Biomedical subjects
Stephen P Wooding
Publications and source records attributed to Stephen P Wooding.
Identification of polymorphisms and balancing selection in the male infertility candidate gene, ornithine decarboxylase antizyme 3.
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.
Sequencing and haplotype analysis of the activator of CREM in the testis (ACT) gene in populations of fertile and infertile males.
cAMP-responsive element modulator (CREM) is a key transcription factor in the differentiation of round spermatids into mature spermatozoa. During spermiogenesis, CREM is regulated in part by activator of CREM in the testis (ACT), which activates CREM in a phosphorylation-independent fashion. We hypothesized that the ACT gene, which is expressed exclusively in the testis, could be involved in male factor infertility in patients with idiopathic-impaired spermatogenesis. To test this hypothesis, we sequenced the coding regions and flanking intronic regions of the ACT gene in 96 azoo- or oligospermic patients and 69 fertile controls. A total of 12 single-nucleotide polymorphisms (SNPs) was identified, and four of them leading to amino acid substitutions. An association study was performed based on calculated haplotype frequencies, and statistically significant differences were found between the patient and control populations for some haplotypes. To help establish the evolutionary relationships between the haplotypes, the coding regions of both the chimpanzee and the gorilla ACT gene were sequenced and evaluated. To test whether the different haplotypes conferred a functional change to the ACT protein, a yeast two-hybrid assay was designed to test the interaction between the two most divergent ACT haplotypes and their known binding partners, CREM and KIF17b. We identified one ACT haplotype that had a 45% reduction in its interaction with CREM. Our results suggest that different haplotypes within the ACT gene may contribute to male factor subfertility.
Genetic variation, classification and 'race'.
New genetic data has enabled scientists to re-examine the relationship between human genetic variation and 'race'. We review the results of genetic analyses that show that human genetic variation is geographically structured, in accord with historical patterns of gene flow and genetic drift. Analysis of many loci now yields reasonably accurate estimates of genetic similarity among individuals, rather than populations. Clustering of individuals is correlated with geographic origin or ancestry. These clusters are also correlated with some traditional concepts of race, but the correlations are imperfect because genetic variation tends to be distributed in a continuous, overlapping fashion among populations. Therefore, ancestry, or even race, may in some cases prove useful in the biomedical setting, but direct assessment of disease-related genetic variation will ultimately yield more accurate and beneficial information.
Signatures of natural selection in the human genome.
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