Ancestral origin of variation in the triosephosphate isomerase gene promoter

Abstract

A high frequency of nucleotide substitutions -5A/G, -8G/A, -24T/G in the triosephosphate isomerase (TPI) gene promoter has been demonstrated in African-Americans. The biological significance of these promoter variants, two of which, -8G/A and -24T/G, occur within regulatory elements essential for transcription, is controversial. The geographical distribution and frequency of allelic variation in the TPI promoter was determined in 378 unrelated normal subjects from sub-Saharan African (n = 103), Caribbean (n = 26), Northern European (n = 57), Mediterranean (n = 55), Middle Eastern (n = 42), Asian Indian (n = 48) and Oriental (n = 47) populations. Five haplotypes were identified: the common haplotype, -5A-8G-24T, -5G, -8A, -5G-8A, and -5G-8A-24G. All, with the exception of the -8A haplotype, were present in geographically dispersed populations. The -5G allele, which was found at varying frequency in all groups, has attained high frequency in the African, Caribbean and Oriental populations. Phylogenetic comparison suggests this may represent the ancestral promoter haplotype. Homozygosity for the -5G-8A haplotype identified in four subjects confirms that these variants are not responsible for a null allele as formerly postulated. Linkage disequilibrium between related TPI promoter haplotypes, -5G, -5G-8A and -5G-8A-24G, and a single nucleotide polymorphism at nt2262 of the TPI gene supports a single ancestral origin for these mutations which precedes the separation of African and non-African populations.

Triosephosphate isomerase deficiency: Facts and doubts

“…These mutations, especially the -5A/G, occurred with high frequency in populations of Sub-Saharan origin but did not occur in Caucasians. Detailed investigation has revealed the high frequency of -5A/G change in Asian populations as well (17), suggesting this is single nucleotide polymorphism. This conclusion is supported by the finding of a G at the -5 position in the chimpanzee (18) and the fact that -5G polymorphism has no detectable effect on erythrocyte TPI activity (16).…”

Triosephosphate isomerase gene promoter variation: -5G/A and -8G/A polymorphisms in clinical malaria groups in two African populations

“…Schneider et al (1998) suggest that the association between the high prevalence of polymorphisms and moderate reduction of enzyme activity may result from a selective advantage for survival. On the other hand, Humphries et al (1999a), based on the high allelic variation at CD4 locus among the TPI1 promoter variants and the loss of LD between CD4 and TPI1 promoter haplotypes, suggested that the haplotype diversification precedes the separation between African and non-African populations that occurred about 100,000 years ago (Flint et al, 1993).…”

“…For the -5 locus the -5G was considered as the ancestral allele because it was the most common allele found in non-human primates (chimpanzee) (http://www. ensembl.org) (Humphries et al, 1999a). Estimates of mutation age for the TPI1 promoter variants, -5G > A and -8G > A, based on CD4 and ATN1 microsatellites are depicted in Table 5.…”

“…However, while the -5G minor allele has global geographical distribution and has attained high frequency in African, Caribbean and Oriental populations, the -8A minor allele had been found in geographically dispersed populations, being more frequent in individuals of African origin (Humphries et al, 1999a;Manco et al, 2009). Humphries et al (1999a) reported that -5G and associated haplotypes were found to be in linkage disequilibrium (LD) with an intragenic polymorphism at nucleotide 2262 in intron 5 (Arya et al, 1997), which could be indicative of a common ancestral origin.…”

“…However, while the -5G minor allele has global geographical distribution and has attained high frequency in African, Caribbean and Oriental populations, the -8A minor allele had been found in geographically dispersed populations, being more frequent in individuals of African origin (Humphries et al, 1999a;Manco et al, 2009). Humphries et al (1999a) reported that -5G and associated haplotypes were found to be in linkage disequilibrium (LD) with an intragenic polymorphism at nucleotide 2262 in intron 5 (Arya et al, 1997), which could be indicative of a common ancestral origin. Schneider et al (1998) suggests that the high incidence of these TPI1 promoter polymorphisms in African-origin populations, associated to a reduced enzyme activity, may have resulted from some selective advantage for survival similarly to glucose-6-phosphate dehydrogenase (G6PD) deficient variants (Luzzatto, 2006) and pyruvate kinase (PK) deficient variants (Machado et al, 2010(Machado et al, , 2012 and hemoglobin polymorphisms (HbS) (Fleming et al, 1979).…”