Elsevier

Nutrition Research

Volume 23, Issue 11, November 2003, Pages 1463-1475
Nutrition Research

A critical role for B-vitamin nutrition in human developmental and evolutionary biology

https://doi.org/10.1016/S0271-5317(03)00156-8Get rights and content

Abstract

Several molecular mechanisms that underpin genomic integrity and function are sensitive to B-vitamin status, and in particular, are responsive to the interaction between folate nutrition and folate dependent enzyme polymorphisms. Mechanisms that may be affected include maintenance of genomic CpG methylation patterns for regulated gene expression, and proficient synthesis of nucleotides to prevent DNA strand breakage. We review some of these important molecular mechanisms that underpin the role of folate and other B-vitamins in disease processes, and discuss how they explain why this vitamin may be an important factor in human evolution. We look at three particular phenomena that link folate status/genes to evolutionary pressures: 1) The evolution of pigmentation to avert the impact of UV light on labile folates needed for developmental processes. 2) The effect of C677T-MTHFR on foetal survival, and 3) the ability of folate to mask harmful developmental mutations.

Introduction

Few nutrients compare with folate and related B-vitamins for their impact on health. Indeed, the ancient precept “Let food be thy medicine and medicine be thy food” could not be more appropriate than when applied to this group of essential micronutrients. Although scientists are slowly becoming aware of the incredible breadth of involvement that folate has in critical life processes, few are aware of the likely role that folate nutrition and variants of folate dependent enzymes have in the evolutionary process. We provide a brief review of the molecular mechanisms that underpin the role of folate in disease processes, and show that some of these same mechanisms could explain why this vitamin may be an important factor in evolution. In addition, we present further experimental data to support this postulate, and to help provide an integrated and compelling argument for the importance of folate and related B-vitamins in the evolution of man.

Folate, vitamin B12, niacin (B3), pyridoxal phosphate (B6) and riboflavin (B2) are members of the B-group of vitamins that until recently were only of interest in the context of overt deficiency diseases such as anaemia and pellagra, or in generalised deficiency conditions where tissues that have a high cell turnover and increased energy demand (i.e. hematopoietic cells, skin, gut, nerve) show a distinct pathology. Recent research has changed this.

Section snippets

Molecular mechanisms

Folate in particular, plays several fundamental and direct roles in the synthesis, repair and expression of DNA [1], [2], while vitamins B2, B6 and B12 play a significant, but lesser role in these same epigenetic phenomena (see Fig. 1). Vitamin B3 as NAD+ acts as sole substrate for poly (ADP-ribose) polymerase-1 (PARP), which is required for cell differentiation, DNA repair, -expression and apoptosis [3]. However, NAD+ is also required as cofactor in nucleotide synthesis, and is co-substrate

Folate and evolution

Clearly, any role of folate in modulating risk for degenerative diseases like cancer, vascular disease or Alzheimer's cannot be considered a selection pressure in driving human evolution. However, at least three phenomena may well link folate metabolism to the evolutionary process.

Conclusion

Clearly, even within a single variant folate gene such as C677T-MTHFR, pleiotropism that stems from the central role of 5,10-methylene-H4folate in several critical biosynthetic pathways leads to either positive or negative modulation in the risk for both developmental and degenerative disorders (depending on folate nutritional status), and likely, by the same mechanisms, influences in utero survival, and hence human evolution.

It is not clear, however, whether folate nutrigenomics affect foetal

Acknowledgements

We acknowledge support provided by ASBAH, The Patrick Berthoud Charitable Trust, The British Heart Foundation and Cerebra.

References (62)

  • I.J. Perry et al.

    Prospective study of serum total homocysteine concentrations and risk of stroke in middle aged British men

    Lancet

    (1995)
  • M. Petri et al.

    Plasma homocysteine as a risk factor for atherothrombotic events in systematic lupus erythematosus

    Lancet

    (1996)
  • L. Brattstrom et al.

    Homocysteine and cardiovascular diseasecause or effect?

    Am J Clin Nutr

    (2000)
  • C.A. Hobbs et al.

    Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down Syndrome

    Am J Hum Genet

    (2000)
  • A. Wilson et al.

    A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida

    Molecular Genetics and Metabolism

    (1999)
  • M.D. Lucock et al.

    Nonenzymatic degradation and salvage of dietary folatePhysicochemical factors likely to influence bioavailability

    Biochemical and Molecular Medicine

    (1995)
  • N. Blau et al.

    Tetrahydrobiopterin deficiencies without hyperphenylalaninemiadiagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency

    Mol Genet Metab

    (2001)
  • M. Lucock et al.

    The impact of phenylketonuria on folate metabolism

    Molecular Genetics and Metabolism

    (2002)
  • N.G. Jablonski et al.

    The evolution of human skin coloration

    Hum Evol

    (2000)
  • M. Lucock et al.

    An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy

    Molecular Genetics and Metabolism

    (2001)
  • P.A. Isotalo et al.

    Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphismsan examination of C677T and A1298C mutations

    Am J Hum Genet

    (2000)
  • E. Munoz-Moran et al.

    Genetic selection and folate intake during pregnancy

    Lancet

    (1998)
  • W.L. Nelen et al.

    Genetic risk factor for unexplained recurrent early pregnancy loss

    Lancet

    (1997)
  • M.G. Wouters et al.

    Hyperhomocysteinemiaa risk factor in women with unexplained recurrent early pregnancy loss

    Fertil Steril

    (1993)
  • N. Rosenberg et al.

    The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans

    Am J Hum Genet

    (2002)
  • R.A. Hegele et al.

    V677 mutation of methylenetetrahydrofolate reductases and cardiovascular disease in Canadian Inuit

    Lancet

    (1997)
  • G. Pepe et al.

    Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10-methylenetetrahydrofolate reductase

    Am J Hum Genet

    (1998)
  • M. Fenesch

    Micronutrients and genomic stabilitya new paradigm for recommended dietary allowances (RDA)

    Food Chem Toxicol

    (2002)
  • J.L. Mills et al.

    Methylenetetrahydrofolate reductase thermolabile variant and oral cleft

    Am J Med Genet

    (1999)
  • D. Roberts et al.

    Clotting and hemorrhage in the placenta–a delicate balance

    N Engl J Med

    (2002)
  • M.D. Lucock et al.

    A differential role for folate in developmental disorders, vascular disease and other clinical conditionsThe importance of folate status and genotype

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