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

合作研究：重复基因功能丧失突变的适应性影响

• 批准号: 1655630
• 负责人: Patrick Krysan
• 金额: $ 33.8万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1655630&HistoricalAwards=false
• 关键词: Collaborative; Research; Fitness; effects; loss

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.

该项目的目标是了解基因复制时突变的影响。DNA中的突变可以导致复制，其中一段DNA序列被复制。在这些情况下，只有当两个基因拷贝都通过进化具有不同的功能而对个体的适应性做出贡献时，它们才能被维持。因此，预期一个基因拷贝的突变消除其功能将降低适应性。与这种预期相反，这种突变的影响似乎表明重复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重复基因突变的影响来探索这种矛盾。这些突变的适应性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，农业和产生新物种中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，并向公众提供外展服务。由于对遗传冗余的过高估计是理解为什么保留重复基因的一个重大挑战，因此有必要对重复基因之间的遗传冗余进行更准确的测量。在该提议中，将在生长室和田间对240对A.拟南芥复制基因。由此产生的适应度数据将与来自大规模分子功能研究、比较基因组数据和现有表型信息的数据相结合，以建立可以预测任何重复基因对的遗传冗余的统计模型。拟议的工作将通过产生更准确的，基于适应度的遗传冗余措施来推进重复基因的进化遗传学研究。这些措施是必不可少的估计净化选择的强度作用于每个重复的副本，这反过来又是理解为什么重复基因持续存在的核心。除了终身健身，乘法健身组件将被估计，以帮助确定潜在的保留选择剂。拟议的研究还将允许评估重复基因的单突变体和双突变体在其适应性效应（加和性，拮抗性或协同上位性）方面的差异，以及适应性效应在更紧张的田间环境中是否更大。该项目还将导致一种新的遗传冗余的定量模型，该模型将整合健身，表型，比较/功能基因组学数据，迄今为止，这些数据主要是孤立研究的。该模型将允许预测全基因组的遗传冗余，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，该模型还将提供对导致重复基因之间冗余的机制的深入了解。