There’s more to heredity than genes

This essay was written by Lisa Melton and was first published in the 2004 Mill Hill Essays.

“What’s done is done, and cannot be undone,” says Lady Macbeth in Shakespeare’s Scottish play. The more we learn about the human body, the more it appears that our genetic makeup dictates our future. Like a game of cards, those holding the court cards are destined for health and success, while those holding the lower cards must content themselves with a grimmer existence.

Just about everywhere you look – diabetes, schizophrenia, Alzheimer’s disease, multiple sclerosis and cancer– faulty genes are implicated. Genes and fate have become closely entwined. But is it fair to attach a ‘destiny’ tag to the DNA we inherit? A growing band of scientists believes not. They argue that genes alone do not run the show, that it is time for a shake up in our long-held views on heredity, about how characteristics are handed down from one generation to another. Everything comes from our genes – and they come from our mum and dad – but what we inherit from our parents is not just naked DNA. There is an extra layer of instructions that is passed on from parent to child that tells genes when to become active, in what tissue, and to what extent. Scientists refer to this additional layer of information as ‘epigenetic’ – outside ordinary genetic inheritance.

Basic hereditary information is spelled out in long chains of DNA letters, known as nucleotides, that make up an organism’s blueprint. Epigenetic information embellishes the genetic blueprint. This extra information is passed from parent to child, and sometimes not. But epigenetic instructions are inherited in an unorthodox way that does not follow the classical rules of heredity. This additional layer of information tells genes when to remain silent or become active, without ever altering the nucleotides that make up our DNA. The more researchers dig, the more they find that epigenetic information may be at the root of cancer, infertility and genetic disease. There is even the controversial possibility that epigenetic patterns are involved in neurological disorders like autism and schizophrenia. Epigenetic inheritance can explain why genetically identical twins are not always identical, and how lifestyle, stress, toxic chemicals and the food we eat influence our susceptibility to disease. Not only is this new thinking challenging the view that DNA is destiny, but it could explain certain mysteries that classical genetics fails to resolve.

Consider a bizarre instance during World War II. A German-imposed food embargo combined with an unusually harsh winter in the Netherlands led to a famine where 30,000 people died. The women who were pregnant at the time, predictably, gave birth to babies that were smaller than normal. What nobody could have foreseen, however, was that the next generation would also have unusually low birth weights despite being well fed. It seems to suggest that: “you are what your grandmother ate”. This is a heretical finding. Environmental factors like diet do not alter the DNA sequence. So how was the effect of this nutritional deficiency experienced by the Dutch mothers passed on to the next generations? That a pregnant woman’s diet might affect her grandchildren contradicts everything we know about inheritance. Astonishingly, it seems to embrace Lamarckism: the notion that evolution occurs by inheriting acquired characteristics. Jean Baptiste Lamarck was Charles Darwin’s main rival and both developed a theory to explain evolution. In 1809, Lamarck put forward the idea that an animal’s changes in behaviour during its lifetime could be inherited by its offspring. For instance a giraffe that stretched to reach leaves at the top of a tree would have young with slightly longer necks. By Lamarck’s reckoning, a dog whose tail had been docked by its owner would give birth to puppies with docked tails. This was easy to test and his ideas were shown to be false.

Now it appears that this French naturalist may have been on to something after all. Last year, with the help of some multicoloured mice, scientists discovered exactly how a mother’s diet affects the genes in her offspring permanently, without actually modifying the genes themselves. The researchers used agouti mice, whose fur is yellow, brown or a mixture of the two, depending on the number of methyl groups tagged onto the “agouti” gene. Pregnant agouti mothers were fed methyl-rich supplements such as folic acid and vitamin B12. This caused dramatic, visible changes in the baby mice born to mothers who had received the supplement. Their offspring had mostly brown fur, whereas the control mice who received no supplements gave birth to mostly yellow babies with a higher susceptibility to obesity, diabetes and cancer. The methyl groups had modified the agouti gene, not just in the mother but in her offspring as well. What the study demonstrates is that a pregnant mother’s diet can affect the likelihood of health problems in her babies. Before we rush to the chemist to stock up on these supplements, it is worth knowing that consuming excessive folic acid can be dangerous too, and what is true for mice may not be true for us. The importance of this study is that it demonstrates how an environmental factor such as diet can dramatically alter what is written in our genes. Methylation was able to tweak gene expression without making any permanent mutations in the DNA.

For complicated organisms like us, this type of inheritance, the epigenetic inheritance, is essential in other ways. Remembering that every cell in the body contains the entire DNA sequence, it is crucial to decide which genes to turn on and which to shut down. For example, we do not want our brain cells to make liver enzymes or skin cells to manufacture blood. Epigenetic marks act as an instruction book that tells each cell how to read its own DNA, when to switch genes on or off. From the Greek prefix epi, which means ‘on’ or ‘over’, epigenetic information affects gene expression without changing the DNA sequence. The best-understood and longest-studied epigenetic marker is DNA methylation. As a general rule it works like this: if a methyl group attaches to a naked cytosine, one of the four DNA ‘letters’ or nucleotides, that gene is silent. But methylation can act either as an accelerator or a brake. It can turn gene expression up or down depending on how much of it is around and what part of the genetic machinery it affects. DNA methylation is the best understood epigenetic modification, but it is not the only one. In very complex organisms such as us, there are a few different epigenetic systems issuing orders, commanding genes what to do.

How the cell packages DNA provides another chance for epigenetic control. In the nucleus, there are globular proteins called histones, which the DNA wraps itself around. Histones were once considered blobs of inert scaffolding whose only purpose was to help pack in a couple of metres of DNA into a tiny cell nucleus. But it is now becoming clear that histones are actively involved in deciding whether the thirty to forty thousand genes within each cell should be switched on or shut down. Researchers have now realised that there is an array of different chemical flags decorating histones – ethyl, acetyl, phosphate, ribosyl and ubiquitin groups – which can control gene expression. From a gene’s standpoint, some marks look like green flags that indicate ‘go’ while others look like red ‘stop’ signs – depending on the pattern of chemical groups. The enzymes that put these flags on and off are important gene regulators. They act like molecular switches, controlling whether or not a gene is expressed. So although DNA reigns supreme as the ultimate heredity molecule, epigenetic factors appear to be the ultimate controllers. Biochemical patterns on histones decide which genes are activated and, unlike DNA, these patterns are constantly changing in response to the environment. Evidence that epigenetic modifications link our environment and our genes is mounting. If a cell is stressed, through exposure to toxic chemicals or ultraviolet light, for example, patterns of phosphate groups change to activate systems that protect the cell. Hormones can also alter gene expression by triggering chemical reactions. The response is quick – it takes only minutes – giving the cell a chance to respond swiftly to challenges posed by an environment that presses for prompt changes. In disease states, epigenetic patterns change quite dramatically. The thrilling possibility is that tinkering with faulty epigenetic marks might open up new ways of controlling devastating diseases such as cancer, Huntington’s and lupus, which have so far eluded scientists’ efforts to find a cure.

In the early 1980s, German and US research teams found a link between cancer and aberrant DNA methylation which, at the time, some found hard to believe. Nowadays we know that in the mammalian genome, about 70 per cent of all cytosine nucleotides are normally methylated. Too little methylation across the genome, or too much methylation can lead to problems, and cancer is one of them. Scientists no longer argue over the importance of epigenetics in cancer. The consensus is that it matters. Academics and pharmaceutical companies are stepping up their efforts to create anti-tumour drugs that work by returning epigenetic patterns to normal. Last May, the drug azacitidine was approved to treat myelodysplastic syndrome –a bone marrow disorder that produces abnormal, immature blood cells and leads to leukaemia. In this type of cancer, the genes that suppress tumours are bogged down and silenced by too many methyls. Azacitidine strips the methyls from them and in doing so, turns these tumour-fighting genes back on.

Another promising strategy targets the histones around which the DNA is entwined. It is well known that the acetyl groups that decorate histones are a benign influence, helping genes to be activated and expressed. But in many cancers the enzymes that take them off are overactive. One tactic to reverse cancer is to find compounds that stop these stripper enzymes to restore acetyl groups on histones. Around twenty different drugs that block these overenthusiastic enzymes are being tested in clinical trials. The hope is that these drugs might restore normal acetylation patterns and, in doing so, return malignant cells to their normal state. In animals, the results have been spectacular. Initial tests in humans have been more than encouraging but it will take at least another five to eight years before any of these drugs reach patients. Epigenetic marks could also explain why we age. Abnormal histone tags are a hallmark of ageing: some marks decrease with age, while others accumulate, causing atypical activity in certain genes. Conversely, epigenetic modifications could also explain the higher incidence of health problems in babies born by high-tech assisted reproduction and why human cloning has remained so difficult to achieve.

In the mammalian embryo, a bizarre phenomenon known as ‘imprinting’ is driven by epigenetic signals. An ‘imprinted’ gene behaves differently depending on which parent it was inherited from. Genes exist in pairs, one from the mother and one from the father. For the vast majority of genes, it is not possible to tell the two genes apart – they behave in the same way regardless of parentage. But imprinted genes are different: in some cases an imprinted gene is only active if it comes from the sperm, in other cases, it is activated if it comes from the egg. The mother’s and father’s imprinted genes are caught in a fierce conflict over the developing embryo. A father wants bigger babies, because they are usually healthier and fitter. But a mother prefers them to be small, because a fetus that grows too large may drain her resources and jeopardise her ability to sustain additional pregnancies. The first imprinted gene to be discovered – a gene for a growth hormone called Igf2, for insulinlike growth factor 2 – is waging this parental battle. While the father’s Igf2 stimulates fetal growth, on the maternal side, an imprinted gene for a receptor that mops up Igf2 tends to suppress growth. If the male and female imprinted genes strike a balance, the result is a normal-sized baby. If a child inherits too many paternal copies of the Igf2 gene, or if the gene is mutated, the balance is broken and the result is Beckwith-Wiedemann syndrome. Affected babies grow unusually rapidly in the womb and certain parts of the body, such as the tongue, grow larger than normal. This disorder of imprinting leads to childhood cancer of the kidney as well as intellectual delay.

Researchers believe there will be many more diseases influenced by imprinting errors. A tantalising possibility is that imprinted genes affect the development of the brain leading some scientists to speculate that autism, schizophrenia, bipolar disorder and other diseases reflect epigenetics in action. Some researchers are analysing methylation patterns across the chromosome in DNA form post-mortem samples of brain tissue. They look at samples from affected and unaffected individuals, homing in on those regions that show clear differences to pinpoint altered patterns of gene expression. To date about fifty imprinted genes have been identified. There may be hundreds of such genes and missing or malfunctioning imprinted genes have been implicated in human diseases, ranging from heritable obesity to childhood cancers. Today, epigenetics has ceased to be an eccentric passion pursued by maverick scientists. There is even an effort to pinpoint every epigenetic variation in the entire human genome. The Human Epigenome Consortium has as its mission the creation of an ‘epigenome map’ that catalogues the genomic positions of distinct methylation variants. Set up in 1999, it is an endeavour spread between British, French and German research centres. The studies involve screening tissue samples from large numbers of people with certain diseases and from unaffected controls. The expectation is that this concerted effort will throw up clues as to why certain human conditions, for example, autoimmune diseases, remain intractable. These new technologies will also be examining the epigenomes of families involved in ongoing studies of autism, bipolar disorder and diabetes. Other research groups studying pairs of twins in which only one suffers from schizophrenia have already found substantial differences in DNA methylation. It will not be a straightforward task to distinguish spurious signals from those relevant to disease, and it is even more complicated by the fact that different tissues may show epigenetic differences.

But in the end, what will epigenetics offer to people suffering from these diseases? It opens up the thrilling possibility of reversing diseases that so far have proved incurable. Epigenetic marks have the advantage of being fully reversible while genome mutations remain fixed. So in whose hands does our destiny lie after all? The mindset has changed: more and more people accept that susceptibility to disease is a combination of genetic and epigenetic modifications, interacting with the environment. Perhaps it is time to ignore Lady Macbeth’s fatalism and quiz our grannies about their diet.

 

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