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      Reciprocal Sign Epistasis between Frequently Experimentally Evolved Adaptive Mutations Causes a Rugged Fitness Landscape

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      PLoS Genetics
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          The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors.

          Author Summary

          How organisms adapt to their environment is of central importance in biology, but the molecular underpinnings of adaptation are difficult to discover. Fitness landscapes illustrate possible steps adaptive evolution can take to increase the evolutionary fitness of individuals within a population, and the shape of the fitness landscape determines the accessibility of the fittest point on the landscape. On a rugged landscape, negative interactions between mutations cause fitness valleys separating fitness peaks, which can constrain adaptation and act as an adaptive barrier. Here, we comprehensively characterized the fitness of mutations that arose in clones during a yeast experimental evolution and found that mutations in two loci, MTH1 and HXT6/HXT7, arose multiple times independently and are individually adaptive. However, when forced to co-occur, the double mutant has a lower fitness than either single mutant and even the wild-type strain. This negative interaction forces these two mutations to remain mutually exclusive during the experimental evolution and results in a rugged fitness landscape, where genetic constraint prevents lineages carrying the MTH1 mutation from reaching the higher fitness peak of HXT6/HXT7. These results show that genetic interactions are central in shaping a very active portion of this fitness landscape.

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          Cancer genes and the pathways they control.

          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
            • Record: found
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            Population genomics of domestic and wild yeasts

            Since the completion of the genome sequence of Saccharomyces cerevisiae in 19961,2, there has been an exponential increase in complete genome sequences accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions3,4, population structure5-8, and sexual versus asexual reproduction9,10. Less well understood at the whole genome level are the evolutionary processes acting within populations and species leading to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to four-fold or more coverage of the genome sequences of over seventy isolates of the baker's yeast, S. cerevisiae, and its closest relative, S. paradoxus. We examine variation in gene content, SNPs, indels, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. Interestingly, S. paradoxus populations are well delineated along geographic boundaries while the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variation.
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              Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems.

              Epistasis, or interactions between genes, has long been recognized as fundamentally important to understanding the structure and function of genetic pathways and the evolutionary dynamics of complex genetic systems. With the advent of high-throughput functional genomics and the emergence of systems approaches to biology, as well as a new-found ability to pursue the genetic basis of evolution down to specific molecular changes, there is a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                April 2011
                April 2011
                28 April 2011
                : 7
                : 4
                : e1002056
                [1]Department of Genetics, Stanford University, Stanford, California, United States of America
                University of Michigan, United States of America
                Author notes

                Conceived and designed the experiments: DJK GS. Performed the experiments: DJK. Analyzed the data: DJK. Contributed reagents/materials/analysis tools: DJK. Wrote the paper: DJK GS.

                Kvitek, Sherlock. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 10 December 2010
                : 7 March 2011
                Page count
                Pages: 11
                Research Article
                Evolutionary Biology
                Evolutionary Processes
                Evolutionary Selection
                Natural Selection
                Genomic Evolution
                Genome Evolution
                Genome Sequencing



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