Most geneticists are still focussing on gene sequences to find out which gene variants go with which diseases. But that's a serious mistake, and for more reasons than one. Dr. Mae-Wan Ho reports.
Evidence is accumulating that environmental factors, like diet, stress and maternal nutrition, can change gene function epigenetically, i.e., without altering the DNA sequence. These factors have been shown to play a role in cancer, stroke, diabetes, schizophrenia, manic depression and other diseases, as well as in shaping behaviour in offspring.
Prenatal and early nutrition can indeed affect people's susceptibility to chronic diseases later on in life; and the effects can persist through successive generations. This goes counter to the intuition of most geneticists, and the molecular mechanisms involved remain largely unknown.
One theory is that it has to do with patterns of gene expression in the genome, which are 'reprogrammed' in the early embryo, when chemical modifications of the DNA takes place, determining patterns of gene expression that become maintained thereafter.
A common modification involves adding a methyl group (CH3-) to CpG (cytosine-guanine) dinucleotides in the DNA of promoters (gene switches necessary for gene expression), which silences the genes occurring downstream. The metabolic intermediate donating the methyl group to CpG is S-adenosylmethionine; and its availability will be influenced by dietary intake of methyl-donors and other co-factors necessary for its synthesis. That may be one way early nutrition can affect adult propensity to disease.
Patterns of DNA methylation are in part determined by transposable elements - mobile genetic units - scattered throughout the human genome, making up more than 35% of the genome. Most transposons are silenced by methylation, but a subset of them is metastable (not quite stable), and can change in methylation, thereby affecting the expression of nearby genes.
Two researchers in the Department of Radiation Oncology, Duke University Medical Center in Durham, USA, suspected that the epigenetic instability of these transposons make them targets for nutritional influence during early development, and designed a test using a strain of yellow agouti (Avy) mice.
The agouti gene encodes a signalling molecule that causes hair-forming cells to switch from producing black melanin to yellow phaeomelanin. Transcription of the gene is initiated from a hair-cycle specific promoter in exon 2 of the agouti (A) allele (variant of the gene). Transient agouti expression in hair follicles during a specific stage of hair growth results in a yellow band on each hair just below the tip, giving the brown (agouti) coat colour of wild-type mice. The nonagouti (a) allele is due to loss of function of the A allele, so a/a homozygotes are black.
The Avy allele of the yellow agouti mice results from the insertion of a retrotransposon into the tail end of the A allele, which causes alternative initiation of transcription from a promoter in the retrotransposon. This results in a wide variation in individual coat colour, which is associated with degree of obesity, glucose tolerance and susceptibility to tumours among littermates that are all heterozygous Avy/a. This was a sign of epigenetic instability.
Previous research had shown that dietary supplements promoting methylation of a/a pregnant mothers shifted the coat colour distribution of the Avy/a offspring, and that the coat colour correlated with the methylation of Avy, suggesting that the dietary supplement altered the coat colour through changing the methylation of Avy.
In a study published in Molecular and Cellular Biology, August 2003, virgin a/a (black) females, 8 weeks of age, were assigned randomly to be fed a control diet or a diet supplemented with the methyl donors and cofactors: folic acid, vitamin B12, choline chloride and anhydrous betaine for two weeks before the females were mated with Avy/a males, and continued throughout pregnancy and lactation. On weaning at age 21 days, the Avy/a offspring were weighed, a sample of DNA taken from the tips of their tail, and the mice photographed, and rated for coat colour.
The coat colour of the offspring ranged from yellow, to slight mottled, mottled, heavily mottled and pseudoagouti (for colour that was almost the same as agouti, indicating the almost complete silencing of the Avy agouti gene expression). The results cleared showed a significant increase in proportions of heavily mottled and pseudoagouti and a significant decrease in proportions of yellow and slightly mottled offspring from mothers given dietary methyl supplements compared to offspring from mothers fed the control diet.
The coat colours were strongly correlated with degree of methylation of the Avy allele associated with the retrotransposon insertion, increasing from 5% or less in yellow, to 10 to 20% in slightly mottled, 25-40% in mottled, 65 to 75% in heavily mottled and 85 to 95% in pseudoagouti.
When these mice produced the next generation the epigenetic effect will persist, so yellow females will tend to produce fewer pseudoagouti offspring than pseudoagouti females. This maternal effect is thought to be due to incomplete erasing of the epigenetic modification at the Avy gene in the female germ line.
This research underlines the importance of maternal nutrition on the long-term health prospects of their offspring. Previous research has already shown that severe methyl donor deficiency (of folic acid) induced gene-specific DNA hypomethylation in rats as well as DNA breaks. The new results show that merely supplementing a mother's diet with extra folic acid, vitamin B12, choline and betaine can also permanently affect the offspring's DNA. The researchers commented, "This finding supports the conjecture that population-based supplementation with folic acid, intended to reduce the incidence of neural tube defects, may have unintended influences on the establishment of epigenetic gene-regulatory mechanisms during human embryonic development."
What it means is that dietary supplements can have unintended effects on gene expression. But in this particular case, while dietary deficiency had been shown to be harmful, no harmful unintended effects have resulted from dietary supplements.
On the contrary, according to a report published in October in the New York Times, another effect of the supplements, pointedly not mentioned in the scientific paper, is that the yellow mice with the active Avy allele, are also obese, while the pseudoagouti mice with the same gene turned off by methylation, are lean and healthy. And obese yellow mothers given the supplements gave birth to healthy brown mice.
Dr. Randy Jirtle, Professor of radiation oncology in Duke University and the lead researcher of the latest scientific paper, was quoted as saying, "Scientists have long known that what pregnant mother eat - whether they are mice, fruit flies or humans - can profoundly affect the susceptibility of their offspring to disease. But until now they have not understood why."
Dr. Thomas Insel, director of the National Institute of Mental Health, remarked that these epigenetic effects could turn out to be much more important than the sequences of genes that most geneticists are still focused on. "The field is revolutionary," he said, "and humbling."
Dr. Arturas Petonis, an associate professor of psychiatry at the Center for Adiction and Mental Health at the University of Toronto, also believes epigenetics may hold the answer to many mysteries that are baffling to classical genetics: why does one identical twin develop schizophrenia and not the other? Why do certain disease genes affect some people much more than others? Why do diseases like autism turn up more frequently in boys than girls?
It now appears that stresses to germ cells and embryos associated with assisted reproductive technologies are also turning up similar epigenetic effects in 'gene imprinting' that have both immediate and long term impacts on the health of the unborn (see "What' wrong with assisted reproductive technologies?" to appear).
Not just gene expression is modifiable by environmental factors. We at ISIS have documented how toxic environmental agents can shuffle genes and cause chronic illnesses (see Health and the fluid genome mini-series, SiS 19 ).
Isn't it time we leave genetic determinism well behind and concentrate on cleaning up our environment and providing healthy nutrition to all, especially for mothers.
For more on exposing the myth of genetic determinism, read Living with the Fluid Genome (link here).
Article first published 22/10/03
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