Abstract
BackgroundThe onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance.MethodsWe performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers.ResultsDetailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity.ConclusionsOur findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
Highlights
The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology
Among the rapidly evolving genes emerging from our noncoding screen, PLA2G4C was identified as the most statistically significant human-lineage accelerated gene (p = 2.2 × 10-7, significant at 10% False Discovery Rate threshold) that was included in a list of preterm birth candidate genes [11]
A phylogenetic tree of coding sequences for PLA2G4C follows the expected mammalian phylogeny (Figure 3), suggesting that the duplication did not include coding sequences. Together these results suggest that neither element would qualify as rapidly evolving along the human lineage due to nucleotide substitution, but the chromosome 19 element may represent a primate-specific change meriting further study
Summary
The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. Genes involved in parturition likely have evolved differentially along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and alleviate the complications arising from such cephalopelvic constraints. The set of genes rapidly evolving on the human and/or higher primate lineage likely includes genes that play important roles in regulating parturition and potentially influence preterm birth risk. Consistent with our hypothesis, we identified FSHR as having rapidly evolved by nucleotide substitution and as being associated with preterm birth risk across independent populations ([5] and (Plunkett J, Doniger S, Orabona G, Morgan T, Haataja R, Hallman M, Puttonen H, Menon R, Kuczynski E, Norwitz E et al: Evolutionary history of FSHR in human predicts role in birth time, submitted))
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