Abstract
Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamine-N-methyltransferase (PEMT) rs12325817. Evidence of negative selection was assessed in 2 populations: one in The Gambia, West Africa, where there is historic evidence of a choline-poor diet, and the other in the United States, with a comparatively choline-rich diet. We used 2 independent methods, and confirmation of our hypothesis was sought via a comparison with SNP data from the Maasai, an East African population with a genetic background similar to that of Gambians but with a traditional diet that is higher in choline. Our results show that frequencies of SNPs known to increase dependence on dietary choline are significantly reduced in the low-choline setting of The Gambia. Our findings suggest that adequate intake levels of choline may have to be reevaluated in different ethnic groups and highlight a possible approach for identifying novel functional SNPs under the influence of dietary selective pressure.—Silver, M. J., Corbin, K. D., Hellenthal, G., da Costa, K.-A., Dominguez-Salas, P., Moore, S. E., Owen, J., Prentice, A. M., Hennig, B. J., Zeisel, S. H. Evidence for negative selection of gene variants that increase dependence on dietary choline in a Gambian cohort.
Highlights
Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamineN-methyltransferase (PEMT) rs12325817
Our results show that frequencies of SNPs known to increase dependence on dietary choline are significantly reduced in the low-choline setting of The Gambia
The model assumes that the 3 populations originate from a common ancestral population, equivalent to a tree merging the 3 groups via 2 internal nodes, with SNP allele frequencies changing from generation to generation, as they are subject to processes of random drift
Summary
Genetic variation plays a role, and 3 functional single-nucleotide polymorphisms (SNPs) in particular are known to increase dependence on dietary choline. Premenopausal female carriers of the T allele of CHDH rs12676 (a nonsynonymous coding SNP) have greater dependence on dietary choline [3]. In men, this allele is associated with lower sperm CHDH protein levels [14]. This allele is associated with lower sperm CHDH protein levels [14] Individuals with this SNP need more choline precursor to drive production of this reaction’s product, betaine, which is necessary for methylation reactions.
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