The wtf meiotic driver gene family has unexpectedly persisted for over 100 million years
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Evaluation Summary:
This paper's central findings - that wtf genes are old, rapidly evolving, and often meiotic drivers - are important and of broad interest to evolutionary biologists and geneticists. The study's main claims are supported by convincing evidence from comparative genomic data, phylogenetic analyses, and functional experiments. However, support for the verbal model of wtf persistence is currently incomplete.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Meiotic drivers are selfish elements that bias their own transmission into more than half of the viable progeny produced by a driver+/driver− heterozygote. Meiotic drivers are thought to exist for relatively short evolutionary timespans because a driver gene or gene family is often found in a single species or in a group of very closely related species. Additionally, drivers are generally considered doomed to extinction when they spread to fixation or when suppressors arise. In this study, we examine the evolutionary history of the wtf meiotic drivers first discovered in the fission yeast Schizosaccharomyces pombe . We identify homologous genes in three other fission yeast species, S. octosporus , S. osmophilus , and S. cryophilus , which are estimated to have diverged over 100 million years ago from the S. pombe lineage. Synteny evidence supports that wtf genes were present in the common ancestor of these four species. Moreover, the ancestral genes were likely drivers as wtf genes in S. octosporus cause meiotic drive. Our findings indicate that meiotic drive systems can be maintained for long evolutionary timespans.
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Author Response
Reviewer #2 (Public Review):
Members of the WTF gene family can result in distorted meiosis (away from predicted Mendelian segregation) due to a "poison-antidote" like system. The authors find that members of the WTF gene family are found in numerous species long diverged species of fission yeast, that these genes show signatures of ongoing adaptive evolution, and that some of the novel wtf genes discovered here can also distort meiosis. Additionally, the authors show that gene conversion is quite common, and suggest that processes like gene conversion, expansion, and contraction underlie the long-term maintenance of this system in the face of potential loss of function by fixation and/or suppression. While interesting, the support for this vague model is unclear, and the novelty of this system compared to other drive …
Author Response
Reviewer #2 (Public Review):
Members of the WTF gene family can result in distorted meiosis (away from predicted Mendelian segregation) due to a "poison-antidote" like system. The authors find that members of the WTF gene family are found in numerous species long diverged species of fission yeast, that these genes show signatures of ongoing adaptive evolution, and that some of the novel wtf genes discovered here can also distort meiosis. Additionally, the authors show that gene conversion is quite common, and suggest that processes like gene conversion, expansion, and contraction underlie the long-term maintenance of this system in the face of potential loss of function by fixation and/or suppression. While interesting, the support for this vague model is unclear, and the novelty of this system compared to other drive systems was not sufficiently justified.
The presented work is interesting, and I trust the bioinformatic and functional work (although both are a bit beyond my specialties). I am quite concerned, however, with the introduction, discussion, and take-home conclusions, which at times go beyond the data presented.
Active meiotic driver genes throughout their history in fission yeasts?
For example, the authors claim that "Our results suggest that the gene family has contained active meiotic driver genes throughout their history in fission yeasts." Evidence for such a claim would be interesting, but very difficult to obtain and not presented in this manuscript. Rather the authors show that wtf genes are present, evolving rapidly, and can distort meiosis in numerous species. What has happened in the intervening 100 million years is unclear, but I would be surprised if it included an unbroken streak of active meiotic drive. It is well known that drivers spread rapidly, and this group's previous modeling of the system showed that a wtf driver would spread rapidly. I also don't know of evidence for a strong enough cost to wtf/homozygotes in this system to sustain long-term balancing selection (which is what is needed for long-term driving). Otherwise, it seems that most of a driver's history would be fixed (or at least locally fixed), and that continuous drive activity is unlikely (unless the authors mean it "could drive").
We agree that we have not demonstrated perpetual meiotic drive over the last 100 million years. Instead, we argue the family has retained the capacity to drive for that amount of time. We have modified the text to be more precise.
We also disagree that long-term balancing selection is needed for long-term drive. Our work suggests an alternative option where long-term drive is not tied to a single locus, but is a property shared across the gene family. Active drive likely comes and goes at individual loci. We propose the evolution of wtf drivers is better described as a cycle of novel drivers being born and spreading (perhaps to local fixation), rather than one driver that is maintained at a given locus for a long time.
The "model"
The authors present a brief verbal "model" of the rejuvenation of wtf drivers by expansion/contraction/non-allelic gene conversion etc. While these processes all appear to occur in this system and likely play an important role in its evolution, it is hard to make much of this model. For example, I have trouble understanding the time scale at which these processes operate (e.g. do we expect fixation - which the authors have previously shown to occur quite rapidly at a single locus - to generally occur before an opportunity for one of these processes to occur and/or before suppression evolves? My sense is "probably"). If the scale of fixation is much more rapid than the other processes this system seems to fit in well with the other case discussed in the intro. Rather, it appears that the true excitement of the system, is the fast rate at which wtf emerges (likely facilitated by expansion/contraction/non-allelic gene conversion, etc.) and perhaps their slow breakdown after fixation (unexplained here).
We have modified our discussion to better highlight the limitations in our understanding and clarify local fixation of a driver from global fixation in the species. We also clarify that mutations can rejuvenate fixed, suppressed, or psuedogenized wtf drivers.
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Evaluation Summary:
This paper's central findings - that wtf genes are old, rapidly evolving, and often meiotic drivers - are important and of broad interest to evolutionary biologists and geneticists. The study's main claims are supported by convincing evidence from comparative genomic data, phylogenetic analyses, and functional experiments. However, support for the verbal model of wtf persistence is currently incomplete.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This paper examines wtf genes in relatives of S. pombe to investigate the evolutionary history of the gene family. Classic theory suggests that distorters like wtf should be fairly transient - the fitness cost due to spore killing should select for suppressors and even if a selfish allele manages to fix, its advantage disappears (under either scenario, the drive function stops, and the allele degrades over time through random mutation). Despite these predictions, the authors provide convincing synteny data to argue that wtf genes were likely present more than 100 million years ago in the common ancestor of S. pombe and its relatives. Using phylogenetic approaches, the authors also show that since this ancient origin, wtf genes have evolved dynamically by gene duplication and gene conversion within descendant …
Reviewer #1 (Public Review):
This paper examines wtf genes in relatives of S. pombe to investigate the evolutionary history of the gene family. Classic theory suggests that distorters like wtf should be fairly transient - the fitness cost due to spore killing should select for suppressors and even if a selfish allele manages to fix, its advantage disappears (under either scenario, the drive function stops, and the allele degrades over time through random mutation). Despite these predictions, the authors provide convincing synteny data to argue that wtf genes were likely present more than 100 million years ago in the common ancestor of S. pombe and its relatives. Using phylogenetic approaches, the authors also show that since this ancient origin, wtf genes have evolved dynamically by gene duplication and gene conversion within descendant lineages. Additionally, by studying the genomic regions surrounding these genes, they discover an association in S. octosporus and S. osmophilus with 5S rDNA, which, like associated LTRs in S. pombe, might facilitate this duplication history. Finally, using transformation experiments, the authors demonstrate that these newly identified wtf genes have the very same poison and antidote functions originally described in S. pombe.
This work is a significant advance in our understanding of the evolution of wtf genes, moving beyond S. pombe to several other distantly related fission yeast species. More generally, it suggests a plausible mechanism for the continued existence of wtf genes across long evolutionary time scales.
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Reviewer #2 (Public Review):
Members of the WTF gene family can result in distorted meiosis (away from predicted Mendelian segregation) due to a "poison-antidote" like system. The authors find that members of the WTF gene family are found in numerous species long diverged species of fission yeast, that these genes show signatures of ongoing adaptive evolution, and that some of the novel wtf genes discovered here can also distort meiosis. Additionally, the authors show that gene conversion is quite common, and suggest that processes like gene conversion, expansion, and contraction underlie the long-term maintenance of this system in the face of potential loss of function by fixation and/or suppression. While interesting, the support for this vague model is unclear, and the novelty of this system compared to other drive systems was not …
Reviewer #2 (Public Review):
Members of the WTF gene family can result in distorted meiosis (away from predicted Mendelian segregation) due to a "poison-antidote" like system. The authors find that members of the WTF gene family are found in numerous species long diverged species of fission yeast, that these genes show signatures of ongoing adaptive evolution, and that some of the novel wtf genes discovered here can also distort meiosis. Additionally, the authors show that gene conversion is quite common, and suggest that processes like gene conversion, expansion, and contraction underlie the long-term maintenance of this system in the face of potential loss of function by fixation and/or suppression. While interesting, the support for this vague model is unclear, and the novelty of this system compared to other drive systems was not sufficiently justified.
The presented work is interesting, and I trust the bioinformatic and functional work (although both are a bit beyond my specialties). I am quite concerned, however, with the introduction, discussion, and take-home conclusions, which at times go beyond the data presented.
Active meiotic driver genes throughout their history in fission yeasts?
For example, the authors claim that "Our results suggest that the gene family has contained active meiotic driver genes throughout their history in fission yeasts." Evidence for such a claim would be interesting, but very difficult to obtain and not presented in this manuscript. Rather the authors show that wtf genes are present, evolving rapidly, and can distort meiosis in numerous species. What has happened in the intervening 100 million years is unclear, but I would be surprised if it included an unbroken streak of active meiotic drive. It is well known that drivers spread rapidly, and this group's previous modeling of the system showed that a wtf driver would spread rapidly. I also don't know of evidence for a strong enough cost to wtf/homozygotes in this system to sustain long-term balancing selection (which is what is needed for long-term driving). Otherwise, it seems that most of a driver's history would be fixed (or at least locally fixed), and that continuous drive activity is unlikely (unless the authors mean it "could drive").The "model"
The authors present a brief verbal "model" of the rejuvenation of wtf drivers by expansion/contraction/non-allelic gene conversion etc. While these processes all appear to occur in this system and likely play an important role in its evolution, it is hard to make much of this model. For example, I have trouble understanding the time scale at which these processes operate (e.g. do we expect fixation - which the authors have previously shown to occur quite rapidly at a single locus - to generally occur before an opportunity for one of these processes to occur and/or before suppression evolves? My sense is "probably"). If the scale of fixation is much more rapid than the other processes this system seems to fit in well with the other case discussed in the intro. Rather, it appears that the true excitement of the system, is the fast rate at which wtf emerges (likely facilitated by expansion/contraction/non-allelic gene conversion, etc.) and perhaps their slow breakdown after fixation (unexplained here). -
Reviewer #3 (Public Review):
The authors combine comparative genomics and functional approaches to show that wtf are old genes that may drive other Schizosaccharomyces species. Their varied approaches convincingly demonstrate that wtfs exist in S. octosporus, S. osmophilus, and S. cryophilis. While the wtfs are highly diverged in sequence, some of their structural features are conserved across species. One interesting finding is that while in S. pombe wtfs are associated with LTRs, in the other species they associate with a different repetitive DNA locus, the 5S rRDNA. This is interesting, as it suggests that wtfs may have spread through non-allelic gene conversion events within lineages. They have evidence that some of the wtfs in S. octosporus are poison-antidote systems with several parallels to the wtfs in S. pombe.
Overall, this …
Reviewer #3 (Public Review):
The authors combine comparative genomics and functional approaches to show that wtf are old genes that may drive other Schizosaccharomyces species. Their varied approaches convincingly demonstrate that wtfs exist in S. octosporus, S. osmophilus, and S. cryophilis. While the wtfs are highly diverged in sequence, some of their structural features are conserved across species. One interesting finding is that while in S. pombe wtfs are associated with LTRs, in the other species they associate with a different repetitive DNA locus, the 5S rRDNA. This is interesting, as it suggests that wtfs may have spread through non-allelic gene conversion events within lineages. They have evidence that some of the wtfs in S. octosporus are poison-antidote systems with several parallels to the wtfs in S. pombe.
Overall, this paper makes an exciting contribution to the poison-antidote killers in yeasts and the drive field more generally. The discovery that wtfs are old and are likely to be spore killers in other species, and likely their common ancestor, is interesting as most drive systems are short-lived. Their proposed mechanism for the spread of wtf-like genes through non-allelic recombination shows parallels to repetitive sequences in other taxa, including some other independent drive systems. The tests for a drive phenotype in S. octoporus are especially interesting.
The author's investigation is thorough and the results are sound, with the combination of approaches being the main strength of the study. The functional assays in S. cerevisiae complement the comparative genomic work and suggest that at least a subset of the non-pombe wtfs are poisons/antidotes. It is not clear that examining patterns of protein localization helps the authors understand if there is functional conservation between wtfs in S. pombe and non-pombe species, however. The interpretation of these analyses is unclear in the current manuscript. The paper is generally well organized and reasoned; however, simplifying the discussion to just communicate the main points would strengthen the paper.
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