Richard C. Francis - Epigenetics: The Ultimate Mystery of Inheritance

What Your Genes Are Wearing

H ERES A PUZZLE . CONSIDER THE CASE OF TWO BROTHERS , when each had reached the age of twenty. One of themcall him Alwas a typical young male. His brother, Bo, however, was not at all typical of young males at this age. Bo looked more like a preadolescent male: poorly developed muscles, absolutely no facial hair, and a voice to match. Their mother was understandably worried about Bo, and soon after his twentieth birthday finally convinced him to see a doctor. Once Bo removed his clothes, the doctor immediately noticed that something was missinghis genitals. A closer inspection revealed that he did in fact have genitals but nothing like those you would expect of a twenty-year-old male. They seemed vestigial. The doctors diagnosis was Kallmann syndrome, a disorder of sexual development. Whats puzzling is this: Al and Bo are identical twins, natures clones. So what happened to Bo? And why didnt it happen to Al?

Kallmann syndrome is an odd-seeming mixture of developmental defects. Not only is sexual development affected, but so too is the sense of smell. Those who suffer from this disorder have greatly impaired olfaction; some have no sense of smell whatsoever. This strange-seeming association reflects the fact that Kallmann syndrome is a developmental defect in a certain part of the embryonic brain called the olfactory placode. As the name implies, it is from this part of the brain that our olfactory sense develops, but it is also from this part of the brain that certain neurons originate that play a huge role in sexual development. During normal sexual development these neurons migrate from the olfactory placode to the hypothalamus. In those with Kallmann syndrome this migration is disrupted.

It is also noteworthy, therefore, that even though only Bos sexual development was impaired, both Al and Bo have an impaired sense of smell; both, in fact, have Kallmann syndrome. Why is Bos case so much more severe? Kallmann syndrome is generally considered a genetic disease. Their discordances sometimes result from essentially random processes at the biochemical level. We are familiar with one form of biochemical randomness, called mutation, which alters the DNA sequence. It is possible but highly unlikely that Bos DNA mutated after the fertilized egg split, in which case the twins would be genetically different. It is much more likely that the differences in Al and Bo are epigenetic in nature. The term epigenetic refers to long-term alterations of DNA that dont involve changes in the DNA sequence itself. Either Als DNA was epigenetically altered in a way that meliorated his Kallmann syndrome, or Bos DNA was epigenetically altered in a way that exacerbated it.

The naked gene consists of DNA in the form of the famous double helix. The genes in our cells are rarely naked, however. They are, rather, clothed in a variety of other organic molecules that are chemically attached. What makes these chemical attachments important is that they can alter the behavior of the genes to which they are attached; they can cause genes to be more or less active. What makes these attachments even more important is that they can stay attached for long periods of time, sometimes a lifetime. Epigenetics is the study of how these long-lasting, gene-regulating attachments are emplaced and removed. Sometimes epigenetic attachments and detachments occur more or less at random, like mutations. Often though, epigenetic changes occur in response to our environment, the food we eat, the pollutants to which we are exposed, even our social interactions. Epigenetic processes occur at the interface of our environment and our genes.

Getting back to twins Bo and Al, it is impossible to say whether their differences reflect random or environmentally induced epigenetic differences. Nor can we know, in this particular instance, what genes are involved. It could be the same genes, the mutations of which are implicated in Kallmann syndrome, or the epigenetic differences may occur in altogether different genes that influence sexual development. We need more than one case study to determine these things.

Al and Bo will continue to epigenetically diverge throughout the course of their lives. These epigenetic differences will make Al or Bo more susceptible to Alzheimers disease, lupus (systemic lupus erythematosus), and cancer, to name a few ailments. The epigenetics of cancer is particularly well studied. In cancer cells, many genes lose their normal methyl attachmentsthey are demethylated . This demethylation results in a host of abnormal gene activities, one consequence of which is unbridled cell proliferation. It is this global demethylation, not any particular mutation, which is the hallmark of cancer. This is good news, because unlike mutations epigenetic changes are reversible. The goal of much medical epigenetics is to find ways to reverse pathological epigenetic events. Many see in epigenetics the potential for a medical revolution.

Another active area of epigenetic research concerns the fetal environment. Al and Bo are less different epigenetically than non-twin brothers because they shared similar environments throughout their lives. This is especially true of the environment they experienced in the womb. Whatever their mothers diet during that period, it affected them equally. The same goes for whatever stress she experienced during pregnancy. More typical siblings, however, can experience quite different fetal environments. The epigenetic alterations that result will make one or the other more susceptible to obesity, diabetes, heart disease, and atherosclerosis, as well as depression, anxiety, and schizophrenia.

Though the epigenetics of what ails us is the most topical, other sorts of epigenetic processes are, for a biologist, more fundamental. Particularly important is the problem of development: how a fertilized egg can become you or me. The problem of development can be broken out into subproblems. There have been major advances in solving one of these subproblems, called cellular differentiation, because of epigenetic research. We all passed through a stage in which we were a hollow ball of generic cells, called stem cells . These stem cells are not only genetically identical; they are physically indistinguishable as well. How, then, do we come to have skin cells, blood cells, neurons, muscle cells, bone cells, and so forth, all of which remain genetically identical? Epigenetics holds the key to unlocking this mystery.