Gene expression phylogenies and ancestral transcriptome reconstruction resolves major transitions in the origins of pregnancy
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Evaluation Summary:
Mika and colleagues reconstruct the evolution of uterine endometrial transcriptomes during pregnancy from 23 diverse species of mammals that differ with respect to their degree of placental invasiveness. Through this analysis the authors infer that the eutherian mammal ancestor had an invasive mode of placentation and that the degree of invasiveness of placentation is reflected on uterine endometrial gene expression during pregnancy. Thus, phylogenetic analysis of gene expression profiles of different mammals groups them on the basis of degree of placental invasiveness, a quite striking finding.
(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 #3 agreed to share their name with the authors.)
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Abstract
Structural and physiological changes in the female reproductive system underlie the origins of pregnancy in multiple vertebrate lineages. In mammals, the glandular portion of the lower reproductive tract has transformed into a structure specialized for supporting fetal development. These specializations range from relatively simple maternal nutrient provisioning in egg-laying monotremes to an elaborate suite of traits that support intimate maternal-fetal interactions in Eutherians. Among these traits are the maternal decidua and fetal component of the placenta, but there is considerable uncertainty about how these structures evolved. Previously, we showed that changes in uterine gene expression contributes to several evolutionary innovations during the origins of pregnancy (Mika et al., 2021b). Here, we reconstruct the evolution of entire transcriptomes (‘ancestral transcriptome reconstruction’) and show that maternal gene expression profiles are correlated with degree of placental invasion. These results indicate that an epitheliochorial-like placenta evolved early in the mammalian stem-lineage and that the ancestor of Eutherians had a hemochorial placenta, and suggest maternal control of placental invasiveness. These data resolve major transitions in the evolution of pregnancy and indicate that ancestral transcriptome reconstruction can be used to study the function of ancestral cell, tissue, and organ systems.
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Evaluation Summary:
Mika and colleagues reconstruct the evolution of uterine endometrial transcriptomes during pregnancy from 23 diverse species of mammals that differ with respect to their degree of placental invasiveness. Through this analysis the authors infer that the eutherian mammal ancestor had an invasive mode of placentation and that the degree of invasiveness of placentation is reflected on uterine endometrial gene expression during pregnancy. Thus, phylogenetic analysis of gene expression profiles of different mammals groups them on the basis of degree of placental invasiveness, a quite striking finding.
(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 #3 agreed to share their name with …
Evaluation Summary:
Mika and colleagues reconstruct the evolution of uterine endometrial transcriptomes during pregnancy from 23 diverse species of mammals that differ with respect to their degree of placental invasiveness. Through this analysis the authors infer that the eutherian mammal ancestor had an invasive mode of placentation and that the degree of invasiveness of placentation is reflected on uterine endometrial gene expression during pregnancy. Thus, phylogenetic analysis of gene expression profiles of different mammals groups them on the basis of degree of placental invasiveness, a quite striking finding.
(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 #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Mika and colleagues reconstruct the evolution of uterine endometrial transcriptomes during pregnancy from 23 diverse species of mammals that differ with respect to their degree of placental invasiveness. Through this analysis the authors infer that the eutherian mammal ancestor had an invasive mode of placentation and that the degree of invasiveness of placentation is reflected on uterine endometrial gene expression during pregnancy. Thus, phylogenetic analysis of gene expression profiles of different mammals groups them on the basis of degree of placental invasiveness, a quite striking finding.
The study is soundly performed and the results clearly presented. I particularly appreciated the authors' statement of caveats and limitations of this type of analysis and the necessity of interpreting these data in …
Reviewer #1 (Public Review):
Mika and colleagues reconstruct the evolution of uterine endometrial transcriptomes during pregnancy from 23 diverse species of mammals that differ with respect to their degree of placental invasiveness. Through this analysis the authors infer that the eutherian mammal ancestor had an invasive mode of placentation and that the degree of invasiveness of placentation is reflected on uterine endometrial gene expression during pregnancy. Thus, phylogenetic analysis of gene expression profiles of different mammals groups them on the basis of degree of placental invasiveness, a quite striking finding.
The study is soundly performed and the results clearly presented. I particularly appreciated the authors' statement of caveats and limitations of this type of analysis and the necessity of interpreting these data in the context of known differences in anatomy and physiology.
The work is an important contribution to our understanding of the evolution of mammalian pregnancy. My only disagreement is the authors' interpretation that "placental invasiveness is regulated by gene expression profiles in the maternal endometrium rather than the fetal portion of the placenta." I believe that one would have to conduct the same analysis on the fetal placenta and examine the evolution of the placental transcriptome with respect to degree of placental invasive. It could be very well be that the degree of convergence of the maternal uterine endometrial transcriptomes is larger than that of the fetal placental transcriptomes, but the opposite could also turn out to be true.
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Reviewer #2 (Public Review):
The authors present a novel phylogenetic and clustering analysis of uterine endometrium transcriptomes to test hypotheses of the evolution of placental invasiveness.
The authors make three distinct claims in their manuscript: 1) epitheliochorial-like placentas evolved early in mammalian stem-lineage, 2) the Eutherian ancestor had an invasive hemochorial placenta, and 3) there is maternal control of placental invasiveness.
To come to these conclusions the authors analyzed a collection of uterine endometrium transcriptomes sampled across placental invasiveness types.
The authors present several lines of evidence to support their claims. First, that maximum-likelihood phylogenetic reconstruction of expression data groups species by placenta-type. The discordance between the known species taxonomy and …
Reviewer #2 (Public Review):
The authors present a novel phylogenetic and clustering analysis of uterine endometrium transcriptomes to test hypotheses of the evolution of placental invasiveness.
The authors make three distinct claims in their manuscript: 1) epitheliochorial-like placentas evolved early in mammalian stem-lineage, 2) the Eutherian ancestor had an invasive hemochorial placenta, and 3) there is maternal control of placental invasiveness.
To come to these conclusions the authors analyzed a collection of uterine endometrium transcriptomes sampled across placental invasiveness types.
The authors present several lines of evidence to support their claims. First, that maximum-likelihood phylogenetic reconstruction of expression data groups species by placenta-type. The discordance between the known species taxonomy and expression-based phylogeny is interpreted as evidence for convergence in gene expression between species with similar placentas.
While this conclusion is supported by the topology of the phylogenies, the authors do not test models of co-evolution between traits (expression and placental invasiveness). The authors determine that there must be "significant convergence" based on observations from the tree topology but do not explicitly test this model. I recommend adding in alternative possibilities in this section, or explicitly testing trait co-evolution.
The authors conduct ancestral state reconstruction and FCM to test the evolutionary origins of placental invasiveness. The ancestrally reconstructed Ancestral Eutherian transcriptional program clusters with extant hemochorial and ancestral thererian and mammalia transcriptomes cluster with non-invasive epitheliochorial placentas. This supports the author's claim that epitheliochorial placentas evolved early in mammalian lineages and that hemochorial placenta is ancestral for eutherians. I am curious, however, how the sampling of species influences this result-especially the inclusion of the armadillo. It appears the armadillo sample may be a significant driver of these results (especially the ancestral eutheria reconstruction). Given the sampling limitations, which the authors discuss, the authors should be cautious in their use of statements like "our results resolve several evolutionary transformations."
Finally, the authors discuss how their results suggest maternal control of placental invasion. Their support for this hypothesis is that endometrial gene expression (maternal) is associated with placental invasiveness. It is unclear to me how the authors determine directionality from the correlation observed. They present relevant findings that support their conclusions, but do not address alternative hypotheses such as fetal controlled placental invasion shaping maternal transcriptomics.
Overall, the analyses conducted here make a significant contribution to our understanding of the evolution of pregnancy in mammals. The methods used are appropriate and the analyses include novel findings on the evolution of placental invasion. I would suggest, however, that the authors ensure that alternative hypotheses are discussed and that they avoid language such as "resolve."
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Reviewer #3 (Public Review):
In this work the authors use available endometrial transcriptomic data from a range of 23 different species covering a range of placental invasiveness to reconstruct an ancestral transcriptome. This was then used as a basis for phylogenetic comparison that could resolve major transitions in the the evolution of the placenta.
A major strength of this work is the use of fuzzy clustering to explore the ancestral transcriptome. This approach allows for the existence of a specific gene in multiple clusters and thus reflects the underlying functional interactions in a manner that accounts for changing function over evolutionary time.
A weakness of the the approaches used is that as yet single cell resolution cannot be achieved in the endometrial data so the "bulk" transcriptome over the different cell types has to …
Reviewer #3 (Public Review):
In this work the authors use available endometrial transcriptomic data from a range of 23 different species covering a range of placental invasiveness to reconstruct an ancestral transcriptome. This was then used as a basis for phylogenetic comparison that could resolve major transitions in the the evolution of the placenta.
A major strength of this work is the use of fuzzy clustering to explore the ancestral transcriptome. This approach allows for the existence of a specific gene in multiple clusters and thus reflects the underlying functional interactions in a manner that accounts for changing function over evolutionary time.
A weakness of the the approaches used is that as yet single cell resolution cannot be achieved in the endometrial data so the "bulk" transcriptome over the different cell types has to be considered. Whilst representing a problem in the assessment of the action of evolution on specific cell types this does not impact the general conclusions presented.
This work will galvanise more detailed analysis of comparative transcriptomic data in the field of endometrial biology. The methods presented are useful over a range of other investigations.
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