City of Hope investigator Judy Singer-Sam, Ph.D., has long wondered why identical twins, who have the same genes and often grow up in similar environments, differ in their chances of developing mental illnesses or brain disorders. Now, her published research on mouse genes shows how biology — rather than simply experience — might account for these differences.
Most genes come in pairs, one each from the mother and father. Cells almost always use both members of the pair — known as alleles — to make a specific gene product. However, Singer-Sam, professor of biology, found that in about 1 percent of the genes examined, one member of a pair was silenced, apparently at random. This process is called monoallelic exclusion. Her study, published in the Dec. 12 issue of Public Library of Science One, reveals how frequently this kind of silencing occurs in the brain.
Singer-Sam and her colleagues analyzed the DNA surrounding about 500 genes in a section of one mouse chromosome. They found at least four cases in which only one member of the pair was active in brain cells, while the other was silenced. If the same pattern applies to humans, monoallelic exclusion could apply to about 250 of the estimated 25,000 human genes.
The incidence of mental disorders can differ between identical twins. Scientists often study twins to observe if traits are determined by genetics or environment, and significant differences between them are often interpreted as meaning that environment plays a predominant role.
Singer-Sam thinks this is an over-simplification. She explained how biological differences could account for different behaviors in twins: Gene pair A and a control addictive behavior, and the a form predisposes a person to addiction. Each identical twin carries two copies, A and a, and only one of the two copies is active. If A is active and a is shut down in certain parts of the brain, then that twin’s behavior is “normal.” But if A is shut down and only a is active, that twin will be predisposed to addiction.
Singer-Sam’s group is studying whether this type of gene silencing occurs in the same genes and at the same rate in humans. “If we discover that a gene is monoallelic and that changes in its expression play a causal role in any condition, then we can start trying to develop ways to turn it off or on,” she said.
Additional City of Hope contributors to the paper were Jinhui Wang, Ph.D., and Zuzana Valo, both in the Division of Biology, and David Smith, Ph.D., in the Division of Information Sciences.
The National Institutes of Health supported the research.