Abstract
BackgroundThere are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine. Since many selenoproteins have antioxidant properties, it is plausible that inter-individual differences in selenoprotein expression or activity could influence risk for a range of complex diseases, such as cancer, infectious diseases as well as deleterious responses to oxidative stressors like cigarette smoke. To capture the common genetic variants for 6 important selenoprotein genes (GPX1, GPX2, GPX3, GPX4, TXNRD1, and SEPP1) known to contribute to antioxidant host defenses, a re-sequence analysis was conducted across these genes with particular interest directed at the coding regions, intron-exon borders and flanking untranslated regions (UTR) for each gene in an 102 individual population representative of 4 major ethnic groups found within the United States.ResultsFor 5 of the genes there was no strong evidence for selection according to the expectations of the neutral equilibrium model of evolution; however, at the GPX1 locus (3p21) there was evidence for positive selection. Strong confirmatory evidence for recent positive selection at the genomic region 3p21 in Asian populations is provided by data from the International HapMap project.ConclusionThe SNPs and fine haplotype maps described in this report will be valuable resources for future functional studies, for population specific genetic studies designed to comprehensively explore the role of selenoprotein genetic variants in the etiology of various human diseases, and to define the forces responsible for a recent selective sweep in the vicinity of the GPX1 locus.
Highlights
There are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine
Polymorphism analysis Six selenoprotein genes (GPX1, GPX2, GPX3, GPX4, SEPP1 and thioredoxin reductase 1 (TXNRD1)) were re-sequenced using the SNP500 polymorphism discovery resource (Table 1), a panel of 102 DNA samples obtained from lymphoblastoid cell lines from 4 ethnically diverse control groups, Caucasian (CA, n = 31), African American (AA, n = 24), Pacific Rim/Asian (PR, n = 24), and Hispanic (HI, n = 23)
EFsigtiumraete2s for linkage disequilibrium (LD) and location of major haplotype blocks across 6 selenoprotein loci Estimates for linkage disequilibrium (LD) and location of major haplotype blocks across 6 selenoprotein loci
Summary
There are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine. It is possible that functional polymorphisms in selenoprotein genes might influence selenoenzyme expression, stability or activity modifying disease outcomes in a manner similar to that observed with selenium deficiency. The 6 genes selected for re-sequencing in this project play an important role in antioxidant defense; they include selenoprotein P (SEPP1), thioredoxin reductase 1 (TXNRD1), and 4 selenium containing glutathione peroxidase genes, GPX1, GPX2, GPX3 and GPX4 [6,7,8]. SEPP1 is a secreted protein that likely functions as a selenium delivery molecule and perhaps as an extracellular antioxidant with glutathione peroxidase-like activity [24]. Cytosolic thioredoxin reductase (TXNRD1) is one of the most abundant selenium-containing proteins and is able to catalyze the reduction of thioredoxin in a reaction that uses electrons from NADPH [27]. It's expression may be regulated in a contrasting pattern to GPX1 in certain cancer systems and disruption of its expression may reverse the phenotype and carcinogenicity of lung cancer cells [28]
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