The Janus Gene
IN THIS SHORT TOUR, I HAVE HAD TIME TO COVER ONLY A FEW highlights of this exciting new science known as epigenetics. Here I want to briefly reprise a few important themes that have emerged during the course of the tour.
The first theme concerns the nature of epigenetic processes: a form of gene regulation. Epigenetic gene regulation is long-term gene regulation, hence epigenetic alterations have long-term effects on gene behavior. Indeed, epigenetic alterations of gene behavior can be longer lasting than mutational alterations of gene behavior. But unlike the alterations of gene behavior caused by mutations, epigenetic alterations of gene behavior are generally reversible.
The second theme is that our environment affects the behavior of our genes, both in the short and the long term. The long-term environmental influences on genes’ behavior come by way of epigenetic processes. Environmentally induced epigenetic alterations that occur early in our lives are especially important. We have explored, in particular, the epigenetic effects of poor nutrition and stress on the fetus and the infant, and their myriad health consequences during adulthood. But our environment continues to epigenetically influence our genes throughout our lives.
The third theme is randomness. Epigenetic processes, like all biological processes, have a random element, and sometimes this random element looms large. This is true, for example, of methylation at the agouti locus, which affects not only coloration but susceptibility to obesity, diabetes, and cancer in mice. X-chromosome inactivation is another epigenetic process for which randomness is critical. Indeed, in this case, we could say that randomness is adaptive. Without it there certainly wouldn’t be any X-women.
Clones, whether natural as in monozygotic twins, or manufactured as in Cc the calico cat, are far from carbon copies. There are a number of reasons for this, some of them epigenetic. In the case of Cc, random X-chromosome inactivation caused her coloration to diverge markedly from that of her mother, to the point that she even lacked one pigment entirely.
Both random and environmentally induced epigenetic differences are evident in monozygotic twins. We began this book with a particularly dramatic case of epigenetic discordance for Kallmann syndrome in human clones. Other examples of clone discordance include Alzheimer’s disease, lupus, cancer, and color discrimination.
Some epigenetic alterations of gene behavior have effects that extend beyond an individual lifetime. This is theme number four. The effect of these transgenerational epigenetic alterations may be direct or indirect. Direct transgenerational effects occur when the epigenetic mark is transmitted directly from parent to offspring, through sperm or egg. This is what I call “true epigenetic inheritance.” True epigenetic inheritance is not common in mammals like us, but it does occur. Indirect transgenerational effects are much more common.
The most direct of these indirect transgenerational epigenetic effects is genomic imprinting, in which the original epigenetic mark in the parent is reproduced with great fidelity in the offspring. Much more indirect are the transgenerational effects observed in the maternal behavior and stress response of rats. Here, the epigenetic alterations that influence these behaviors are recreated through the social interactions that they both influence and are influenced by. This transgenerational effect is a positive feedback loop involving gene action and social interaction. Whether direct or indirect, these transgenerational epigenetic effects should expand our notion of inheritance.
The fifth and final theme is actually a meta-theme, a theme comprised of the previous four themes. This meta-theme concerns some of our basic intuitions about the role of genes in explaining biological processes ranging from protein synthesis to cellular differentiation and cancer. Genes are traditionally viewed as biochemical executives that initiate and direct these processes, in contradistinction to all other biochemicals within a cell, which function in a more blue-collar way. I used the metaphor of the theatrical production, the play, to illustrate this view: Genes are the directors, proteins the actors, and all other biochemicals act as stagehands. From an alternative perspective, advocated here, this play is more improvisational and genes are more like members of an ensemble cast, a cast that includes proteins and other biochemical actors. Gene actions are as much effect as cause during protein synthesis, and genomic activity is as much effect as cause during cellular differentiation, both normal and pathological.
From this alternative perspective, genes have two faces, two aspects, like the Roman deity Janus, the god of doorways and gates, of entryways and exits, of beginnings and endings. Only one aspect, the outward-facing, causal aspect, is acknowledged on the traditional account. The result is a simplistic and distorted view of genes and gene actions. For genes also have another aspect, the inward-facing, responsive aspect. This responsive aspect of the Janus gene is highlighted in epigenetic research, the payoffs of which, even in these early days, have been enormous.