An evolutionary genomic perspective on preterm birth, genome editing, and pregnancy in the human species

The processes of labor and birth have a complex evolutionary history, with substantial variation among species showing differences in gestational length, offspring number, anatomy, and rates of fetal development. Understanding the genomic basis of pregnancy is therefore a focus of evolutionary research, given the importance of reproductive success in processes such as natural selection, mutation, genetic drift, and migration. Disruptions to normal pregnancy processes include preterm birth, which can arise from multiple factors, including infection, anatomical variation, injury, age, parity, and multiple gestation and other obstetrical syndromes as well (e.g., preeclampsia, and stillbirth). These factors each influence unique and overlapping networks of candidate genes and biological pathways. Here we synthesize evidence from comparative genomics, population genetics, and vertebrate reproductive biology to show that many PTB-relevant genes, including those involved in progesterone signaling, innate immunity, placental regulation, and chromosome 19 gene clusters, have undergone lineage- or population-specific evolutionary change. Integrating evolutionary insights with functional genomics, machine learning, and modern genome-editing technologies, we provide a principled framework to distinguish conserved, high-risk targets from evolutionarily flexible loci, guiding safer mechanistic studies and future interventions to reduce PTB risk. From an initial list of approximately 1,500 genes involved in pregnancy, we identified those that show evidence of recent evolutionary change for which functional inference is possible. We review some specific nucleotide sites that, when disrupted via CRISPR gene editing, are likely to impact the processes of labor and birth. These loci fall within protein coding genes, transposable elements, transcription factor binding sites, and non-coding RNAs. They are found in nuclear hormone receptors (e.g., PGR), genes with placenta- and uterine-specific expression patterns (e.g., LGALS13), as well as signaling molecules and immunological loci. Finally, we provide evidence that gene activity and sequence variation differ across species and provide examples of pathway differences between chimpanzees (nociception) and humans (inflammation).