GENES

October 7, 2003
By SANDRA BLAKESLEE

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 lean and healthy.

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 offspring.

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 boys than girls?

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 expressed.

Sometimes the coils are made tighter so that active genes are inactivated.

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 environmental factors.

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 hand.

”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. Waterland said.

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 subsequent generations.

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.

http://www.nytimes.com/2003/10/07/science/07GENE.html?ex=1073110808&ei=1&en=ae5cacb7454101e1