This year marks the sixth straight year that the reinstated Zuckerkandl Prize has been awarded. This is an award in honor of Founding Editor Emile Zuckerkandl for the top paper published in the Journal of Molecular Evolution to appear in a print issue during the calendar year, as judged by a committee. The award committee consisted of Ugo Bastolla, Kerry Geiler-Samerotte, and Maeva Perez this year. The panel focused in on four finalists and struggled to choose among these excellent papers to decide upon a prize winner. The four finalist papers spanned the gamut of molecular evolution from sex chromosome evolution to enzyme evolution, to methods focused on mutational scans of membrane proteins and to ancestral sequence reconstruction. We are pleased to announce that the 2024 winner is “Stochastic Epigenetic Modification and Evolution of Sex Determination in Vertebrates” by Braciamore et al. (2024). Throughout vertebrate evolution, there have been multiple independent transitions from environmental to genetic sex determination, with many proposed mechanisms for these transitions involving antagonistic selection. Through a modelling approach that does not rely on deterministic selection, this paper proposes a mechanism whereby the stochastic epigenetic silencing of a sex determination gene can influence the dynamics of fixation of silencing mutations within the locus. The authors show that this process maintains an equilibrated sex-ratio and is sufficient to enable the evolution of heteromorphic sex chromosomes from a homomorphic state. This extends conceptually to a general mechanism through which epigenetic modifications can influence genetic evolution. The three runner up papers are “Scaling up Functional Analyses of the G Protein-Coupled Receptor Rhodopsin” by Scott et al. (2024), “Frustration can Limit the Adaptation of Promiscuous Enzymes Through Gene Duplication and Specialisation” by Schmutzer et al. (2024), and “Extant Sequence Reconstruction: The Accuracy of Ancestral Sequence Reconstructions Evaluated by Extant Sequence Cross‑Validation” by Sennett and Theobald (2024). Scott et al. (2024) and Chen et al. (2024) from the same research group developed methods including a fluorescence assay to characterize the effects of mutations on the function of membrane proteins. A clever experimental design that tied membrane protein function to downstream expression of a fluorescent protein enabled the scale up in exploration of sequence space. They applied the method to rhodopsin receptors, belonging to the large family of G-protein coupled receptors, scaling up the exploration of their sequence space and extending some general results on mutational effects already known for globular proteins. Schmutzer et al. (2024) presents a theory of enzyme evolution based on the tradeoffs between different reactions catalyzed by the same promiscuous enzyme, which suggests that frustration that may result from reactions that cannot be simultaneously selected may be an important factor in the evolution of enzyme families, including through gene duplication and sub-functionalization. Their theory predicts the observed bimodal distribution of promiscuous enzymes with peaks of specialist and of generalist enzymes. Sennett and Theobald (2024) provide a first solution to a key limitation of ancestral sequence reconstruction; how to assess the accuracy of the reconstructions? Their approach proposes to cross-validate ancestral sequence reconstruction methods by predicting extant sequences according to an evolutionary model. The paper establishes an important role for model selection in ancestral sequence reconstruction, as different models yield varying performance levels. The Journal of Molecular Evolution is proud to congratulate the authors of all of these works and the winners of the award, which includes a US$250 cash prize to the first author of the winning paper. The journal is proud to have published these papers in 2024 and looks forward to receiving more outstanding submissions in 2025. Branciamore, S., Rodin, A.S. & Riggs, A.D. Stochastic Epigenetic Modification and Evolution of Sex Determination in Vertebrates. J Mol Evol 92, 861–873 (2024). https://doi.org/10.1007/s00239-024-10213-9 Chen, S.K., Liu, J., Van Nynatten, A. et al.Sampling Strategies for Experimentally Mapping Molecular Fitness Landscapes Using High-Throughput Methods. J Mol Evol 92, 402–414 (2024). https://doi.org/10.1007/s00239-024-10179-8 Schmutzer, M., Dasmeh, P. & Wagner, A. Frustration can Limit the Adaptation of Promiscuous Enzymes Through Gene Duplication and Specialisation. J Mol Evol 92, 104–120 (2024). https://doi.org/10.1007/s00239-024-10161-4 Scott, B.M., Chen, S.K., Van Nynatten, A. et al. Scaling up Functional Analyses of the G Protein-Coupled Receptor Rhodopsin. J Mol Evol 92, 61–71 (2024). https://doi.org/10.1007/s00239-024-10154-3 Sennett, M.A., Theobald, D.L. Extant Sequence Reconstruction: The Accuracy of Ancestral Sequence Reconstructions Evaluated by Extant Sequence Cross-Validation. J Mol Evol 92, 181–206 (2024). https://doi.org/10.1007/s00239-024-10162-3 David Liberles David A Liberles (to subscribe/unsubscribe the EvolDir send mail to golding@mcmaster.ca)