Genes not the only predictor of a human's fate, even in identical twins

Outside factors affect life's outcomes

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The two were identical twins with identical careers as famous newspaper advice columnists.

So, how did one die of bone marrow cancer 11 1/2 years before her twin died of Alzheimer's disease complications?

It's the age-old question: If twins are identical, with exactly the same genome and cells, why don't they die of the same disease at the same age?

On Jan. 16, Pauline Friedman Phillips, the woman who wrote under the pen name Abigail Van Buren or "Dear Abby," died at 94 from Alzheimer's. Her twin, Esther Friedman Lederer, who wrote as Ann Landers, died of multiple myeloma on June 22, 2002.

This is no modern mystery. As it proves out for identical twins, their dissimilar fates represent the rule rather than the exception.

The Kray brothers, both murderous English gangsters, fit the same odd pattern. Ronnie, 61, collapsed and died in jail in 1995 after his third heart attack (probably due to his habit of smoking 100 cigarettes a day), leaving behind twin brother Reginald, who would die at age 66 -- five years later -- from cancer while incarcerated in a mental hospital.

Researchers once felt the human genome was life's blueprint that determined traits and behaviors and even signaled what disease would cause the person's death.

But 21st-century scientific studies reveal that for identical or "monozygotic" twins, the similarities end when the zygote, or the fertilized egg, splits into two zygotes. From that point on, body chemistry, environment, life's experiences, behaviors and random chance take control.

The human genome: subject to external factors

Epigenetics is a scientific field still in its infancy that is working to explain how external factors regulate the human genome by activating and deactivating genes and DNA sequences.

The genome has been described as nature, and the epigenome as nurture.

"When you have identical twins, their appearance is identical. That's predominantly genetics," said Robert Nicholls, a professor of medicine at Children's Hospital of Pittsburgh of UPMC. "As they age, other factors come into play."

Twins are put in different classrooms and exposed to different behaviors. They develop different interests and have different exposures. They grow up and one might marry someone who smokes while the other's spouse doesn't.

"A number of phenomena change what disease a person might get," the UPMC geneticist said.

You might have two identical cars in the showroom, but what happens to the car depends on who's driving it. One might stay in the showroom, while the other becomes a race car or one used for mud bogging.

"The promise was, if we could sequence the human genome, we would understand the causes of cancer and diabetes and other diseases. But that promise was not fulfilled," said Art Petronis, a geneticist at the Campbell Family Research Institute affiliated with the University of Toronto. "We have sequenced human genomes, and the sequencing technology now is cheap. But we still don't understand" why cancer and diabetes and other diseases with a high degree of inheritability cannot be predicted solely by genetics.

Only two major diseases -- Huntington's disease and sickle cell anemia -- follow strict rules of inheritance because they are solidly based on inherited DNA sequences, he said.

A report by the University of Utah's Genetic Science Learning Center shows that identical twins share the same height at a rate approaching 90 percent, with a high correlation for reading disabilities. If one twin has autism there's a greater than 50 percent chance that the other will also. Alzheimer's disease and schizophrenia are shared about 50 percent of the time. But other diseases coexist at lower rates, with fraternal twins (which come from separately fertilized eggs) sharing diseases at even lower rates than those of identical twins.

Epigenetics is 'like a dimmer switch' on a light fixture

"Identical twins definitely are at a higher risk of sharing a disease," said Tim Spector, a genetic epidemiologist at King's College, London. He's operated the EpiTwin Project for 20 years that has studied 11,000 pairs of identical twins in greater detail than any other group of twins in the world. "They may have twice or three times the risk of having the same disease, but that hardly becomes more than a 50-50 chance, even in common diseases."

Even for twins with genetic predispositions for diseases or mental disorders, their likelihood of developing or sharing those diseases can't be predicted based on DNA sequences or genes alone.

If the genome is the light bulb, epigenetics is "like a dimmer switch rather than a light switch," Dr. Spector said.

Two identical houses are decorated with an equal number, color, size and patterns of holiday lights. Each light bulb exists at the identical place of its matching light bulb on the other house, and the identical bulbs are arranged in identical groups and patterns. These light bulbs represent the DNA with groups of lights representing genes or DNA sequences that determine traits, behaviors and predisposition to disease.

When the electricity goes on, the two houses and their thousands of lights look exactly the same. That's the case when that initial fertilized egg divides into two.

But then epigenetics take control.

Now each light bulb or group of bulbs has its own on-off switch or dimmer switch. Different environmental factors outside the houses or goings-on inside the houses affect which bulbs or groups of bulbs are dimmed or brightened. In time, the two identical houses now have lighting that might still look somewhat similar but can be dramatically different.

As twins mature, their shared genomes change only slightly, but their epigenomes change sometimes drastically, producing even greater variances in the two, Dr. Spector said. Yet another epigenetic factor is random changes in certain DNA sequences, which cause further variations as the twins age.

An understanding of epigenetics is the new complication in genetics but necessary to understanding how it works, Dr. Petronis said.

On average, identical twins are born once in every 200 births, said Dr. Spector, whose book "Identically Different: Why We Can Change Our Genes" is scheduled for a May release in the United States. Today's geneticists would consider it a bigger news story had Ann Landers and twin sister Abby died of the same disease at the same time.

Few studies of identical twins occur in the United States because American twins don't stay together as frequently as those in Britain and continental Europe. Many sets of twins in Dr. Spector's EpiTwin Project in London continue living close to one another or together.

But even in those cases, his team has found dramatic variations and in rarer cases, complete opposites.

"In the past we focused on the group that lived together and wore the same pajamas and slept in bunk beds," he said. "But in taking case histories of twins, we focused on why they are different -- why one is gay and the other straight, one has cancer and one doesn't, one is outgoing and the other is shy, one has autism and the other doesn't, and one is atheist and the other is a fundamentalist."

Correction/Clarification: (Published January 30, 2013) Advice columnist Abigail Van Buren died 11 1/2 years after the death of her twin sister, Ann Landers. In an earlier version of this story, a caption for a photo accompanying the story contained an error in the order of their deaths. mobilehome - lifestyle - health - science

David Templeton: or 412-263-1578.


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