Different reports show that the prevalence of the 677C>T polymorphism of the MTHFR gene differs dramatically among human populations. Evidence of this dynamism can be observed in many reports: frequency variations between populations that are geographically very close, even in the same country [8]; changes found in the same race or ethnic group such as Africans [10, 11] and African-Americans [12]; the high prevalence of the 677C>T poymorphism in populations with special nutritional features such as Mexicans [9] and Japanese [13]; and changes in frequencies between generations of the same population, as has been observed in Spain [5], Switzerland [6] and Japan [7].

There are numerous interpretations of this great diversity, and most tend to be related to adaptation to external conditions such as climate or nutritional status. Dependence of folate degradation on skin pigmentation [17], nutritional habits or human intervention periconceptional periods could explain this genetic variation. Definitely, external factors in combination with different levels of MTHFR enzyme activity, conditioned by polymorphisms, could influence the fetal viability of certain genotypes.

In 1998, we suggested the possibility of genetic selection in Spain in favor of the mutants of the 677C>T polymorphism in the MTHFR gene based on the fact that treatment with vitamins and folates during pregnancy increased the viability of fetuses with the TT homozygous genotype. This hypothesis was based on the increase in the number of mutated individuals found in our population since the mid-1970s [5] and the coincident increased intake of vitamins and folate by pregnant women in Spain [18, 19]. In 2002, a new study found changes in genotype frequencies for the 677C>T and 1298A>C polymorphisms in different age groups. Total homocysteine (tHcy) levels in plasma were also analyzed according to the different genotype interactions [20]. That study hypothesized about fetal viability and about a genetic selection model on the basis of non-linkage disequilibrium between both polymorphisms. Recently, a study with fetal and control populations showed the strong influence of these polymorphisms, though mainly of the 677C>T polymorphism, on spontaneous early abortion [21]. In the present study, significant changes in allelic and genotypic frequencies are detected, as is Hardy-Weinberg disequilibrium, at the 677C>T polymorphism. We hypothesize that there is a dynamic process of genetic selection that favors the T allele. This process of selection started during the last quarter of the 20th century, during which the frequency for mutant homozygous (TT) rose significantly from 14% to 24%. We propose that this increase in mutants is due to the inclusion of an external factor that enhances mutant fetal viability.

If we apply the mathematical model for dynamic selection developed for diploid organisms with sexual reproduction, the T allele could reach to 90% in seven generations in our population (Figure 1A). However, this model assumes selection in a constant environment that applies to all individuals in the population studied. In our case, we suggest that the external factor is related to an increase in folate and vitamin intake in women in periconceptional period and does not affect to all individuals [18, 19]. We assume that prediction of a classic selection model in this case is only theoretical.

On the basis of a competition between alleles in which an environmental factor favors one allele versus the other, the final result would be that predicted by the previous mathematical model. However in this case, the environment is not selecting against the wild type allele but rather allowing the survival of more mutated alleles. Therefore, the expected result would be not a systematic increase of the mutated allele but the creation of an allelic balance dependent on vitamin and folate abundance conditions. In this case, the mutation would have a lower influence on fetal viability (Figure 1B).

The results showed an increase in mutated genotypes (CT and TT) and a strong protection against abortion by the wild type genotype (CC), which is practically non-existent in the SA group. The frequency of the CC genotype shows no change over the decade studied (1980–1989), which indicates that folate does not exert a visible effect on this genotype. However, the frequency of the mutated allele increases during this decade, especially in fetuses from abortions, and this increase correlated with the increase of the T allele in the control population. This finding suggests that the effect of folate is crucial to viability during the early stages of embryonic development, but, even with folate, not all embryos will survive until birth.

In this population, the mutant allele with lower enzymatic activity has higher fitness than the wild type. In the folate cycle, it can be observed that 5,10-methyleneTHF availability may be important. 5,10-methyleneTHF is the substrate for several reactions in the cycle, but two of them (5-methylTHF and thymidilate synthesis) might be essential for embryo development in folate deficiency conditions.

In both cases, complete or limited MTHFR activity will produce higher or lower 5,10-methyleneTHF availability, which might be an essential factor for embryo development, such that a greater folate levels can compensate the lower enzymatic activity of the mutant.

The implications of this polymorphism in nucleotide synthesis have not yet been determined, but certain data, such as high levels of uric acid found in mutated subjects [22, 23], suggest that there are different turnover rates associated with different polymorphisms.