Epistasis and the evolution of selfing
Epistasis, inbreeding depression and the evolution of self-fertilization
The evolution of selfing results from a balance between multiple evolutionary forces. Selfing provides an "automatic advantage" due to the higher efficiency of selfers to transmit their genes via selfed and outcrossed offspring. Selfed offspring, however, may suffer from inbreeding depression. In principle the ultimate evolutionary outcome is easy to predict from the relative magnitude of these two evolutionary forces [1,2]. Yet, several studies explicitly taking into account the genetic architecture of inbreeding depression noted that these predictions are often too restrictive because selfing can evolve in a broader range of conditions [3,4].
The present work by Abu Awad and Roze  provides an analytic understanding of these results. Abu Awad and Roze analyse the evolution of selfing in a multilocus model where some loci are coding for selfing while others are under direct selection. The evolution of selfing depends on (i) the classical benefit of selfing (automatic advantage), (ii) the cost of selfing due to inbreeding depression, (iii) the association between the loci coding for selfing and the loci under direct selection (likely to be positive because selfing is expected to be found in better purged genetic backgrounds) and (iv) the association between the loci coding for selfing and the linkage between loci under selection (this final term depends on the magnitude and the type of epistasis). Because these last two terms depend on genetic associations they are expected to play in when selection is strong and recombination is small. These last two terms explain why selfing is evolving under a range of conditions which is broader than predicted by earlier theoretical models. The match between the approximations for the different terms acting on the evolution of selfing and individual based simulations (for different fitness landscapes) is very convincing. In particular, this analysis also yields new results on the effect of different types of epistasis on inbreeding depression.
Another remarkable and important feature of this work is its readability. The analysis of multilocus models rely on several steps and approximations that often result in overwhelmingly complex papers. Abu Awad and Roze’s paper  is dense but it provides a very clear and comprehensive presentation of the interplay between multiple evolutionary forces acting on the evolution of selfing.
 Holsinger, K. E., Feldman, M. W., and Christiansen, F. B. (1984). The evolution of self-fertilization in plants: a population genetic model. The American Naturalist, 124(3), 446-453. doi: 10.1086/284287
 Lande, R., and Schemske, D. W. (1985). The evolution of self‐fertilization and inbreeding depression in plants. I. Genetic models. Evolution, 39(1), 24-40. doi: 10.1111/j.1558-5646.1985.tb04077.x
 Charlesworth, D., Morgan, M. T., and Charlesworth, B. (1990). Inbreeding depression, genetic load, and the evolution of outcrossing rates in a multilocus system with no linkage. Evolution, 44(6), 1469-1489. doi: 10.1111/j.1558-5646.1990.tb03839.x
 Uyenoyama, M. K., and Waller, D. M. (1991). Coevolution of self-fertilization and inbreeding depression I. Mutation-selection balance at one and two loci. Theoretical population biology, 40(1), 14-46. doi: 10.1016/0040-5809(91)90045-H
 Abu Awad, D. and Roze, D. (2020). Epistasis, inbreeding depression and the evolution of self-fertilization. bioRxiv, 809814, ver. 4 peer-reviewed and recommended by PCI Evol Biol. doi: 10.1101/809814
Sylvain Gandon (2020) Epistasis and the evolution of selfing. Peer Community in Evolutionary Biology, 100093. 10.24072/pci.evolbiol.100093
Revision round #12019-12-11
Decision round #1
This is a very impressive piece of work on a technically difficult but biologically very relevant question. The model clarifies the role different components of epistasis on inbreeding depression and on the evolution of selfing. The introduction replaces this model in among previous studies that have addressed this subject.
I am very much willing to recommend this preprint but it would be great to use the comments from both reviewers to improve the manuscript. The paper is beautifully written but very dense. There are two main parts (inbreeding depression and evolution of selfing) but many subcases. I don't know if it is feasible but it would be great to provide a way (an additional figure?) to summarize some aspects of your work to the less theoretically-oriented readers. You may want to try provide a schematic description of some features of your model. Visualizing the different components of epistasis would be useful given their importance in your model. Also it would be great to see what it means for the fitness landscape to assume that epistasis is fixed or distributed. You may want to introduce sooner in the text the deleterious mutation rate (not explicitly mentioned before line 276).