The genetic architecture of the load linked to dominant and recessive self-incompatibility alleles in Arabidopsis halleri and A. lyrata
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eLife assessment
This study presents valuable empirical work and simulations that are relevant for the evolution of genetic load linked to self-incompatibility alleles in Arabidopsis. The evidence supporting the findings is solid but could be improved by a more detailed quantitative assessment of the impacts of deleterious alleles and their dominance. The simulation results are somewhat incomplete, as details of the approach and code do not appear to be available, but this could be easily remedied. The work will be of relevance to geneticists interested in the evolution of allelic diversity in similar systems.
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Abstract
The long-term balancing selection acting on mating-types or sex determining genes is expected to lead to the accumulation of deleterious mutations in the tightly linked chromosomal segments that are locally “sheltered” from purifying selection. However, the factors determining the extent of this accumulation are poorly understood. Here, we took advantage of variations in the intensity of balancing selection along a dominance hierarchy formed by alleles at the sporophytic self-incompatibility system of the Brassicaceae to compare the pace at which linked deleterious mutations accumulate among them. We first experimentally measured the phenotypic manifestation of the linked load at three different levels of the dominance hierarchy. We then sequenced and phased polymorphisms in the chromosomal regions linked to 126 distinct copies of S -alleles in two populations of Arabidopsis halleri and three populations of A. lyrata . We find that linkage to the S -locus locally distorts phylogenies over about 10-30kb along the chromosome. The more intense balancing selection on dominant S -alleles results in greater fixation of linked deleterious mutations, while recessive S -alleles accumulate more linked deleterious mutations that are segregating. Hence, the structure rather than the overall magnitude of the linked genetic load differs between dominant and recessive S -alleles. Our results have consequences for the long-term evolution of new S -alleles, the evolution of dominance modifiers between them, and raise the question of why the non-recombining regions of some sex and mating type chromosomes expand over evolutionary times while others, such as that the S -locus of the Brassicaceae, remain restricted to small chromosomal regions.
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eLife assessment
This study presents valuable empirical work and simulations that are relevant for the evolution of genetic load linked to self-incompatibility alleles in Arabidopsis. The evidence supporting the findings is solid but could be improved by a more detailed quantitative assessment of the impacts of deleterious alleles and their dominance. The simulation results are somewhat incomplete, as details of the approach and code do not appear to be available, but this could be easily remedied. The work will be of relevance to geneticists interested in the evolution of allelic diversity in similar systems.
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Reviewer #1 (Public Review):
Summary:
The paper combines phenotypic and genomic analyses of the "sheltered load" (i.e. the accumulation of deleterious mutations linked to S-Loci that are hidden from selection in the homozygous state) in Arabidopsis. The authors compare results to previous theoretical predictions concerning the extent of the load in dominant vs recessive S-alleles, and further develop exciting theory to reconcile differences between previous theory and observed results.
Strengths:
This is a very nice combination of theory and data to address a classical question in the field.
Weaknesses:
The "genetic load" is a poorly defined concept in general, and its quantification via the number of putatively deleterious mutations is quite difficult. Furthermore counting up the number of derived mutations at fully constrained …
Reviewer #1 (Public Review):
Summary:
The paper combines phenotypic and genomic analyses of the "sheltered load" (i.e. the accumulation of deleterious mutations linked to S-Loci that are hidden from selection in the homozygous state) in Arabidopsis. The authors compare results to previous theoretical predictions concerning the extent of the load in dominant vs recessive S-alleles, and further develop exciting theory to reconcile differences between previous theory and observed results.
Strengths:
This is a very nice combination of theory and data to address a classical question in the field.
Weaknesses:
The "genetic load" is a poorly defined concept in general, and its quantification via the number of putatively deleterious mutations is quite difficult. Furthermore counting up the number of derived mutations at fully constrained nucleotides may not be a great estimate of the load, and certainly does not allow for evaluation of recessivity -- a concept critical to ideas concerning the sheltered load. Alternative approaches - including estimating the severity of mutations - could be helpful as well. This imperfection in available approaches to test theory must be acknowledged more strongly by the authors.
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Reviewer #2 (Public Review):
Summary:
This study looks into the complex dominance patterns of S-allele incompatibilities in Brassicaceae, through which it attempts to learn more about the sheltering of deleterious load. I found several weak points in the analyses that diminished my excitement about the results. In particular, the way in which deleterious mutations were classified lacked the ability to distinguish the severity of the mutations and thus their expected associated dominance. Furthermore, the simulation approach could have provided this exact sort of insight but was not designed to do so, making this comparison to the empirical data also less than exciting for me.
Major and minor comments:
I think the introduction (or somewhere before we dive into it in the results) of the dominance hierarchy for the S-alleles needs a more …
Reviewer #2 (Public Review):
Summary:
This study looks into the complex dominance patterns of S-allele incompatibilities in Brassicaceae, through which it attempts to learn more about the sheltering of deleterious load. I found several weak points in the analyses that diminished my excitement about the results. In particular, the way in which deleterious mutations were classified lacked the ability to distinguish the severity of the mutations and thus their expected associated dominance. Furthermore, the simulation approach could have provided this exact sort of insight but was not designed to do so, making this comparison to the empirical data also less than exciting for me.
Major and minor comments:
I think the introduction (or somewhere before we dive into it in the results) of the dominance hierarchy for the S-alleles needs a more in-depth explanation. Not being familiar with this beforehand really made this paper inaccessible to me until I then went to find out more before continuing. I would expect this paper to be broad enough that self-contained information makes it accessible to all readers. For example, lines 110-115 could be in the Introduction.
Along with my above comment, perhaps it is not my place to comment, but I find the paper not of a broad enough scope to be of interest to a broad readership. This S-allele dominance system is more than simple balancing selection, it is a very complex and specific form of dominance between several haplotypes, and the mechanism of dominance does not seem to be genetic. I am not sure that it thus extrapolates to broad comments on general dominance and balancing selection, e.g. it would not be the same as considering inversions and this form of balancing selection where we also expect recessive deleterious mutations to accumulate.
It would have been particularly interesting, or a nice addition, to see deleterious mutations classed by something like SNPeff or GERP where you can have different classes of moderate to severe deleterious variants, which we would expect also to be more recessive the more deleterious they are. In line with my next comment on the simulations, I think relative differences between mutations expected to be more or less dominant may be even more insightful into the process of sheltering which may or may not be going on here.
In the simulations, h=0 and s=0.01 (as in Figure 5) for all deleterious mutations seems overly simplistic, and at the convenient end for realistic dominance. I think besides recessive lethals which we expect to be close to h=0 would have a much larger selection coefficient, and other deleterious mutations would only be partially recessive at such an s value. I expect this would change some of the simulation results seen, though to what degree I am not certain. It would be nice to at least check the same exact results for h=0.3 or 0.2 (or additionally also for recessive lethals, e.g. h=0 and s=-0.9). I would also disagree with the statement in line 677, many studies have shown, particularly those on balancing selection, that partially recessive deleterious mutations are not eliminated by natural selection and do play a role in population genetic dynamics. I am also not surprised that extinction was found for higher s values when the mutation rate for such mutations was very high and the distribution of s values was constant. An influx of such highly deleterious mutations is unlikely to ever let a population survive, yet that does NOT mean that in nature, the rare influx of such mutations does lead to them being sheltered. I find overall that the simulation results contribute very little, to none, to this paper, as without something more realistic, like a simultaneous distribution of s and h values, you cannot say which, if any class of these mutations are the ones expected to accumulate because of S-allele dominance. Rather they only show the disappointing or less exciting result that fully recessive, weakly deleterious mutations (which I again think do not even exist in nature as I said above) have minor, to no effect across the classes of S-allele dominance. They provide no insight into whether any type of recessive deleterious mutation can accumulate under the S-allele dominance hierarchy, and that is the interesting question at hand. I would either remove these simulations or redo them in another approach. The authors never mention what simulation approach was used, so I can only assume this is custom, in-house code. Yet I do not find that code provided on the github page. I do not know if the lack of a distribution for h and s values is then a choice or a programming limitation, but I see it as one that should be overcome if these simulations are meant to be meaningful to the results of the study.
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