Genomics of preterm birth

Abstract

The molecular mechanisms controlling human birth timing at term, or resulting in preterm birth, have been the focus of considerable investigation, but limited insights have been gained over the past 50 years. In part, these processes have remained elusive because of divergence in reproductive strategies and physiology shown by model organisms, making extrapolation to humans uncertain. Here, we summarize the evolution of progesterone signaling and variation in pregnancy maintenance and termination. We use this comparative physiology to support the hypothesis that selective pressure on genomic loci involved in the timing of parturition have shaped human birth timing, and that these loci can be identified with comparative genomic strategies. Previous limitations imposed by divergence of mechanisms provide an important new opportunity to elucidate fundamental pathways of parturition control through increasing availability of sequenced genomes and associated reproductive physiology characteristics across diverse organisms.

Figure 1.

The evolving roles of progesterone (P4) and prostaglandins (PG) in reproduction. The extended pregnancy coincides with coupling of prostaglandins with progesterone dynamics.

Figure 2.

Phylogenetic tree of placental mammals (eutherians), with marsupials as outgroup. Model species are shown in bold. Local progesterone withdrawal (LPW) refers to the evidence for progesterone withdrawal in a particular tissue, such as cervix in mice or placenta in sheep, regardless of the presence of systemic progesterone decrease (SPW). Black indicates presence, red absence of a phenomenon, and white is the lack of information. Bicolored boxes indicate heterogeneity across species of a group. LPS, luteo–placental shift (i.e., the dependence on ovarian P4 is shorter than gestational time); CL, corpus luteum. Note the lack of information on local progesterone withdrawal.

Figure 3.

Strategy for using comparative genomics to identify human gene evolution associated with adaptations in birth timing and risk for preterm birth. Homologous genes are aligned, and coding region changes (increased number of nonsynonymous to synonymous nucleotide changes (dN/dS) or loss of constraint in conserved noncoding regions reveal human rate accelerated regions. Genes associated with these regions are then used as nonphysiologically biased candidates for association studies.