Francis Crick and James Watson became household names for their 1953 discovery of the structure of DNA, and that breakthrough formed the basis for our understanding of how attributes are passed on from one generation to the next. But DNA – the genome – isn’t the whole of the story. Since the 1970s, the role of the ‘epigenome’ has come under ever-greater scrutiny. The epigenome is the name given to tiny chemical modifications made by factors such as environment and diet to DNA and the proteins it wraps around. Epigenetic research studying these modifications has thrown up some surprising results. While your green eyes or dark skin are due to the DNA you inherited from your mother, your wiry build could have something to do with how your grandmother was living while she was carrying her.
The extraordinary process of development starts with a single cell with limitless potential and ends, in humans, with trillions of cells that have become specialised. Several decades ago, no one knew what happened to the DNA when cells became specialised. One hypothesis was that cells got rid of the DNA they no longer needed. For example, brain cells would ‘lose’ genes that code for haemoglobin, the pigment that carries oxygen in the blood, while liver cells would abandon DNA coding for keratin.
In the 1970s Prof John Gurdon, working first in Oxford and subsequently in Cambridge, disproved this theory. He removed the nuclei from frogspawn and replaced them with the nuclei from adult frog cells. The frogspawn developed into tadpoles and finally frogs. This demonstrated that there is no difference in the DNA of different cells from an individual. In 1996, Ian Wilmut, Keith Campbell and colleagues at the Roslin Institute proved that the same is true in mammals when they cloned Dolly the sheep, using a nucleus from an adult sheep mammary cell.
The birth of epigenetics
In 2012, Gurdon was awarded a Nobel Prize for his work. Over the decades since his discovery, researchers – such as those at the multinational Roadmap Epigenomics Project – have made enormous strides in identifying the mechanisms behind epigenetic phenomena. These mechanisms are dependent on tiny chemical modifications to DNA, and to certain proteins called histones that are associated with our genetic material. These modifications are referred to as ‘epigenetic modifications’.
Hundreds of different enzymes can add or remove epigenetic modifications at different positions on the genome, and hundreds of other proteins can bind to various combinations of modifications and change the way the genome is used. These epigenetic modifications change in response to environmental stimuli, and allow our cells to adapt their expression of particular genes to a change in circumstance. Epigenetics therefore provides the bridge between nature (our genome) and nurture (our environment).
Epigenetics in humans
Some epigenetic responses to the environment are established early in life, such as in the first trimester of human pregnancy. An example of this has previously been seen in the Netherlands. Towards the end of WWII, certain regions of the country suffered catastrophic food shortages. Calorie intake dropped to less than 40 per cent of normal levels for a period of several months that became known as the ‘Hunger Winter’. Babies conceived during this period were normal at birth, but as they matured they began to show increased levels of adult obesity and Type 2 diabetes. This is because their genes were epigenetically modified during early development to enable the individuals to make the best use of what scarce nutrition there was. This would be an advantage if the famine had continued, but in a society with limitless access to food, this epigenetic alteration is problematic.
Epigenetics provides researchers with a new way of understanding the foetal origins of adult disease, and is actively investigated in long-term epidemiological studies such as the Avon Longitudinal Study of Parents and Children that has been following nearly 15,000 families since the early 1990s. Rodents that experience traumatic early life experiences establish epigenetic neuronal patterns that affect their stress levels in adulthood. Similar mechanisms may underlie the negative effects that early childhood abuse has on adult mental health in humans.
Epigenetics and heredity
We know that genetic information is passed on from parent to child, but what about epigenetic information? In the 1980s, Prof Azim Surani at the University of Cambridge demonstrated that this does happen. In fact, successful reproduction in placental mammals positively requires transmission of appropriate epigenetic modifications from both parents. Using in vitro fertilisation techniques in mice, Surani showed that live animals can only be born if an egg and a sperm nucleus fuse together in an egg. No live young were born if he used two egg nuclei or two sperm nuclei, even though at a genetic level all three situations were identical.
More evidence that epigenetic information is passed on from parent to child comes from a strain of mice called the ‘Agouti viable yellow’. These mice can be fat and golden, skinny and brown, or all types in-between. All Agouti viable yellow mice are genetically identical; their differences are caused by epigenetic modifications to a certain region of the genome. The offspring tend to look like their parents, showing that they are inheriting this epigenetic information. But it’s not always perfect – some of the baby mice are different from their parents, which demonstrates that the transmission of epigenetic information is fuzzy. The proportion of the offspring that have a different appearance varies in response to environmental stimuli, such as giving alcohol to the mothers.
So according to the research carried out on the mice, epigenetic information is passed on from parent to offspring and can also be influenced by the environment. This raises the next question: can epigenetically-mediated responses to the environment be passed on from parent to offspring?
Classical Darwinian models of evolution would say no, as this idea has more in common with the theory of inheritance of acquired characteristics proposed by Jean-Baptiste Lamarck, the 19th Century French naturalist who was Darwin’s main rival. But this certainty is increasingly coming under threat. There are some indications from the Dutch Hunger Winter subjects, for example, that the metabolic defects suffered by those who experienced famine in childhood are now being passed on to future generations.
Epigenetics and evolution
Unfortunately, it is incredibly difficult to separate the effects of genetics, epigenetics and environment in human populations. So for greater certainty, researchers have once again turned to rodents.
A number of studies have shown that when male rodents are malnourished, their offspring are metabolically impaired. But it’s experiments using fear-conditioning techniques that have really shaken up the field. Male mice were trained to associate a particular smell with an electric shock, and after repeated exposures the smell alone was enough to trigger a fear response. When the offspring of the mice were tested, they were also frightened by the smell, even though they had never been exposed to the electric shock. The mice also had the same epigenetic modifications to key genes in the brain as their traumatised fathers.
Does this mean that the Darwinian model of evolution is dead? Of course it isn’t, even though there are now epigeneticists who refer to themselves as neo-Lamarckians. Most of the time, eggs and sperm are protected from epigenetic changes to the environment, and relatively few newly established modifications are likely to make it through to the next generation. Even when they do, the modifications and the effects they cause tend to die out within a few generations. This is what we would expect, as epigenetic alterations are intrinsically unstable.
But this transfer of epigenetic information across generations probably provides short-term advantageous adaptations to temporary changes in the environment without affecting the underlying genetic code that has evolved over thousands of years. The epigenetic inheritance takes place under certain conditions, but is unlikely to be a major player in long-term natural selection.
Despite this, there is an increasing and facile tendency to ‘blame’ epigenetic inheritance for current problems, especially with respect to the human obesity epidemic. Fascinating though this field is, it’s not a get-out. The most important things that are happening to your health are happening here and now: no one gains weight in 2015 just because their grandad had a fondness for doughnuts in the 1960s!