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

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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.