title: 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.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Jevon
authors.initials: J
authors.lastname: Plunkett
authors.forename: Scott
authors.initials: S
authors.lastname: Doniger
authors.forename: Guilherme
authors.initials: G
authors.lastname: Orabona
authors.forename: Thomas
authors.initials: T
authors.lastname: Morgan
authors.forename: Ritva
authors.initials: R
authors.lastname: Haataja
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
authors.forename: Hilkka
authors.initials: H
authors.lastname: Puttonen
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.forename: Edward
authors.initials: E
authors.lastname: Kuczynski
authors.forename: Errol
authors.initials: E
authors.lastname: Norwitz
authors.forename: Victoria
authors.initials: V
authors.lastname: Snegovskikh
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Vineta
authors.initials: V
authors.lastname: Fellman
authors.forename: Emily A
authors.initials: EA
authors.lastname: DeFranco
authors.forename: Bimal P
authors.initials: BP
authors.lastname: Chaudhari
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGregor
authors.forename: Jude J
authors.initials: JJ
authors.lastname: McElroy
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Oetjens
authors.forename: Kari
authors.initials: K
authors.lastname: Teramo
authors.forename: Ingrid
authors.initials: I
authors.lastname: Borecki
authors.forename: Justin
authors.initials: J
authors.lastname: Fay
authors.forename: Louis
authors.initials: L
authors.lastname: Muglia
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000818:Animals; D016022:Case-Control Studies; D015331:Cohort Studies; D019143:Evolution, Molecular; D005260:Female; D005387:Finland; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D036801:Parturition / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D047928:Premature Birth / Q000235:genetics*; D011962:Receptors, FSH / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
chemical_list: D011962:Receptors, FSH