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1. Global epistasis emerges from a generic model of a complex trait

   https://doi.org/10.7554/eLife.64740  

   Reddy, Gautam ; Desai, Michael M ( March 2021 , eLife)

   null (Ed.)

   Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread ‘microscopic’ epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the origin of this ‘global’ epistasis remains unknown. Here, we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by reanalyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity. 

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2. It Takes Two to Make a Thing Go Right: Epistasis, Two-Component Response Systems, and Bacterial Adaptation

   https://doi.org/10.3390/microorganisms12102000  

   Sanders, Brittany R ; Thomas, Lauren S ; Lewis, Naya M ; Ferguson, Zaria A ; Graves, Joseph L ; Thomas, Misty D ( October 2024 , Microorganisms)

   Shimada, Tomohiro (Ed.)

   Understanding the interplay between genotype and fitness is a core question in evolutionary biology. Here, we address this challenge in the context of microbial adaptation to environmental stressors. This study explores the role of epistasis in bacterial adaptation by examining genetic and phenotypic changes in silver-adapted Escherichia coli populations, focusing on the role of beneficial mutations in two-component response systems (TCRS). To do this, we measured 24-hour growth assays and conducted whole-genome DNA and RNA sequencing on E. coli mutants that confer resistance to ionic silver. We showed recently that the R15L cusS mutation is central to silver resistance, primarily through upregulation of the cus efflux system. However, here we show that this mutation’s effectiveness is significantly enhanced by epistatic interactions with additional mutations in regulatory genes such as ompR, rho, and fur. These interactions reconfigure global stress response networks, resulting in robust and varied resistance strategies across different populations. This study underscores the critical role of epistasis in bacterial adaptation, illustrating how interactions between multiple mutations and how genetic backgrounds shape the resistance phenotypes of E. coli populations. This work also allowed for refinement of our model describing the role TCRS genes play in bacterial adaptation by now emphasizing that adaptation to environmental stressors is a complex, context-dependent process, driven by the dynamic interplay between genetic and environmental factors. These findings have broader implications for understanding microbial evolution and developing strategies to combat antimicrobial resistance.

    

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3. The effect of weak clonal interference on average fitness trajectories in the presence of macroscopic epistasis

   https://doi.org/10.1093/genetics/iyac028  

   Guo, Yipei ; Amir, Ariel ; Jain, ed., K. ( February 2022 , Genetics)

   Adaptation dynamics on fitness landscapes is often studied theoretically in the strong-selection, weak-mutation regime. However, in a large population, multiple beneficial mutants can emerge before any of them fixes in the population. Competition between mutants is known as clonal interference, and while it is known to slow down the rate of adaptation (when compared to the strong-selection, weak-mutation model with the same parameters), how it affects the shape of long-term fitness trajectories in the presence of epistasis is an open question. Here, by considering how changes in fixation probabilities arising from weak clonal interference affect the dynamics of adaptation on fitness-parameterized landscapes, we find that the change in the shape of fitness trajectory arises only through changes in the supply of beneficial mutations (or equivalently, the beneficial mutation rate). Furthermore, a depletion of beneficial mutations as a population climbs up the fitness landscape can speed up the rescaled fitness trajectory (where adaptation speed is measured relative to its value at the start of the experiment), while an enhancement of the beneficial mutation rate does the opposite of slowing it down. Our findings suggest that by carrying out evolution experiments in both regimes (with and without clonal interference), one could potentially distinguish the different sources of macroscopic epistasis (fitness effect of mutations vs change in fraction of beneficial mutations).

    

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4. Higher-fitness yeast genotypes are less robust to deleterious mutations

   https://doi.org/10.1126/science.aay4199  

   Johnson, Milo S. ; Martsul, Alena ; Kryazhimskiy, Sergey ; Desai, Michael M. ( October 2019 , Science)

   Natural selection drives populations toward higher fitness, but second-order selection for adaptability and mutational robustness can also influence evolution. In many microbial systems, diminishing-returns epistasis contributes to a tendency for more-fit genotypes to be less adaptable, but no analogous patterns for robustness are known. To understand how robustness varies across genotypes, we measure the fitness effects of hundreds of individual insertion mutations in a panel of yeast strains. We find that more-fit strains are less robust: They have distributions of fitness effects with lower mean and higher variance. These differences arise because many mutations have more strongly deleterious effects in faster-growing strains. This negative correlation between fitness and robustness implies that second-order selection for robustness will tend to conflict with first-order selection for fitness.

    

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5. Patterns of pan‐genome occupancy and gene coexpression under water‐deficit in Brachypodium distachyon

   https://doi.org/10.1111/mec.16661  

   Sancho, Rubén ; Catalán, Pilar ; Contreras‐Moreira, Bruno ; Juenger, Thomas E. ; Des Marais, David L. ( August 2022 , Molecular Ecology)

   Natural populations are characterized by abundant genetic diversity driven by a range of different types of mutation. The tractability of sequencing complete genomes has allowed new insights into the variable composition of genomes, summarized as a species pan‐genome. These analyses demonstrate that many genes are absent from the first reference genomes, whose analysis dominated the initial years of the genomic era. Our field now turns towards understanding the functional consequence of these highly variable genomes. Here, we analysed weighted gene coexpression networks from leaf transcriptome data for drought response in the purple false bromeBrachypodium distachyonand the differential expression of genes putatively involved in adaptation to this stressor. We specifically asked whether genes with variable “occupancy” in the pan‐genome – genes which are either present in all studied genotypes or missing in some genotypes – show different distributions among coexpression modules. Coexpression analysis united genes expressed in drought‐stressed plants into nine modules covering 72 hub genes (87 hub isoforms), and genes expressed under controlled water conditions into 13 modules, covering 190 hub genes (251 hub isoforms). We find that low occupancy pan‐genes are under‐represented among several modules, while other modules are over‐enriched for low‐occupancy pan‐genes. We also provide new insight into the regulation of drought response inB. distachyon, specifically identifying one module with an apparent role in primary metabolism that is strongly responsive to drought. Our work shows the power of integrating pan‐genomic analysis with transcriptomic data using factorial experiments to understand the functional genomics of environmental response.

    

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