The Epigenetics Revolution (17 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
These model systems have been really useful in demonstrating that transgenerational inheritance of a non-genetic phenotype does actually occur, and that this takes place via epigenetic modifications. This is truly revolutionary. It confirms that for some very specific situations Lamarckian inheritance is taking place, and we have a handle on the molecular mechanism behind it. But the
agouti
and kinked tail phenotypes in mice both rely on the presence of specific retrotransposons in the genome. Are these special cases, or is there a more general effect in play? Once again, we return to something that has a bit more immediate relevance for us all. Food.
agouti
and kinked tail phenotypes in mice both rely on the presence of specific retrotransposons in the genome. Are these special cases, or is there a more general effect in play? Once again, we return to something that has a bit more immediate relevance for us all. Food.
The epigenetics of obesity
As we all know, an obesity epidemic is developing. It’s spreading worldwide, although it’s advancing at a particularly fast rate in the more industrialised societies. The frankly terrifying graph in
Figure 6.3
displays the UK figures for 2007
8
, showing that about two out of every three adults is overweight (body mass index of 25 or over) or obese (body mass index of 30 or over). The situation is even worse in the USA. Obesity is associated with a wide range of health problems including cardiovascular disease and type 2 diabetes. Obese individuals over the age of 40 will die, on average, 6 to 7 years earlier than non-obese people
9
.
Figure 6.3
displays the UK figures for 2007
8
, showing that about two out of every three adults is overweight (body mass index of 25 or over) or obese (body mass index of 30 or over). The situation is even worse in the USA. Obesity is associated with a wide range of health problems including cardiovascular disease and type 2 diabetes. Obese individuals over the age of 40 will die, on average, 6 to 7 years earlier than non-obese people
9
.
Figure 6.3
The percentage of the UK population that was overweight or obese in 2007.
The percentage of the UK population that was overweight or obese in 2007.
The data from the Dutch Hunger Winter and other famines support the idea that poor nutrition during pregnancy has effects on offspring, and that these consequences can be transmitted to subsequent generations as well. In other words, poor nutrition can have epigenetic effects on later generations. The data from the Överkalix cohort, although more difficult to interpret, suggested that excess consumption at key points in a boy’s life can have adverse consequences for later generations. Is it possible that the obesity epidemic in the human population will have knock-on effects for children and grandchildren? As we don’t really want to wait 40 years to work this out, scientists are again turning to animal models to try to gain some useful insights.
The first animal data suggested that nutrition might not have much effect transgenerationally. The change in coat pattern of pups when pregnant
agouti
mice were given diets high in methyl donors didn’t transmit to the next generation
10
. But perhaps this is too specialised a model. In 2010, two papers were published that should at least give us pause for thought. They were published in two of the best journals in the world –
Nature
and
Cell
. In both cases, the researchers overfed male animals and then monitored the effects on their offspring. By restricting their experiments to males, they didn’t need to worry about the intra-uterine and cytoplasmic complications that cause such (metaphorical) headaches if studying females.
agouti
mice were given diets high in methyl donors didn’t transmit to the next generation
10
. But perhaps this is too specialised a model. In 2010, two papers were published that should at least give us pause for thought. They were published in two of the best journals in the world –
Nature
and
Cell
. In both cases, the researchers overfed male animals and then monitored the effects on their offspring. By restricting their experiments to males, they didn’t need to worry about the intra-uterine and cytoplasmic complications that cause such (metaphorical) headaches if studying females.
One of the studies used a breed of rat called Sprague-Dawley. This is an albino rat, with a chilled-out temperament that makes it easy to keep and handle. In the experiments male Sprague-Dawleys were given a high-fat diet, and allowed to mate with females who had been fed an ordinary diet. The over-fed males were overweight (hardly a surprise), had a high percentage of fat to muscle and had many of the symptoms found in type 2 diabetes in humans. Offspring were normal weight but they too had the diabetes-type abnormalities
11
. Many of the genes that control metabolism and how mammals burn fuel were mis-regulated in these offspring. For reasons that aren’t understood, it was particularly the daughters that showed this effect.
11
. Many of the genes that control metabolism and how mammals burn fuel were mis-regulated in these offspring. For reasons that aren’t understood, it was particularly the daughters that showed this effect.
A completely independent group studied the effects of diet in an inbred mouse strain. Male mice were fed a diet that was abnormally low in protein. The diet had an increased percentage of sugar to make up for this. The males were mated to females on a normal diet. The researchers examined the expression of genes in the liver (the body’s major organ when it comes to metabolism) in three-week-old pups from these matings. Analysing large numbers of mouse pups, they found that the regulation of many of the genes involved in metabolism was abnormal in the offspring of the males that had been fed the modified diet
12
. They also found changes in the epigenetic modifications in the livers of these pups.
12
. They also found changes in the epigenetic modifications in the livers of these pups.
So, both these studies show us that, at least in rodents, a father’s diet can directly influence the epigenetic modifications, gene expression and health of his offspring. And not because of environment – this isn’t like the human example of a child getting fat because their Dad only ever feeds them super-sized portions of burgers and chips. It’s a direct effect and it occurred so frequently in the rats and mice that it can’t have been due to diet-induced mutations, they just don’t happen at that sort of rate. So the most likely explanation is that diet induces epigenetic effects that can be transmitted from father to child. Although the data are quite preliminary, the results from the mouse study in particular support this.
If you look at all the data in its entirety – from humans to rodents, from famine to feast – a quite worrying pattern emerges. Maybe the old saw of ‘we are what we eat’ doesn’t go far enough. Maybe we’re also what our parents ate and what their parents ate before them.
This might make us wonder if there is any point following advice on healthy living. If we are all victims of epigenetic determinism, this would suggest that our dice have already been rolled, and we are just at the mercy of our ancestors’ methylation patterns. But this is far too simplistic a model. Overwhelming amounts of data show that the health advice issued by government agencies and charities – eating a healthy diet rich in fruit and vegetables, getting off the sofa, not smoking – is completely sound. We are complex organisms, and our health and life expectancy are influenced by our genome, our epigenome and our environment. But remember that even in the inbred
agouti
mice, kept under standardised conditions, researchers couldn’t predict exactly how yellow or how fat an individual mouse in a newborn litter would become. Why not do everything that we can to improve our chances of a healthy and long life? And if we are planning to have children, don’t we want to do whatever we can to nudge them that bit closer to good health?
agouti
mice, kept under standardised conditions, researchers couldn’t predict exactly how yellow or how fat an individual mouse in a newborn litter would become. Why not do everything that we can to improve our chances of a healthy and long life? And if we are planning to have children, don’t we want to do whatever we can to nudge them that bit closer to good health?
There will always be things we can’t control, of course. One of the best-documented examples of an environmental factor that has epigenetic consequences, lasting at least four generations, is an environmental toxin. Vinclozolin is a fungicide, which tends to be used particularly frequently in the wine industry. If it gets into mammals it is converted into a compound that binds to the androgen receptor. This is the receptor that binds testosterone, the male hormone that is vital for sexual development, sperm production and a host of other effects in males. When vinclozolin binds to the androgen receptor, it prevents testosterone from transmitting its usual signals to the cells, and so blocks the normal effects of the hormone.
If vinclozolin is given to pregnant rats at the time when the testes are developing in the embryos, the male offspring are born with testicular defects and have reduced fertility. The same effect is found for the next three generations
13
. About 90 per cent of the male rats are affected, which is far too high a percentage to be caused by classic DNA mutation. Even the highest known rates of mutation, at particularly sensitive regions of the genome, are at least ten-fold less frequent than this. In these rat experiments, only one generation was exposed to vinclozolin, yet the effect lasted for at least four generations, so this is another example of Lamarckian inheritance. Given the male transmission pattern, it is likely this is another example of an epigenetic inheritance mechanism. A follow-on publication from the same research group has identified regions of the genome where vinclozolin treatment leads to unusual DNA methylation patterns
14
.
13
. About 90 per cent of the male rats are affected, which is far too high a percentage to be caused by classic DNA mutation. Even the highest known rates of mutation, at particularly sensitive regions of the genome, are at least ten-fold less frequent than this. In these rat experiments, only one generation was exposed to vinclozolin, yet the effect lasted for at least four generations, so this is another example of Lamarckian inheritance. Given the male transmission pattern, it is likely this is another example of an epigenetic inheritance mechanism. A follow-on publication from the same research group has identified regions of the genome where vinclozolin treatment leads to unusual DNA methylation patterns
14
.
The rats in the studies described above were treated with high doses of vinclozolin. These were much larger than humans are believed to encounter in the environment. Nonetheless, effects such as these are one of the reasons why some authorities are beginning to investigate if artificial hormones and hormone disrupters in the environment (from excretion of chemicals present in the contraceptive pill, to certain pesticides) have the potential to cause subtle, but potentially transgenerational effects in the human population.
The animals went in two by two, hurrah! Hurrah!
Traditional song
Sometimes, the best science starts with the simplest of questions. The question may seem so obvious that almost nobody thinks to ask it, let alone answer it. We just don’t challenge things that seem completely self-evident. Yet occasionally, when someone stands up and asks, ‘How does that happen?’, we all realise that a phenomenon that seems too obvious to mention, is actually a complete mystery. This is true of one of the most fundamental aspects of human biology, one we almost never think about.
When mammals (including humans) reproduce, why does this require a male and a female parent?
In sexual reproduction the small, very energetic sperm swim like crazy to get to the large, relatively sedentary egg. When a winning sperm penetrates the egg, the nuclei from the two cells fuse to create the zygote that divides to form every cell in the body. Sperm and eggs are referred to as gametes. When gametes are produced in the mammalian body, each gamete receives only half the normal number of chromosomes. This means they only have 23 chromosomes, one of each pair. This is known as a haploid genome. When the two nuclei fuse after a sperm has penetrated the egg, the chromosome number is restored to that of all ordinary cells (46) and the genome is called diploid. It’s important that the egg and the sperm are both haploid, otherwise each generation would end up with twice as many chromosomes as its parents.
We could hypothesise that the reason why mammals all have a mother and father is because that’s what we need to introduce two haploid genomes to one another, to create a new cell with a full complement of chromosomes. Certainly it’s true that this is what normally happens but this model would also imply that the only reason why biologically we need a parent of each sex is because of a delivery system.
Conrad Waddington’s grandson
In 2010 Professor Robert Edwards received the Nobel Prize in Physiology or Medicine for his pioneering work in the field of in vitro fertilisation, which led to the so-called test tube babies. In this work, eggs were removed from a woman’s body, fertilised in the laboratory, and re-implanted back into the uterus. In vitro fertilisation was hugely challenging, and Professor Edwards’ success in human reproduction was built on years of painstaking work in mice.
This mouse work laid the foundation for a remarkable series of experiments, which demonstrated there’s a lot more to mammalian reproduction than just a delivery system. The major force in this field is Professor Azim Surani, from Cambridge University, who started his scientific career by obtaining his PhD under the supervision of Robert Edwards. Since Professor Edwards received his early research training in Conrad Waddington’s lab, we can think of Azim Surani as Conrad Waddington’s intellectual grandson.
Azim Surani is another of those UK academics who carries his prestige very lightly, despite his status. He is a Fellow of the Royal Society and a Commander of the British Empire, and has been awarded the prestigious Gabor Medal and Royal Society Royal Medal. Like John Gurdon and Adrian Bird, he continues to break new ground in a research area that he pioneered over a quarter of a century ago.
Starting in the mid 1980s, Azim Surani carried out a programme of experiments which showed unequivocally that mammalian reproduction is much more than a matter of a delivery system. We don’t just need a biological mother and a biological father because that’s how two haploid genomes fuse to form one diploid nucleus. It actually matters enormously that half of our DNA comes from our mother and half from our father.
Figure 7.1
shows what a just-fertilised egg looks like, before the two genomes meet. It’s simplified and exaggerated, but it will serve our purpose. The haploid nuclei from the egg and the sperm are called pronuclei.
shows what a just-fertilised egg looks like, before the two genomes meet. It’s simplified and exaggerated, but it will serve our purpose. The haploid nuclei from the egg and the sperm are called pronuclei.
We can see that the female pronucleus is much bigger than the male one. This is very important experimentally, as it means that we can tell the different pronuclei apart. Because we can tell them apart, scientists can transfer a pronucleus from one cell to another, and be certain about which one they transferred. They know if they transferred a pronucleus that came from the father’s sperm (male pronucleus) or from the mother’s egg (female pronucleus).
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