A Pregnant Mother's Diet May Turn the Genes Around
With the help of some fat yellow mice, scientists have
discovered exactly how a mother's diet can permanently
alter the functioning of genes in her offspring without
changing the genes themselves.
The unusual strain of mouse carries a kind of trigger near
the gene that determines not only the color of its coat but
also its predisposition to obesity, diabetes and cancer.
When pregnant mice were fed extra vitamins and supplements,
the supplements interacted with the trigger in the fetal
mice and shut down the gene. As a result, obese yellow
mothers gave birth to standard brown baby mice that grew up
Scientists have long known that what pregnant mothers 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, said
Dr. Randy Jirtle, a professor of radiation oncology at Duke
and senior investigator of the study, which was reported in
the Aug. 1 issue of Molecular and Cellular Biology.
The research is a milestone in the relatively new science
of epigenetics, the study of how environmental factors like
diet, stress and maternal nutrition can change gene
function without altering the DNA sequence in any way.
Such factors have been shown to play a role in cancer,
stroke, diabetes, schizophrenia, manic depression and other
diseases as well as in shaping behavioral traits in
Most geneticists are focusing on sequences of genes in
trying to understand which gene goes with which illness or
behavior, said Dr. Thomas Insel, director of the National
Institute of Mental Health. "But these epigenetic effects
could turn out to be much more important. The field is
revolutionary," he said, "and humbling."
Epigenetics may indeed hold answers to many mysteries that
classical genetic approaches have been unable to solve,
said Dr. Arturas Petronis, an associate professor of
psychiatry at the Center for Addiction and Mental Health at
the University of Toronto.
For example, why does one identical twin develop
schizophrenia and not the other? Why do certain disease
genes seem to affect or "penetrate" some people more than
others? Why do complex diseases like autism turn up in more
For answers, epigeneticists are looking at biological
mechanisms other than mutation that affect how genes
function. One, called methylation, acts like a gas pedal or
brake. It can turn gene expression up or down, on or off,
depending on how much of it is around and what part of the
genetic machinery it affects.
During methylation, a quartet of atoms called a methyl
group attaches to a gene at a specific point and induces
changes in the way the gene is expressed.
The process often inactivates genes not needed by a cell.
The genes on one of the two X chromosomes in each female
cell are silenced by methylation.
Methyl groups and other small molecules may sometimes
attach to certain spots on chromosomes, helping to relax
tightly coiled strands of DNA so that genes can be
Sometimes the coils are made tighter so that active genes
Methyl groups also inactivate remnants of past viral
infections, called transposons. Forty percent of the human
genome is made up of parasitic transposons.
Finally, methyl groups play a critical role in controlling
genes involved in prenatal and postnatal development,
including some 80 genes inherited from only one parent.
Because these so-called imprinted genes must be methylated
to function, they are vulnerable to diet and other
When a sperm and egg meet to form an embryo, each has a
different pattern of methylated genes. The patterns are not
passed on as genes are, but in a chemical battle of the
sexes some of the egg and sperm patterns do seem to be
inherited. In general, the egg seems to have the upper
"We're compounds, mosaics of epigenetic patterns and gene
sequences," said Dr. Arthur Beaudet, chairman of the
molecular and human genetics department at Baylor College
of Medicine in Houston. While DNA sequences are commonly
compared to a text of written letters, he said, epigenetics
is like the formatting in a word processing program.
Though the primary letters do not vary, the font can be
large or small, Times Roman or Arial, italicized, bold,
upper case, lower case, underlined or shadowed. They can be
any color of the rainbow.
Methylation is nature's way of allowing environmental
factors to tweak gene expression without making permanent
mutations, Dr. Jirtle said.
Fleeting exposure to anything that influences methylation
patterns during development can change the animal or person
for a lifetime. Methyl groups are entirely derived from the
foods people eat. And the effect may be good or bad.
Maternal diet during pregnancy is consequently very
important, but in ways that are not yet fully understood.
For his experiment, Dr. Jirtle chose a mouse that happens
to have a transposon right next to the gene that codes for
coat color. The transposon induces the gene to overproduce
a protein that turns the mice pure yellow or mottled yellow
and brown. The protein also blocks a feeding control center
in the brain. Yellow mice therefore overeat and tend to
develop diabetes and cancer.
To see if extra methylation would affect the mice, the
researchers fed the animals a rich supply of methyl groups
in supplements of vitamin B12, folic acid, choline and
betaine from sugar beets just before they got pregnant and
through the time of weaning their pups. The methyl groups
silenced the transposon, Dr. Jirtle said, which in turn
affected the adjacent coat color gene. The babies, born a
normal brownish color, had an inherited predisposition to
obesity, diabetes and cancer negated by maternal diet.
Unfortunately the scientists do not know which nutrient or
combination of nutrients silence the genes, but noted that
it did not take much. The animals were fed only three times
as much of the supplements as found in a normal diet.
"If you looked at the mouse as a black box, you could say
that adding these methyl-rich supplements to our diets
might reduce our risk of obesity and cancer," Dr. Jirtle
said. But, he added, there is strong reason for caution.
The positions of transposons in the human genome are
completely different from the mouse pattern. Good maps of
transposons in the human genome need to be made, he said.
For that reason, it may be time to reassess the way the
American diet is fortified with supplements, said Dr. Rob
Waterland, a research fellow in Dr. Jirtle's lab and an
expert on nutrition and epigenetics.
More than a decade ago, for example, epidemiological
studies showed that some women who ate diets low in folic
acid ran a higher risk of having babies with abnormalities
in the spinal cord and brain, called neural tube defects.
To reduce this risk, folic acid was added to grains eaten
by all Americans, and the incidence of neural tube defects
fell substantially. But while there is no evidence that
extra folic acid is harmful to the millions of people who
eat fortified grains regularly, Dr. Waterland said, there
is also no evidence that it is innocuous.
The worry is that excess folic acid may play a role in
disorders like obesity or autism, which are on the rise, he
said. Researchers are just beginning to study the question.
Epidemiological evidence shows that undernutrition and
overnutrition in critical stages of development can lead to
health problems in second and third generations, Dr.
A Dutch famine near the end of World War II led to an
increased incidence of schizophrenia in adults who had been
food-deprived during the first trimester of their mothers'
pregnancy. Malnourishment among pregnant women in the South
during the Civil War and the Depression has been proposed
as an explanation for the high incidence of stroke among
And the modern American diet, so full of fats and sugars,
could be exerting epigenetic effects on future generations,
positive or negative. Abnormal methylation patterns are a
hallmark of most cancers, including colon, lung, prostate
and breast cancer, said Dr. Peter Laird, an associate
professor of biochemistry and molecular biology at the
University of Southern California School of Medicine.
The anticancer properties attributed to many foods can be
linked to nutrients, he said, as well as to the distinct
methylation patterns of people who eat those foods. A
number of drugs that inhibit methylation are now being
tested as cancer treatments. Psychiatrists are also getting
interested in the role of epigenetic factors in diseases
like schizophrenia, Dr. Petronis said.
Methylation that occurs after birth may also shape such
behavioral traits as fearfulness and confidence, said Dr.
Michael Meaney, a professor of medicine and the director of
the program for the study of behavior, genes and
environment at McGill University in Montreal.
For reasons that are not well understood, methylation
patterns are absent from very specific regions of the rat
genome before birth. Twelve hours after rats are born, a
new methylation pattern is formed. The mother rat then
starts licking her pups. The first week is a critical
period, Dr. Meaney said. Pups that are licked show
decreased methylation patterns in an area of the brain that
helps them handle stress. Faced with challenges later in
life, they tend to be more confident and less fearful.
"We think licking affects a methylation enzyme that is
ready and waiting for mother to start licking," Dr. Meaney
said. In perilous times, mothers may be able to set the
stress reactivity of their offspring by licking less. When
there are fewer dangers around, the mothers may lick more.