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，复制一段DNA序列。在这些情况下，只有当两个基因都通过进化为具有不同功能的个体来促进个体的健康时，这两个基因拷贝才能保持。因此，预计一个基因拷贝的突变会消除其功能，从而降低适合度。与这一预期相反，这种突变的影响似乎表明重复的基因具有相同的功能。这个项目将通过观察模式植物拟南芥中复制基因突变的影响来探索这一矛盾。这些突变的适合度效应将被测量，并与现有数据相结合，以预测重复基因之间的冗余程度。归根结底，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具有重要意义的新特征至关重要。该项目还将培训几名本科生和研究生，并向公众提供宣传。由于高估基因冗余是理解为什么保留重复基因的主要挑战，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。在这项建议中，将在生长室和田间比较240对拟南芥复制基因的单个突变体(每个重复中都有突变)、双突变体(两个重复中的突变)和野生型植物之间的寿命适应性差异。由此产生的适合度数据将与大规模分子功能研究的数据、比较基因组数据和现有的表型信息相结合，以建立可以预测任何重复基因对的遗传冗余的统计模型。这项拟议的工作将通过产生更准确的、基于适应度的遗传冗余测量来推进重复基因的进化遗传学研究。这些措施对于估计作用于每个复制副本的净化选择的强度至关重要，而这反过来又是理解为什么重复基因持续存在的核心。除了终生健康外，还将估计乘性健康成分，以帮助识别导致保留的选择性因素。这项拟议的研究还将评估重复基因的单突变和双突变在适应度效应(加性、拮抗或协同上位性)方面的差异，以及在压力更大的田间环境中适应度效应是否更大。该项目还将产生一种新颖的、量化的遗传冗余模型，该模型将整合迄今主要单独研究的适应性、表型、比较/功能基因组学数据。该模型将允许在全基因组范围内预测遗传冗余，预计将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，该模型还将提供导致重复基因之间冗余的机制的洞察。

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.