Genetic recapitulation of human pre-eclampsia risk during convergent evolution of reduced placental invasiveness in eutherian mammals
Open accessAbstract
The relationship between phenotypic variation arising through individual development and phenotypic variation arising through diversification of species has long been a central question in evolutionary biology. Among humans, reduced placental invasion into endometrial tissues is associated with diseases of pregnancy, especially pre-eclampsia, and reduced placental invasiveness has also evolved, convergently, in at least 10 lineages of eutherian mammals. We tested the hypothesis that a common genetic basis underlies both reduced placental invasion arising through a developmental process in human placental disease and reduced placental invasion found as a derived trait in the diversification of Euarchontoglires (rodents, lagomorphs, tree shrews, colugos and primates). Based on whole-genome analyses across 18 taxa, we identified 1254 genes as having evolved adaptively across all three lineages exhibiting independent evolutionary transitions towards reduced placental invasion. These genes showed strong evidence of enrichment for associations with pre-eclampsia, based on genetic-association studies, gene-expression analyses and gene ontology. We further used in silico prediction to identify a subset of 199 genes that are likely targets of natural selection during transitions in placental invasiveness and which are predicted to also underlie human placental disorders. Our results indicate that abnormal ontogenies can recapitulate major phylogenetic shifts in mammalian evolution, identify new candidate genes for involvement in pre-eclampsia, imply that study of species with less-invasive placentation will provide useful insights into the regulation of placental invasion and pre-eclampsia, and recommend a novel comparative functional-evolutionary approach to the study of genetically based human disease and mammalian diversification.
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Epitheliochorial placentation avoids many of the immunological and hemodynamic problems associated with invasive forms of placentation that underlie complications of human pregnancy such as pre-eclampsia.
“Epitheliochorial placentation avoids many of the immunological and hemodynamic problems associated with the invasive forms that underlie complications of human pregnancy, such as pre-eclampsia, and these may have operated as selective pressures over the millennia (131, 170, 231).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [170]
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Hou, Z., Sterner, K. N., Romero, R. J., Than, N. G., Grau, J. M. G., Weckle, A. L., Xing, J., Benirschke, K., Goodman, M., & Wildman, D. E. (2012) · Genome Biology and Evolution · doi:10.1093/gbe/evs045 · Cited by 29 · see citing works
Hamai, Y., Fujii, T., Yamashita, T., Kozuma, S., Okai, T., & Taketani, Y. (1998) · Placenta · doi:10.1016/s0143-4004(98)90003-0 · Cited by 28 · see citing works
Expression of endogenous retrovirus-like transcripts in bovine trophoblastic cells
Koshi, K., Ushizawa, K., Kizaki, K., Takahashi, T., & Hashizume, K. (2011) · Placenta · doi:10.1016/j.placenta.2011.04.002 · Cited by 25 · see citing works
Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs
Katoh, M., & Katoh, M. (2005) · Oncology Reports · doi:10.3892/or.14.4.1083 · Cited by 24 · see citing works
C-jun and jun-B oncogene expression during placental development
Dungy, L. J., Siddiqi, T. A., & Khan, S. (1991) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(91)90045-s · Cited by 24 · see citing works
PESNPdb: A comprehensive database of SNPs studied in association with pre-eclampsia
Tuteja, G., Cheng, E., Papadakis, H., & Bejerano, G. (2012) · Placenta · doi:10.1016/j.placenta.2012.09.016 · Cited by 21 · see citing works
Gene expression in placentation of farm animals: An overview of gene function during development
Barreto, R. D. S. N., Bressan, F. F., Oliveira, L. J., Pereira, F. T. V., Perecin, F., Ambrósio, C. E., Meirelles, F. V., & Miglino, M. A. (2011) · Theriogenology · doi:10.1016/j.theriogenology.2011.03.001 · Cited by 17 · see citing works
OLAYEMI, O., Strobino, D. M., Aimakhu, C. O., Adedapo, K. S., Kehinde, A. O., Odukogbe, A.-T. A., & Salako, B. O. (2010) · Australian and New Zealand Journal of Obstetrics and Gynaecology · doi:10.1111/j.1479-828x.2009.01115.x · Cited by 16 · see citing works
Fat body of the frogRana esculenta: An ultrastructural study
Zancanaro, C., Merigo, F., Digito, M., & Pelosi, G. (1996) · Journal of Morphology · doi:10.1002/(sici)1097-4687(199603)227:3 · Cited by 15 · see citing works
The Expression of the Transcription Factors SNAI1 and SNAI2 Throughout Pre-Implantation Development.
Bell, C., & Watson, A. J. (2009) · Biology of Reproduction · doi:10.1093/biolreprod/81.s1.240 · Cited by 2 · see citing works
Flagged first, then by citations
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Placental Origins of Chronic Disease
Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · see citing works
Open questions in the study of de novo genes: what, how and why
McLysaght, A., & Hurst, L. D. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.78 · Cited by 208 · see citing works
Uterine artery blood flow, fetal hypoxia and fetal growth
Browne, V. A., Julian, C. G., Toledo-Jaldin, L., Cioffi-Ragan, D., Vargas, E., & Moore, L. G. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0068 · Cited by 127 · see citing works
“pr et er m (% ) 17 [7 ,3 7] (2 3) 5 [1 ,9 ]( 12 5) 19 [5 ,3 3] (2 9) , 0.”
BackgroundOxidative stress in pregnancy complicated by preeclampsia
Juan-Reyes, S. S., Gómez‐Oliván, L. M., Islas‐Flores, H., & Dublán‐García, O. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108255 · Cited by 97 · see citing works
The human placenta: new perspectives on its formation and function during early pregnancy
Burton, G. J., & Jauniaux, E. R. M. (2023) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2023.0191 · Cited by 76 · see citing works
“Avoidance of the complex immunological interactions ensuing from invasive implantation, and their potential involvement in complications of pregnancy, may have been a key selective pressure [14].”
BackgroundEvolutionary divergence of embryo implantation in primates
Siriwardena, D., & Boroviak, T. (2022) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2021.0256 · Cited by 38 · see citing works
Oxidative stress and the evolutionary origins of preeclampsia
Elliot, M. G. (2016) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2016.02.003 · Cited by 36 · see citing works
Self-citationPlacentation in the Human and Higher Primates
Burton, G. J., & Jauniaux, E. R. M. (2021) · Advances in anatomy, embryology and cell biology · doi:10.1007/978-3-030-77360-1_11 · Cited by 28 · see citing works
Viruses and the placenta: the essential virus first view
Villarreal, L. P. (2016) · Apmis · doi:10.1111/apm.12485 · Cited by 24 · see citing works
“Biologically, the placenta varies greatly between species (69), especially its invasiveness (70).”
BackgroundEvidence of positive selection associated with placental loss in tiger sharks
Swift, D. G., Dunning, L. T., Igea, J., Brooks, E. J., Jones, C. S., Noble, L. R., Ciezarek, A., Humble, E., & Savolainen, V. (2016) · BMC Evolutionary Biology · doi:10.1186/s12862-016-0696-y · Cited by 21 · see citing works
“Other studies have used genomics to test for signatures of positive selection associated with placental evolution in mammals [67, 68].”
BackgroundLaBella, A. L., Abraham, A., Pichkar, Y., Fong, S., Zhang, G., Muglia, L. J., Abbot, P., Rokas, A., & Capra, J. A. (2020) · Nature Communications · doi:10.1038/s41467-020-17258-6 · Cited by 13 · see citing works
The transformative potential of an integrative approach to pregnancy
Eidem, H. R., McGary, K. L., Capra, J. A., Abbot, P., & Rokas, A. (2017) · Placenta · doi:10.1016/j.placenta.2017.07.010 · Cited by 11 · see citing works
Kim, M., Cooper, B. A., Venkat, R., Phillips, J. B., Eidem, H. R., Hirbo, J. B., Nutakki, S., Williams, S. M., Muglia, L. J., Capra, J. A., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1137 · Cited by 9 · see citing works
Human evolution: brain, birthweight and the immune system
Burton, G. J., Moffett, A., & Keverne, B. (2015) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2014.0061 · Cited by 9 · see citing works
“Elliot MG, Crespi BJ. 2015 Genetic recapitulation of human pre-eclampsia risk during convergent evolution of reduced placental invasiveness in eutherian mammals.”
BackgroundOverexpression of Long Noncoding RNA Uc.187 Induces Preeclampsia-Like Symptoms in Pregnancy Rats
Huang, J., Qian, Y., Cheng, Q., Yang, J., Ding, H., & Jia, R. (2020) · American Journal of Hypertension · doi:10.1093/ajh/hpaa011 · Cited by 9 · see citing works
Development of a cardiovascular and lymphatic network model during human pregnancy
Carson, J. (2019) · doi:10.23889/suthesis.50058 · Cited by 8 · see citing works
Pavličev, M., & Wagner, G. P. (2022) · MedComm · doi:10.1002/mco2.174 · Cited by 7 · see citing works
The Etiopathogenesis of Preeclampsia: Where Do We Stand Now?
Laskowska, M., Bednarek, A., & Stworowski, M. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14227992 · Cited by 5 · see citing works
“In contrast, premature hemoperfusion and hyperoxia in early pregnancy can lead to decreased VEGF and a premature increase in PlGF, which is likely to underlie weaker villous vascular development, superficial trophoblast invasion, abnormal placental development, and pregnancy complications [69–72].”
Integrating evolution into medical education for women’s health care practitioners
Power, M. L., Snead, C. M., Reed, E. G., & Schulkin, J. A. (2020) · Evolution Medicine and Public Health · doi:10.1093/emph/eoaa009 · Cited by 5 · see citing works
Hirbo, J. B., Eidem, H. R., Rokas, A., & Abbot, P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0144155 · Cited by 4 · see citing works
“Recent work has suggested that there might be convergence of genetic factors that underlie placental diseases like PE and larger evolutionary patterns in placental traits in mammals [136].”
BackgroundStearns, S. C., & Medzhitov, R. M. (2024) · doi:10.1093/oso/9780192871978.003.0013 · Cited by 2 · see citing works
Natural Selection as a Driver for the Genetic Component of Preeclampsia
Сереброва, В. Н., Trifonova, E. A., & Степанов, В. А. (2021) · Molecular Biology · doi:10.1134/s0026893321020308 · Cited by 1 · see citing works
Сереброва, В. Н., Trifonova, E. A., & Степанов, В. А. (2021) · Russian Journal of Genetics · doi:10.1134/s1022795421010142 · Cited by 1 · see citing works
“Phylogenetic tree of the Euarchonta grandorder with characteristics of the histological type of placentation of its representatives (according to [106] in our own modification).”
BackgroundMethodBurton, G. J., & Jauniaux, E. R. M. (2017) · Cambridge University Press eBooks · doi:10.1017/9781139976787.004
Genetic Variants in Preeclampsia During Pregnancy: A Hospital-Based Case–Control Study
Slobodchikova, T., Taizhanova, D., Туймебаевна, А. Ж., Vazenmiller, D., Mustafin, R., & Izmailovich, M. R. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14113850
“Another study [46] demonstrated that the risk alleles of the USF1 gene are predictive of both cardiovascular disease and severe preeclampsia development during pregnancy.”
Memory and Threshold Based Variants of Squirrel Search Algorithms: Application to Real Life Problems
Jana, B., Agarwal, M. C., & Acharyya, S. (2025) · SN Computer Science · doi:10.1007/s42979-025-04351-0
“Many widely known preeclampsia genes including CCL18 [40], PDK [41], SKP1 [42], MMP1 [43], CHL1 [44], TGFBRAP1 [45], BDKRB1 [46], MAPK8 [47] have been identified among the selected genes.”
- Authors
- Elliot, M. G., & Crespi, B. J.
- Affiliations
- University of Cambridge (GB)
- Simon Fraser University (CA)
- Corresponding author
- Elliot, Michael G.
- Venue
- Philosophical Transactions of the Royal Society B: Biological Sciences
- Publisher
- The Royal Society
- Published
- 2015-03-05
- Volume
- 370
- Issue
- 1663
- Pages
- 20140069
- ISSN
- 0962-8436 (ISSN-L)
- 1471-2970
- PMC
- PMC4305170
- OpenAlex
- W2017921408
- Cited by
- 26
- References
- 111
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 1 · 2017: 2 · 2016: 5 · 2015: 4
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- preeclampsia, placental invasion, convergent evolution, placental mammals, Euarchontoglires, placental development, natural selection, candidate genes, placental disease, primates, colugos, tree shrew, lagomorphs
- MeSH terms
- Adaptation, Biological, Animals, Biological Evolution, Female, Genes, Humans, Mammals, Placenta Diseases, Pre-Eclampsia, Pregnancy, Selection, Genetic, Species Specificity, Genomics
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