From PPROM to caul: The evolution of membrane rupture in mammals

Abstract

Rupture of the extraembryonic membranes that form the gestational sac in humans is a typical feature of human parturition. However, preterm premature rupture of membranes (PPROM) occurs in approximately 1% of pregnancies, and is a leading cause of preterm birth. Conversely, retention of an intact gestational sac during parturition in the form of a caul is a rare occurrence. Understanding the molecular and evolutionary underpinnings of these disparate phenotypes can provide insight into both normal pregnancy and PPROM. Using phylogenetic techniques we reconstructed the evolution of the gestational sac phenotype at parturition in 55 mammal species representing all major viviparous mammal groups. We infer the ancestral state in therians, eutherians, and primates, as in humans, is a ruptured gestational sac at parturition. We present evidence that intact membranes at parturition have evolved convergently in diverse mammals including horses, elephants, and bats. In order to gain insight into the molecular underpinnings of the evolution of enhanced membrane integrity we also used comparative genomics techniques to reconstruct the evolution of a subset of genes implicated in PPROM, and find that four genes (ADAMTS2, COL1A1, COL5A1, LEPRE1) show significant evidence of increased nonsynonymous rates of substitution on lineages with intact membranes as compared to those with ruptured membranes. Among these genes, we also discovered that 17 human SNPs are associated with or near amino acid replacement sites in those mammals with intact membranes. These SNPs are candidate functional variants within humans, which may play roles in both PPROM and/or the retention of the gestational sac at birth.

Keywords: Evolution; Fetal membranes; Gestational sac; Mammals; PPROM; Positive selection.

Fig. 1

Examples of intact and ruptured gestational sac at parturition. A. Sonogram of a human fetus in the uterus with premature preterm rupture of fetal membranes (PPROM) as indicated by the white arrow (Devlieger et al., 2003). Image by permission of Wiley InterScience. B. Chimpanzee and neonate with ruptured gestational sac (Hirata et al., 2011). Image by permission of The Royal Society (http://www.youtube.com/watch?v=dfd0fzX9M5g). C. Harbor seal and neonate with intact gestational sac. Photo courtesy of Mauricio Mena. D. Horse and neonate with intact gestational sac. Photo courtesy of Orlando Alamillo. (http://www.youtube.com/watch?v=BHzWgrr7MHI).

Fig. 2

Evolution of intact and ruptured gestational sacs at parturition. Reconstruction of the evolution of the gestational sac at parturition on a phylogenetic tree of 55 mammal species from 12 orders using maximum parsimony. Blue = species with intact membranes; green = partially intact; black = ruptured membrane at birth; Pac. wh.-sided dolphin = Pacific white-sided dolphin.

Fig. 3

Adaptive evolution in COL1A2. Phylogenetic tree of mammals used in this study with COL1A2 branch-specific dN/dS above each branch, N*dN and S*dS values below each branch. COL1A2 shows evidence of adaptive evolution (dN/dS > 1.0) on three branches highlighted in red. Names of each species are colored with blue for intact gestational sac, green for partial gestational sac, and black for ruptured gestational sac. Abbreviations: dN/dS = ratio of non synonymous substitution rate/synonymous substitution rate; N*dN = nonsynonymous changes; S*dS = synonymous changes.