An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing

Abstract

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

Polymorphisms in NR5A2, gene encoding liver receptor homolog-1 are associated with preterm birth

“…One SNP in FSHR gene (rs6165) showed a P value <0.05 in the gestation age <32-wk group and PPROM group, but did not reach formal levels of significance once corrected for multiple comparisons. Notably our results did not replicate the previously described associations of FSHR polymorphisms and PTB (19,20). In addition, SNPs in SERPINH1 did not show an association with PPROM cases as shown previously (21).…”

“…Familial trends and racial disparities of prematurity also suggest that genetics influence this trait (9)(10)(11). A number of case-control and family-based studies have evaluated candidate genes chosen from some of the pathways associated with PTB (12)(13)(14)(15)(16)(17).…”

“…LRH1 has been shown to play an important role in establishing and sustaining pregnancy in animal models (18). Polymorphisms in FSHR encoding follicle-stimulating hormone receptor have been found to be associated with PTB in a Finnish as well as an African-American population (19,20). Dysregulation of FSHR may contribute to early uterine contractility.…”

Metabolic hypothesis for human altriciality

“…However, it is more commonly proposed that human gestation length and altriciality are a solution to the uniquely human "obstetrical dilemma" (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), also called the "obstetric dilemma" and, henceforth, referred to as OD. The OD hypothesis proposes that Pleistocene hominins faced antagonistic selection pressures on locomotor requirements and encephalization.…”

Common Oxytocin Receptor Gene Polymorphisms and the Risk for Preterm Birth

“…These studies have traditionally focused on one or a few candidate genes, chosen based on our current understanding of physiology. More recently, genome-wide linkage analyses in families with recurrent PTB and large-scale association studies have revealed further susceptibility genes for PTB [9,21,24].…”