Research article

Identification of polymorphisms and balancing selection in the male infertility candidate gene, ornithine decarboxylase antizyme 3

Greg L Christensen^1,2 , Ivaylo P Ivanov³ , Stephen P Wooding³ , John F Atkins^3,4 , Anna Mielnik⁵ , Peter N Schlegel^5,6 and Douglas T Carrell^1,2

¹  Andrology and IVF Laboratories, University of Utah School of Medicine, Salt Lake City, UT, USA

²  Department of Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA

³  Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA

⁴  Biosciences Institute, University College, Cork, Ireland

⁵  Department of Urology, Weil Medical College of Cornell University, New York, NY, USA

⁶  Center for Biomedical Research, The Population Council, New York, NY, USA

author email corresponding author email

BMC Medical Genetics 2006, 7:27doi:10.1186/1471-2350-7-27

Published:	16 March 2006

Abstract

Background

The antizyme family is a group of small proteins that play a role in cell growth and division by regulating the biosynthesis of polyamines (putrescine, spermidine, spermine). Antizymes regulate polyamine levels primarily through binding ornithine decarboxylase (ODC), an enzyme key to polyamine production, and targeting ODC for destruction by the 26S proteosome. Ornithine decarboxylase antizyme 3 (OAZ3) is a testis-specific antizyme paralog and the only antizyme expressed in the mid to late stages of spermatogenesis.

Methods

To see if mutations in the OAZ3 gene are responsible for some cases of male infertility, we sequenced and evaluated the genomic DNA of 192 infertile men, 48 men of known paternity, and 34 African aborigines from the Mbuti tribe in the Democratic Republic of the Congo. The coding sequence of OAZ3 was further screened for polymorphisms by SSCP analysis in the infertile group and an additional 250 general population controls. Identified polymorphisms in the OAZ3 gene were further subjected to a haplotype analysis using PHASE 2.02 and Arlequin 2.0 software programs.

Results

A total of 23 polymorphisms were identified in the promoter, exons or intronic regions of OAZ3. The majority of these fell within a region of less than two kilobases. Two of the polymorphisms, -239 A/G in the promoter and 4280 C/T, a missense polymorphism in exon 5, may show evidence of association with male infertility. Haplotype analysis identified 15 different haplotypes, which can be separated into two divergent clusters.

Conclusion

Mutations in the OAZ3 gene are not a common cause of male infertility. However, the presence of the two divergent haplotypes at high frequencies in all three of our subsamples (infertile, control, African) suggests that they have been maintained in the genome by balancing selection, which was supported by a test of Tajima's D statistic. Evidence for natural selection in this region implies that these haplotypes may be associated with a trait other than infertility. This trait may be related to another function of OAZ3 or a region in tight linkage disequilibrium to the gene.