title: Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Detailed 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.
  
  
  CONCLUSIONS
  Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Jevon
authors.initials: J
authors.lastname: Plunkett
authors.forename: Scott
authors.initials: S
authors.lastname: Doniger
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authors.forename: Ritva
authors.initials: R
authors.lastname: Haataja
authors.forename: Mikko
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authors.lastname: Hallman
authors.forename: Hilkka
authors.initials: H
authors.lastname: Puttonen
authors.forename: Ramkumar
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authors.lastname: Menon
authors.forename: Edward
authors.initials: E
authors.lastname: Kuczynski
authors.forename: Errol
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authors.lastname: Norwitz
authors.forename: Victoria
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authors.lastname: Snegovskikh
authors.forename: Aarno
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authors.lastname: Palotie
authors.forename: Leena
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authors.lastname: Peltonen
authors.forename: Vineta
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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: John
authors.initials: J
authors.lastname: Oates
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGregor
authors.forename: Jude J
authors.initials: JJ
authors.lastname: McElroy
authors.forename: Kari
authors.initials: K
authors.lastname: Teramo
authors.forename: Ingrid
authors.initials: I
authors.lastname: Borecki
authors.forename: Justin C
authors.initials: JC
authors.lastname: Fay
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D002888:Chromosomes, Human, Pair 19; D019143:Evolution, Molecular; D054513:Group IV Phospholipases A2 / Q000235:genetics*; D006801:Humans; D007438:Introns; D016254:Mutagenesis, Insertional; D036801:Parturition / Q000235:genetics*; D010802:Phylogeny; D047928:Premature Birth / Q000208:ethnology / Q000235:genetics*; D011323:Primates / Q000235:genetics* / Q000502:physiology; D011453:Prostaglandins / Q000096:biosynthesis
chemical_list: D011453:Prostaglandins; C472331:PLA2G4C protein, human; D054513:Group IV Phospholipases A2