Open Access Research article

Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth

Jevon Plunkett12, Scott Doniger3, Thomas Morgan14, Ritva Haataja5, Mikko Hallman5, Hilkka Puttonen6, Ramkumar Menon78, Edward Kuczynski9, Errol Norwitz9, Victoria Snegovskikh9, Aarno Palotie10111213, Leena Peltonen101112, Vineta Fellman1415, Emily A DeFranco16, Bimal P Chaudhari17, John Oates18, Olivier Boutaud18, Tracy L McGregor1, Jude J McElroy1, Kari Teramo6, Ingrid Borecki19, Justin C Fay20 and Louis J Muglia121*

Author affiliations

1 Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

2 Human and Statistic Genetics Program, Washington University School of Medicine, St. Louis, MO 63110, USA

3 Computational Biology Program, Washington University School of Medicine, St. Louis, MO 63108, USA

4 Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

5 Institute of Clinical Medicine, Department of Pediatrics, University of Oulu, Oulu 90014, Finland

6 Departments of Obstetrics and Gynecology, University Central Hospital, Helsinki 00290, Finland

7 The Perinatal Research Center, Nashville, TN 37203

8 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA

9 Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA

10 Biomedicum Helsinki Research Program in Molecular Medicine, University of Helsinki, Helsinki 00290, Finland

11 The Finnish Genome Center, University of Helsinki, Helsinki 00290, Finland

12 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

13 Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK

14 Department of Pediatrics, Lund University, Lund 22185, Sweden

15 Department of Pediatrics, University of Helsinki, Helsinki 00290, Finland

16 Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA

17 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA

18 Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN 37232, USA

19 Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108, USA

20 Department of Genetics and Center for Genome Sciences, Washington University School of Medicine, St. Louis, MO 63108, USA

21 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, and Vanderbilt Kennedy Center for Human Development, Vanderbilt University, Nashville, TN 37232, USA

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Citation and License

BMC Medical Genomics 2010, 3:62  doi:10.1186/1755-8794-3-62

Published: 24 December 2010

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.