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Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

Alexander Semmler12, Susanna Moskau2, Holger Lutz2, Peter Meyer3 and Michael Linnebank12*

Author Affiliations

1 Department of Neurology, University Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland

2 Department of Neurology, University Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany

3 Institute of Molecular Medicine, Sperberstr. 2, 81827 Munich, Germany

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BMC Research Notes 2011, 4:439  doi:10.1186/1756-0500-4-439

Published: 24 October 2011



The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G.


Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele.


Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.