Diet Trumping Genes
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.
Sources for this report are posted on ISIS members’ website. Full details here
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.
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