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1. Epistasis Storyboarded

   https://doi.org/10.1525/abt.2022.84.9.562  

   Babaian, Caryn; Kumar, Sudhir (November 2022, The American Biology Teacher)

   Through the artistic planning tool known to comic book artists and animators as storyboarding, students will embark on comic book–style adventures to plan, describe, and visualize the complex life of genes through the non-Mendelian concept of epistasis. Using storyboard templates, conceptual layouts, sketch booking, and cut-out genetic elements, students will construct their interpretation of the gene-gene interactions of epistasis. The incomplete story of the epistasis of human eye color will serve as the theme for this storyboard, which will also become its own assessment tool, inviting educators into a realm of a true STEAM experience. 

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2. Compensatory mutations and epistasis for protein function

   https://doi.org/10.1016/j.sbi.2017.10.009  

   Storz, Jay F (June 2018, Current Opinion in Structural Biology)
3. Detecting genetic epistasis by differential departure from independence

   https://doi.org/10.1007/s00438-022-01893-3  

   Sharma, Ruby; Sadeghian Tehrani, Zeinab; Kumar, Sajal; Song, Mingzhou (May 2022, Molecular Genetics and Genomics)

   Countering prior beliefs that epistasis is rare, genomics advancements suggest the other way. Current practice often filters out genomic loci with low variant counts before detecting epistasis. We argue that this practice is far from optimal because it can throw away strong epistatic patterns. Instead, we present the compensated Sharma–Song test to infer genetic epistasis in genome-wide association studies by differential departure from independence. The test does not require a minimum number of replicates for each variant. We also introduce algorithms to simulate epistatic patterns that differentially depart from independence. Using two simulators, the test performed comparably to the original Sharma–Song test when variant frequencies at a locus are marginally uniform; encouragingly, it has a marked advantage over alternatives when variant frequencies are marginally nonuniform. The test further revealed uniquely clean epistatic variants associated with chicken abdominal fat content that are not prioritized by other methods. Genes involved in most numbers of inferred epistasis between single nucleotide polymorphisms (SNPs) belong to pathways known for obesity regulation; many top SNPs are located on chromosome 20 and in intergenic regions. Measuring differential departure from independence, the compensated Sharma–Song test offers a practical choice for studying epistasis robust to nonuniform genetic variant frequencies. 

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4. Ensemble epistasis: thermodynamic origins of nonadditivity between mutations

   https://doi.org/10.1093/genetics/iyab105  

   Morrison, Anneliese J; Wonderlick, Daria R; Harms, Michael J (July 2021, Genetics)

   Masel, J (Ed.)

   Abstract Epistasis—when mutations combine nonadditively—is a profoundly important aspect of biology. It is often difficult to understand its mechanistic origins. Here, we show that epistasis can arise from the thermodynamic ensemble, or the set of interchanging conformations a protein adopts. Ensemble epistasis occurs because mutations can have different effects on different conformations of the same protein, leading to nonadditive effects on its average, observable properties. Using a simple analytical model, we found that ensemble epistasis arises when two conditions are met: (1) a protein populates at least three conformations and (2) mutations have differential effects on at least two conformations. To explore the relative magnitude of ensemble epistasis, we performed a virtual deep-mutational scan of the allosteric Ca2+ signaling protein S100A4. We found that 47% of mutation pairs exhibited ensemble epistasis with a magnitude on the order of thermal fluctuations. We observed many forms of epistasis: magnitude, sign, and reciprocal sign epistasis. The same mutation pair could even exhibit different forms of epistasis under different environmental conditions. The ubiquity of thermodynamic ensembles in biology and the pervasiveness of ensemble epistasis in our dataset suggests that it may be a common mechanism of epistasis in proteins and other macromolecules. 

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5. Nested epistasis enhancer networks for robust genome regulation

   https://doi.org/10.1126/science.abk3512  

   Lin, Xueqiu; Liu, Yanxia; Liu, Shuai; Zhu, Xiang; Wu, Lingling; Zhu, Yanyu; Zhao, Dehua; Xu, Xiaoshu; Chemparathy, Augustine; Wang, Haifeng; et al (September 2022, Science)

   Machine learning and multiplexed screening elucidates enhancer networks regulating gene expression in health and disease states. 

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