1. Evolutionary Biology
  2. Medicine
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Developing a theoretical evolutionary framework to solve the mystery of parturition initiation

  1. Antonis Rokas  Is a corresponding author
  2. Sam Mesiano
  3. Ortal Tamam
  4. Abigail LaBella
  5. Ge Zhang
  6. Louis Muglia  Is a corresponding author
  1. Department of Biological Sciences, Vanderbilt University, United States
  2. Department of Reproductive Biology, Case Western Reserve University and Department of Obstetrics and Gynecology, University Hospitals of Cleveland, United States
  3. The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University, Israel
  4. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics. University of Cincinnati College of Medicine, United States
  5. Burroughs Wellcome Fund, Research Triangle Park, United States
Review Article
Cite this article as: eLife 2020;9:e58343 doi: 10.7554/eLife.58343
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5 figures and 1 table


Neonatal deaths as a function of gestational age at birth for singleton pregnancies in the US in 2015.

Data reflect outcomes of 3,849,557 pregnancies demonstrating optimal survival between 38 and 40 weeks of completed gestation. This optimal survival time coincides with the peak of birth timing during pregnancy as shown by number of total live births. Drawn from data in JAMA Pediatr. 2018 Jul; 172(7): 627–634 (Ananth et al., 2018).

Pregnancy-associated traits are influenced by both maternal and fetal genetics.

One framework for studying the maternal and fetal genetic effects in pregnancy is to consider the mother/fetus pair as a unit with three haplotypes, h1, h2, and h3. The maternal-fetal compound genome of pregnancy genetically contributes to maternal phenotypes (blue) through the actions of the maternal transmitted (h1, red) and non-transmitted haplotypes (h2, yellow). Fetal phenotypes are genetically determined by the maternal transmitted (h1) and the paternal transmitted (h3) haplotypes which may display parent of origin effects. The maternal environment, shaped by h1 and uniquely by h2, also influences pregnancy outcomes including pregnancy duration through maternal effects.

Comparative biochemical strategies for initiating parturition in sheep, mouse, and human species.

The steroids estrogen and progesterone are conserved components, but the tissues involved and superimposed innovations, such as CRH in humans, likely result in divergence of final pathways for birth.

Testable theoretical models for determining the onset of parturition in eutherian mammals.

Model one represents a fixed clock in the mother or fetus to determine when birth happens (y = 0). The precise day is determined by a physiological rate constant (r) that determines when, for a given woman, birth would occur. The time (t) is measured in months in this representation. Model two reflects a parturition inhibition signal (Si) that must go below a threshold (th0) for birth (B) to occur. Model three alternatively proposes a parturition stimulation signal (Sp) that must exceed a threshold for birth to occur. Model four displays that both Si and Sp are involved in determining the timing for birth, and parturition occurs as a crossover when Sp >Si.

Muridae phylogeny and divergence times of the spiny mouse, Mongolian gerbil and house mouse with their associated pregnancy characteristics.

Image of Mongolian gerbil is from https://en.wikipedia.org/wiki/Mongolian_gerbil#/media/File:Meriones_unguiculatus_(wild).jpg, image of spiny mouse from https://commons.wikimedia.org/wiki/File:Acomys.cahirinus.cahirinus.6872.jpg, and image of house mouse from https://en.wikipedia.org/wiki/House_mouse#/media/File:Mouse_white_background.jpg.

© 2010, Wikimedia Commons. Mongolian gerbil image courtesy of Wikimedia Commons. Published under a CC BY-SA 2.5 license

© 2005, Wikimedia Commons. Spiny mouse image courtesy of Wikimedia Commons. Published under a CC BY-SA 3.0 license

© 2005, Wikimedia Commons. Spiny mouse image courtesy of Wikimedia Commons. Published under a CC BY-SA 2.5 license

© 2005, Wikimedia Commons. Spiny mouse image courtesy of Wikimedia Common. Published under the GNU Free Documentation license


Table 1
Comparative analysis of P4 source, maintenance, and role in parturition initiation for rodent, sheep, and human pregnancy.

P4 SourcePregnancy MaintenanceParturition InitiationMechanism of Initiation
RodentCLP4Systemic P4 withdrawalEndometrium production of PGF2α.
CL regression.
SheepCL transition to PlacentaP4Systemic P4 withdrawalIncreased activity of the fetal HPA axis.
Increase of cortisol.
Decrease P4 production.
HumanCL transition to PlacentaP4No systemic P4 withdrawal (tissue or target cell resistance)Potential contributors:
Change in progesterone receptor isoforms.
Change in PR cofactors.
PR post translational modifications.
Local metabolism of P4.

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