Dosage compensation by upregulation of maternal X alleles in both males and females in young plant sex chromosomes
Genomic imprinting mediates dosage compensation in a young plant XY system
Sex chromosomes evolve as recombination is suppressed between the X and Y chromosomes. The loss of recombination on the sex-limited chromosome (the Y in mammals) leads to degeneration of both gene expression and gene content for many genes . Loss of gene expression or content from the Y chromosome leads to differences in gene dose between males and females for X-linked genes. Because expression levels are often correlated with gene dose , these hemizygous genes have a lower expression levels in the heterogametic sex. This in turn disrupts the stoichiometric balance among genes in protein complexes that have components on both the sex chromosomes and autosomes , which could have serious deleterious consequences for the heterogametic sex.
To overcome these deleterious effects of degeneration, the expression levels of dosage sensitive X-linked genes, and in some organisms, entire X chromosomes, are compensated, the expression of the single copy of in the heterogametic sex being increased. Dosage compensation for such genes has evolved in several species, restoring similar expression levels as in the ancestral state in males and/or equal gene expression in males and females [4-8]. The mechanisms for dosage compensation are variable among species and their evolutionary paths are not fully understood, as the few model sex chromosomes studied so far have old, and highly degenerate sex chromosomes [4-7].
Muyle et al.  studied the young sex chromosomes of the plant Silene latifolia, which has young sex chromosomes (4 MY) and highly variable dosage compensation [10, 11]. The authors used both an outgroup species without sex chromosomes for obtaining a proxy for ancestral expression levels before Y degeneration, and implemented methods to identify sex-linked genes and disentangle paternal versus maternal allele expression . Using these elements, Muyle et al.  reveal upregulation of maternal X alleles in both males and females in the young S. latifolia sex chromosomes , possibly by genomic imprinting. The upregulation in both sexes of the maternal X alleles likely yields non-optimal gene expression in females, which is strikingly consistent with the theoretical first step of dosage compensation as postulated by Ohno , which predicts restoration of ancestral expression in males, over-expression in females, and unequal expression in the two sexes. These findings provide surprising insight into the earliest stages of dosage compensation, one of the most intriguing aspects of evolutionary biology.
 Bachtrog D. 2013. Y chromosome evolution: emerging insights into processes of Y-chromosome degeneration? Nature Reviews Genetics 14: 113–124. doi: 10.1038/nrg3366
 Malone JH, Cho D-Y, Mattiuzzo NR, Artieri CG, Jiang L, Dale RK, Smith HE, McDaniel J, Munro S, Salit M, Andrews J, Przytycka TM and Oliver B. 2012. Mediation of Drosophila autosomal dosage effects and compensation by network interactions. Genome Biology 13: R28. doi: 10.1186/gb-2012-13-4-r28
 Pessia E, Makino T, Bailly-Bechet M, McLysaght A and Marais GAB. 2012. Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proceedings of the National Academy of Sciences of the United States of America. 109: 5346–5351. doi: 10.1073/pnas.1116763109.
 Graves JAM. 2016. Evolution of vertebrate sex chromosomes and dosage compensation. Nature Reviews Genetics 17: 33–46. doi: 10.1038/nrg.2015.2
 Mank JE. 2013. Sex chromosome dosage compensation: definitely not for everyone. Trends in Genetics 12: 677–683. doi: 10.1016/j.tig.2013.07.005
 Pessia E and Engelstädter J. 2014. The evolution of X chromosome inactivation in mammals: the demise of Ohno’s hypothesis? Cellular and Molecular Life Sciences 71: 1383–1394. doi: 10.1007/s00018-013-1499-6
 Muyle A, Shearn R and Marais GAB. 2017. The evolution of sex chromosomes and dosage compensation in plants. Genome Biology and Evolution 9: 627–645. doi: 10.1093/gbe/evw282
 Ohno S. 1967. Sex chromosomes and sex linked genes. Springer, Berlin Heidelberg New York.
 Muyle A, Zemp N, Fruchard C, Cegan R, Vrana J, Deschamps C, Tavares R, Picard F, Hobza R, Widmer A and Marais GAB. 2018. Genomic imprinting mediates dosage compensation in a young plant XY system. bioRxiv 118695, ver. 6 peer-reviewed by Peer Community In Evolutionary Biology. doi: 10.1101/179044
 Papadopulos AST, Chester M, Ridout K and Filatov DA. 2015. Rapid Y degeneration and dosage compensation in plant sex chromosomes. Proceedings of the National Academy of Sciences of the United States of America 112: 13021–13026. doi: 10.1073/pnas.1508454112
 Bergero R, Qiu S and Charlesworth D. 2015. Gene loss from a plant sex chromosome system. Current Biology 25: 1234–1240. doi: 10.1016/j.cub.2015.03.015
 Muyle A, Kafer J, Zemp N, Mousset S, Picard F and Marais GAB. 2016. SEX-DETector: a probabilistic approach to study sex chromosomes in non-model organisms. Genome Biology and Evolution 8: 2530–2543. doi: 10.1093/gbe/evw172
Tatiana Giraud and Judith Mank (2018) Dosage compensation by upregulation of maternal X alleles in both males and females in young plant sex chromosomes. Peer Community in Evolutionary Biology, 100044. 10.24072/pci.evolbiol.100044
Revision round #207 Feb 2018
Decision round #2
We have now received two referee reports for your resubmitted manuscript. Both referees are positive in their assessment of the revised version of your paper, although one has some additional suggestions. In particular, the referee would like more discussion on some findings that are only in supplementary material while not completely fitting the message of the main text, such as the findings on the X-hemizygous contigs and on the validated contigs.
We have read through the paper ourselves and found also that the previous concerns were satisfactorily addressed, but we had the following suggestions:
- It would be useful to explain how you dealt with multiple SNPs in X/Y contigs. We understand from the equation E = r/ (n * l) that Y and X expression is a composite, but have the authors looked to see whether all SNPs in X/Y contigs show concordant parent-of-origin imprinting, or whether the significant is driven by one or two SNPs in a contig? Lack of concordance across SNPs in a single coding sequence has been an issue in previous studies of parent of origin imprinting (Gregg, Zhang, Weissbourd, Luo, Scroth, Haig, Dulac Science 2010 & Gregg, Zhang, Butler, Haig, Dulac Science 2010). Related to this, is the composite nature of Y vs X expression the cause of the wide confidence intervals in Fig 1?
-Another question lies with the different categorization of dosage compensation in Silene over the past few years. Initial reports by these authors indicated “rapid evolution of dosage compensation” (Muyle et al PLOS Biology 2012), followed by reports by other teams of “largely absent dosage compensation” in Silene (Bergero et al. Current Biology 2015), “highly variable dosage compensation” (Papadopulos et al. PNAS 2015) and most recently “incomplete dosage compensation” (Zemp et al. Nature Plants 2016). It would be helpful to explain why these characterizations lack concordance. Is it due to methodological differences, or different sets of X/Y genes? Or is it just the result of different operational definitions?
-Please make sure all data are made available (both new genomic and transcriptomic data, as well as the identity of sex-linked contigs, with accession numbers given in the text when applicable). Al Supplementary tables should be either in the main PDF or with an associated doi number. -1st paragraph P2: replace “Although, sensu stricto” by “Yet, sensu stricto”
-1st paragraph P2 : I would find useful for a broad audience to have a brief explanation about the rationale of Ohno’s hypothesis on the evolution of dosage compensation. Why would it be more advantageous to have a suboptimal gene expression in females than in males?
-1st paragraph P4: a reference is needed in the sentence about convergence with marsupials.
-P3: “validated contigs”: unclear enough
After you have satisfactorily addressed these minor concerns, we will be happy to write a recommendation for your preprint.
Tatiana Giraud and Judith Mank
Reviewed by anonymous reviewer, 05 Dec 2017 11:02
Reviewed by anonymous reviewer, 12 Dec 2017 17:43
Revision round #104 Dec 2017
Decision round #1
This manuscript has been evaluated by two referees, who agree that the findings represent an important advance in our understanding of the early stages of dosage compensation in sex chromosomes, an important topic in evolutionary biology. The second referee nevertheless raises concerns about the lack of a reverse cross, which impedes disentangling maternal/paternal imprinting from strain effects. The second referee also suggests that the discussion should be more balanced, highlighting the differences in pattern strength found between figures and experiments. Both referees further suggest some improvements regarding clarity, mainly on the hypotheses in the introduction and discussion, on the outgroup and the methods, and they have a list of questions which the revised manuscript should answer to. The main figures are missing and should be added in the PDF. In addition to these referees’ suggestions, I also have the following recommendations for improving the manuscript. As a non-specialist of dosage compensation, I found the main text hard to understand and had to read the text several times to fully understand hypotheses and findings. If the authors target a broad audience, it would be useful to expose more clearly hypotheses and inferences, using less specific jargon. If room is needed, I would move the discussion on proximal mechanisms to supplementary text, and also the discussion about buffering explaining sex equality, as this pattern is not found in the present study. In addition, I wondered whether "using the ratio of Y over X expression levels in males as a proxy for Y degeneration" could not be circular. Indeed, the ratio of Y over X expression levels in males includes both the effect of Y degeneration and X compensation in males, and not only degeneration. Looking at dosage compensation as a function of a measure of Y degeneration that integrates dosage compensation may sound circular. I do not think the inferences are circular though, but I would be more careful in the definitions in the text and in the figures, and it may be better to take as a measure of Y degeneration differences or ratio of expression between Y and the outgroup autosome? About the main figures, why are they plotted and statistically analysed as discrete classes rather than as continuous variables? To sum up, there is potential for a highly interesting and novel contribution to the field of evolutionary biology. However, the paper needs careful revision along the lines above. If you are able to accommodate these points, I would encourage resubmission to PCI Evol Biol for recommendation.