Evolutionary gene markers of uterine disease and ageing

Supervisors

Manuel Irimia
CRG, 2nd supervisor

Objectives

The uterus is the perennial support organ of internal pregnancy, one of the most important evolutionary innovations of placental mammals. In primates, the uterus has acquired additional adaptations, and in particular menstruation, a new mechanism of tissue renewal and regeneration. The acquisition of menstruation has gone hand in hand with an increased incidence in uterine diseases such an endometrial cancers, as well as with the apparition of new diseases such as endometriosis. In this project, we will leverage evolutionary genomics methods to uncover how changes in gene expression have shaped disease prevalence and evolutionary novelty in the human uterus.

Methodology

The project relies on evolutionary modeling of gene expression to identify genes of particular interest for uterine function, either because their expression is more conserved than expected, or on the contrary, because their expression diverged particularly fast in primates or in humans. The student will leverage an exceptional single-cell atlas of gene expression in the uterus of 7 primate species and several other mammals, as well as other functional genomics resources from the lab, to characterize how gene expression has evolved in this organ. Further, the student will then confront this information with genetic variants involved in uterine diseases to understand how variations in gene expression shape disease risk in this organ. The project involves phylogenetic modeling, statistical modeling, and the development of AI models for functional, evolutionary and medical genomics.

Required Skills

The ideal candidate will have training in bioinformatics, genomics, computer science or a related discipline. Computational experience is
required: proficiency in at least one scientific programming language is expected. Experience with high-throughput genomics data or
evolutionary genetics/genomics is highly appreciated, although not a requirement.

Expected Results

This project is expected to shed light on the genetic architecture of human uterine diseases, and on the evolutionary dynamics at work in the uterus, an under-studied female reproductive organ. We expect that the results of this work will illuminate the origins of common yet poorly understood disorders such as endometriosis.

Planned Secondments

CRG (Irimia) in year 2 (2 months) to receive training on gene expression and alternative splicing analyses.

FLI (Valenzano) in year 3 (2 weeks) to learn about ageing research and complementary GWAS approaches.

Enrolment in doctoral programs

The student will be enrolled at the BioSPC doctoral school at Université Paris Cité, France. The student will carry out their research at Institut Pasteur in Paris, under the supervision of Dr Camille Berthelot, and will benefit from institutional support by the Graduate office at Institut Pasteur. The Institut Pasteur is one of the leading biomedical research institutions worldwide, offering a supportive and diverse environment for PhD students.

References

Emera, D., Romero, R., Wagner, G., 2012. The evolution of menstruation: A new model for genetic assimilation. Bioessays 34, 26–35. https://doi.org/10.1002/bies.201100099

Evans, J., Salamonsen, L.A., Winship, A., Menkhorst, E., Nie, G., Gargett, C.E., Dimitriadis, E., 2016. Fertile ground: human endometrial programming and lessons in health and disease. Nature Reviews Endocrinology 12, 654–667. https://doi.org/10.1038/nrendo.2016.116

Mostafavi, H., Spence, J.P., Naqvi, S., Pritchard, J.K., 2023. Systematic differences in discovery of genetic effects on gene expression and complex traits. Nat Genet 1–10. https://doi.org/10.1038/s41588-023-01529-1