Perceptions of epigenetics

meanings for different people. Epigenetics is an extreme case, because it has several meanings with independent roots. To Conrad Waddington, it was the study of epigenesis: that is, how genotypes give rise to phenotypes during development. By contrast, Arthur Riggs and colleagues defined epigenetics as “the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence”: in other words, inheritance, but not as we know it. These definitions differ markedly, although they are often conflated as though they refer to a single phenomenon. Waddington’s term encompasses the activity of all developmental biologists who study how gene activity during development causes the phenotype to emerge, but it suffers from the disadvantage that developmental biologists themselves rarely, if ever, use this word to describe their field. In this sense, the usage is obsolete. The definition put forward by Riggs and colleagues tells us what epigenetics is not (inheritance of mutational changes), leaving open what kinds of mechanism are at work. In this article, I give examples of how epigenetic phenomena are studied and interpreted, and I propose a revised definition that embodies contemporary usage of the word. The molecular basis of heritable epigenetics has been studied in a variety of organisms. The DNA methylation system and the Polycomb/ Trithorax systems come closest to the ideal, because alterations in these systems are often inherited by subsequent generations of cells and sometimes organisms (Box 1). A classic case of what Robin Holliday named epimutation is the peloric variant of toadflax (Linaria) flowers (Fig. 1), first described by Linnaeus. In this variant, heritable silencing of the gene Lcyc, which controls flower symmetry, is due not to a conventional mutation (that is, a mutation in the nucleotide sequence) but to the stable transmission of DNA methylation at this locus from generation to generation. Although most variants arising in laboratory plants are due to conventional mutations rather than epimutations of this kind, examples of transgenerational epigenetics are now well documented in plants (see page 418) and fungi. In animals, however, the transmission of epigenetic traits between organismal generations has, so far, been detectable only by using highly sensitive genetic assays. The mouse agouti locus (also known as nonagouti), which affects coat colour, is the best-studied example, being affected by the extent of DNA methylation at an upstream transposon. Genetically identical parents whose agouti genes are in different epigenetic states tend to produce offspring with different coat colours, although the effect is variable. Despite the paucity of data from animal studies, this type of epigenetics has caught the general imagination because, in principle, it is stable but potentially affected by the environment. The possibility that acquired ‘marks’ can be passed from parents to children has a deliciously lamarckian flavour that has proved difficult to resist as a potential antidote to genetic determinism. A recent BBC television science programme hailed the advent of epigenetics as a profound shift in our understanding of inheritance (http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ ghostgenes.shtml). It summarized the implications of the emergent science as follows: “At the heart of this new field is a simple but contentious idea — that genes have a ‘memory’. That the lives of your grandparents — the air they breathed, the food they ate, even the things they saw — can directly affect you, decades later, despite your never experiencing these things yourself.” Is there any evidence for these heady claims, and how reliable is it? The answer to the first part of the question is yes.