复基因对遗传冗余的统计模型。拟议的工作将通过产生更准确的、基于适应度的基因冗余测量来推进重复基因的进化遗传研究。这些测量对于估计作用于每个重复拷贝的纯化选择的强度是必不可少的，这反过来又对理解重复基因持续存在的原因至关重要。除了终生适应度，乘法适应度成分将被估计，以帮助确定潜在的保留选择性因子。拟议的研究还将允许评估重复基因的单突变和双突变在适应性效应（加和性、拮抗性或协同上位性）方面的差异，以及适应性效应是否在更有压力的野外环境中更大。该项目还将产生一种新的遗传冗余定量模型，该模型将整合适应性、表型、比较/功能基因组学数据，这些数据迄今为止大多是单独研究的。该模型将允许对全基因组的遗传冗余进行预测，并有望适用于广泛的分类群，包括非模式生物。最后，由于与基因功能相关的异质分子数据将被整合，该模型还将提供对导致重复基因之间冗余的机制的见解。

The goal of this project is to understand the effects of mutations when genes have duplicated copies. Mutations in DNA can lead to duplication where a stretch of a DNA sequence is copied. In these situations both gene copies will be maintained only if they both contribute to the fitness of an individual by evolving to have different functions. Thus, it is expected that a mutation of one gene copy that eliminates its function will reduce fitness. Contrary to this expectation, effects of such mutation appear to indicate that duplicate genes share the same function. This project will explore this contradiction by looking at the effects of mutations in duplicated genes in the model plant, Arabidopsis thaliana. The fitness effects of these mutations will be measured and combined with existing data to predict the degree of redundancy between duplicate genes. Ultimately, this knowledge is essential for deciphering how duplicate genes contribute to disease as well as novel traits that are important in medical science, agriculture and in generating new species. The project will also train several undergraduate and graduate students and provide outreach to the general public.Because overestimates of genetic redundancy present a major challenge in understanding why duplicate genes are retained, more accurate measures of genetic redundancy between duplicate genes are necessary. In this proposal, lifetime fitness differences between single mutants (with mutations in each duplicate), double mutants (mutations in both duplicates), and wild type plants will be compared in the growth chamber and in the field for 240 pairs of A. thaliana duplicate genes. The resulting fitness data will be integrated with data from large-scale molecular functional studies, comparative genomic data, and existing phenotype information to establish statistical models that can predict genetic redundancy of any duplicate gene pair. The proposed work will advance evolutionary genetic studies of duplicate genes by producing more accurate, fitness-based measures of genetic redundancy. These measures are essential for estimating the strength of purifying selection acting on each duplicate copy, which in turn is central for understanding why duplicate genes persist. In addition to lifetime fitness, multiplicative fitness components will be estimated to help identify the selective agents underlying retention. The proposed research will also allow the assessment of how single and double mutants of duplicate genes differ in their fitness effects (additivity, antagonistic or synergistic epistasis) and if the fitness effects are greater in more stressful field environments. The project will also lead to a novel, quantitative model of genetic redundancy that will integrate fitness, phenotype, comparative/functional genomics data that to date have been mostly studied in isolation. The model will allow prediction of genetic redundancy genome-wide and is expected to be applicable across a broad range of taxa, including non-model organisms. Finally, because heterogeneous molecular data relevant to gene functions will be integrated, the model will also provide insight into the mechanisms leading to redundancy between duplicate genes.