Gene On/Off Instructions Inherited Via Shadowy Mechanism

Studies in Twins, Mice Turn Up Clues

April 6, 2009 • Science Update

Microarray technology was used for the epigenome scan

The first large-scale study of its kind in twins has turned up evidence that we inherit instructions for the turning on and off of genes via mechanisms beyond the traditional sequence differences in the genetic code. Moreover, the results suggest that early random errors in replicating these instructions may trump environmental influences in shaping us.

NIMH Grantee Art Petronis, M.D., Ph.D., University of Toronto, and colleagues, report on their findings in identical and fraternal twins in the February, 2009 issue of Nature Genetics.

Background

Even though they share the same genes, identical twins often differ in important ways. For example, if one identical twin develops schizophrenia, the other twin is spared the illness in about half of cases — despite evidence that at least 70 percent of the risk for the disorder is traceable to genetic factors.

The discrepancy has traditionally been attributed to environmental factors - and more recently to environmental effects on epigenetic marks, or changes in a cell's instructions for the turning on and off of genes. Petronis and colleagues instead propose that these marks are partially inherited, but via a secondary molecular mechanism. And, that chance errors in replicating them begin accumulating from the moment sperm meets egg. These chance variations ultimately account for risk to develop complex disorders like schizophrenia more than environmental factors, he argues.

Traditional notions of heritability hold that fraternal twins differ more than identical twins simply because the former don't share the same DNA , the fixed sequence of letters in our genetic code. By contrast, Petronis and colleagues suggest that fraternal twins also may differ more because they have more divergent sets of instructions for turning genes on and off.

To pinpoint such divergences, the researchers searched for how often twins shared a common type of epigenetic mark created when a molecule called a methyl group attaches to a certain part of DNA. Much as a police "boot" immobilizes a car, such methylation slaps a chemical handcuff on a gene's expression. Thus, it serves as a key mechanism for regulating what proteins and tissues get made.

The study checked for the telltale marks at 6,000 chromosomal locations in cells from three different types of tissue – blood, cheek and gut – in 100 sets of identical and fraternal twins.

Results of This Study

Cells from cheek swabs revealed that patterns of methylation were more similar in identical than fraternal twins. But even in identical twins, epigenetic differences were commonplace throughout the genome.

Significance

The greater epigenetic divergences in fraternal twins suggests that some of our epigenome is inherited, since they developed from separate cells.

"Our DNA replicates a thousand times more reliably than our epigenomes," Petronis explained. "Over millions of cell divisions, errors mount up in instructions for gene expression, resulting in significant divergences even among individuals who originated in the same cell."

Some of our epigenetic inheritance survives these many cell divisions and may help set the stage for development of disorders like schizophrenia, in interaction with environmental, hormonal and other factors, he proposes. Such mechanisms may help explain features of the disorder that don't fit classical modes of inheritance — such as delayed onset in the late teens, the fluctuating course of symptoms, gender differences, and the fact that some cases are sporadic while others are familial. Systematic, large-scale, epigenome-wide studies may lead to major insights into the molecular basis of such psychiatric illnesses, he says.

What's Next?

Clues about how epigenetic inheritance works are emerging from animal studies — even evidence that acquired traits can be biologically passed-on to progeny. In the most recent of these studies, mice inherited skills learned by their mothers early in life.

Larry Feig, Ph.D., of Tufts University, and colleagues, exposed pre-adolescent female mice bred to have memory defects to two weeks of an environment enriched with novel objects, social interaction and opportunities for exercise. This experience reversed the genetically-engineered memory defect by unlocking a latent cellular process known to enhance learning and memory.

In adulthood, these mice gave birth to offspring with the same genetic memory defect. To control for effects of nurture, the pups were raised by non-enriched foster mothers. When they reached pre-adolescence, these offspring performed memory tasks as well as their birth mothers, even though they had not been exposed to them behaviorally or to the enriched environment. The same latent cellular process that enhances memory was unlocked for a time. However, their memory worsened during adolescence and the enhancement was not transmitted to the next generation.

The researchers determined that the epigenetic inheritance occurred at the time the mouse embryo was created. They also pinpointed a formerly unknown neural pathway that unlocked the latent memory-enhancing process.

The study, funded by NIH's NCI  and NINDS , is reported in the February 4, 2009 Journal of Neuroscience.

References

DNA methylation profiles in monozygotic and dizygotic twins . Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A. Nat Genet. 2009 Jan 18.

Environmental studies of schizophrenia through the prism of epigenetics . Oh G, Petronis A. Schizophr Bull. 2008 Nov;34(6):1122-9. Epub 2008 Aug 14. PMID: 18703665

Transgenerational rescue of a genetic defect in long-term potentiation and memory formation by juvenile enrichment . Arai JA, Li S, Hartley DM, Feig LA. J Neurosci. 2009 Feb 4;29(5):1496-502. PMID: 19193896