AS TWIN pregnancies go, it was happily uneventful. The identical baby girls lazed in the comfort of their mother’s belly until they were full term and born in a Dutch hospital. But after their birth, doctors noticed . One girl was quite normal. The other had two vaginas, two colons and a spinal cord that split in two towards the bottom of her back.
It was the beginning of two new lives, and of years of surgery and care for one of the twins. It was also the start of a biological mystery that took the best part of a decade to solve. From looking at the placenta, doctors knew the girls were identical twins. So how could twins who shared the same genes be so different?
It is well known that identical twins can grow into very different adults, and not just with respect to their personalities: physical differences become increasingly apparent with age, too. These are usually attributed to differences in their environment. The twin girls’ differences were profound and there from birth. They had shared the same environment – their mother’s womb. So what was going on?
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Resolving this mystery is helping to explain not just why identical twins can be different, but why we all turn out as we do. For over a century, the orthodoxy has been that we are the product of both our genes and our environment. Although there has been fierce argument about which is more important – the nature versus nurture debate – biologists have agreed that it must be a mixture of the two. But the latest findings suggest there is more to it than that: if we could reset the clock to the moment you were conceived and rerun your life over and over again, you would turn out differently every time despite having the same genes and being brought up in the same environment. Yet how is that possible? What else can there be besides nature and nurture?
Twins have been at the heart of the nature versus nurture debate ever since Darwin’s cousin, the scientist Francis Galton, started looking at the issue over a century ago. Today, around the world take part in studies aiming to assess the relative roles of genes and the environment in everything from ageing to disease, and from bullying to religious belief.
These twin studies rest on a few simple assumptions. Twins usually grow up together, so share the same environment. Identical twins develop when a fertilised egg splits in two, so their DNA is exactly the same. Non-identical twins develop when separate eggs are fertilised by separate sperm, so their DNA differs. If identical twins are more similar with regard to a particular trait than non-identical twins, the rationale goes, then that trait – hair colour, say – must be down to their genes. If identical twins are no more similar than non-identical twins with regard to a trait – such as the language they speak – then that trait is more likely to be due to the environment.
But cases like that of the Dutch twins threaten to throw a spanner in the works, so researchers were keen to discover what made them so physically different before they were even born. The first suggestion was that the twins were not entirely identical. “You can find identical twins who differ genetically, but they’re the exception rather than the rule,” says Dorret Boomsma of VU University Amsterdam, a member of the team that studied these two girls.
Two things can make identical twins genetically different. Sometimes, when a fertilised egg splits, mistakes are made. In extreme cases, entire chromosomes can be present in one twin but absent in the other. This turned out to be the case for . One lost a Y chromosome when the egg split, so the triplets developed into two boys and a girl.
Twin mystery
Even when eggs split with no genetic errors, mutations later on can lead to differences. If a mutation occurs very early in development, almost all of the cells in the body of one twin may inherit it, while none of the cells in the other twin will have it. Most mutations effect, but occasionally they hit key genes. The characteristics of the Dutch twin with a divided spine pointed to a particular gene, because they resembled those of an unusual mouse strain with a bifurcating tail. These mice have a mutation in a gene called Axin, which helps guide body layout during development.
So the team sequenced this gene in each girl but were surprised to find no difference between them. That led them to wonder if something else had happened to prevent the Axin gene from working.
We have long known about epigenetic marks– chemical labels added to DNA that alter the activity of genes without altering the actual sequence. In particular, if a stretch of DNA has lots of added methyl groups, the activity of nearby genes is suppressed. So the team took a closer look at the Axin gene in blood cells from the twins.
Sure enough, the girl with the split spine had unusually high levels of methylation around the gene. So while other causes cannot yet be ruled out, the researchers think the most likely explanation is that in one twin methylation levels high enough to shut the gene down, affecting her physical development.
Mystery solved? Far from it. What pushed methylation levels above a critical threshold in one twin but not in the other? “That’s the million-dollar question,” says team member Nick Martin of the Queensland Institute of Medical Research in Australia.
What’s more, many other differences between twins are also being linked to variations in methylation. It is now relatively cheap and easy to study methylation levels, so the last few years have seen a surge in research. Of particular interest are identical twins like the Dutch girls, where one has a particular condition or disease and the other does not. For a wide range of disorders including cancer, rheumatoid arthritis and autism, researchers have found different methylation profiles in the affected twins.
Even more intriguingly, are starting to be linked to differences in behaviour. For instances, in one pair of identical twin sisters – one a danger-defying war journalist, the other a risk-averse office manager – differences were found in a gene implicated in stress and anxiety. No one is claiming that these marks alone explain the sisters’ different behaviours. But they might help explain why the journalist is less anxious in dangerous situations, which could have influenced her career choice.
Or it could be that the methylation differences between the office manager and war journalist are the result of their different behaviours and environments, rather than the cause. None of the twin studies proves that methylation differences trigger diseases or alter behaviour. “The findings are correlative,” cautions epigeneticist Jonathan Mill of the Institute of Psychiatry at King’s College London, who has carried out such .
Indeed, it is clear that much, if not most, epigenetic variability is driven by the world we live in. Studies show that all kinds of environmental factors, from pesticides and pollutants to diet, smoking and alcohol, can alter methylation patterns. And once methylation patterns have changed, there can be lasting effects. When smokers kick the habit, for instance, their methylation patterns rapidly return almost to normal. But can persist for decades – perhaps helping to explain why ex-smokers remain at an increased risk of cancer and respiratory problems years after they stub out their last cigarette. Many studies suggest that particular methylation changes contribute to cancers.
So methylation changes can be both effect and cause. The environment plays a key role in shaping our epigenetic profiles, which in turn influences the activity of our genes, which in turn may shape our behaviour, lifestyle choices and health – our environment – and so it goes on. That might explain why the epigenomes of identical twins diverge over the years, as a .
Identically different
“It could be that the methylation patterns of identical twins become more dissimilar because they experience increasingly different environments,” says Bastiaan Heijmans of Leiden University Medical Center in the Netherlands, who led the study. Our epigenetic profiles, it seems, mimic our individual, divergent paths, environments and experiences. They are as unique as we are.
But if so much is down to the environment, how can identical twins, who share the same womb and so much of their early life experiences, be different even before they are born? Twin researchers Jeff Craig and Richard Saffery of the Murdoch Children’s Research Institute in Melbourne, Australia, have identified in identical twins born as early as 32 weeks.
This could partly be due to subtle physical differences, such as variations in the size of their umbilical cords. It might also be partly due to random events, such as a failure to copy epigenetic marks when cells divide. A small change in a single cell early in development could end up affecting many organs in the resulting adult, for example.
Andrew Feinberg of Johns Hopkins University School of Medicine in Baltimore, Maryland, thinks that not only are some of the epigenetic differences between individuals a result of random events, but that this randomness is built-in – an evolved feature. His studies suggest that within our genome, there are hundreds of regions where methylation patterns are neither genetically predestined nor set by the environment, but vary widely from individual to individual. And these regions seem to include many key developmental genes (żěè¶ĚĘÓƵ, 10 January 2011).
So what is going on? Feinberg thinks it is a way for evolution to hedge its bets. Many animals have to survive in a constantly changing environment. Random epigenetic changes produce more variation in genetically similar offspring, increasing the chances that some of them will survive, he argues.
If your head is starting to spin, brace yourself. It seems that the amount of random epigenetic variability can itself vary depending on the environment. In mice given certain dietary supplements, there was increased variability in their methylation patterns ().
Just how important these random variations are is not yet clear. The ideal study would be to raise a batch of clones in exactly the same environment and see how they turn out. This clearly cannot be done with people, but it can be done with mice. In one such experiment, 40 radio-tagged mice spent three months living together in the same five-storey cage, decked out with flower pots, tubes and toys, while researchers recorded their every move ().
At first the mice behaved in a similar way, but over time their exploratory patterns began to differ. “They developed different personalities,” says team member Gerd Kempermann at the .
The study adds to the evidence that animals can indeed turn out differently even if their genes and environment are identical. What it also suggests is that these differences can arise through a dynamic, interactive process. So a slightly more active mouse might explore a little more than a less active one. It might bump into more of its cage mates and take an enjoyable tumble down a plastic tube, which might in turn fuel its wanderlust, making it better at climbing and more likely and able to seek out further new experiences. Indeed, Kempermann found that the most adventurous mice grew the most new neurons in their hippocampus, a brain region linked to learning and memory. Tiny initial differences become amplified, feeding back to biology and behaviour, sculpting individuality.
The study did not look at the cause of these subtle differences but, as the mediator between genes and the environment – nature and nurture – epigenetics is a prime candidate. “Epigenetics is a potential mechanism to explain our findings,” Kempermann says. Epigenetic variations could initially arise randomly or as a result of physical differences in the womb, or a mixture of both. “Twins may share the same womb, but experience it very differently,” says Craig.
These tiny initial epigenetic differences might influence gene activity and sculpt our interaction with the environment, which then feeds back into the epigenome, amplifying the message. This then further influences gene expression, shaping our biology, behaviour and the way we experience the world. “The environment isn’t what happens to us. We make our own environment,” says geneticist Robert Plomin of London’s Institute of Psychiatry. Add a dash of serendipity – one twin having an accident or illness, say – and these unique experiences set them on a trajectory to individuality.
Of course, most of us don’t worry too much about what makes us unique. We don’t have clones running around in the form of a twin brother or sister. But these findings suggests there is more to our uniqueness than our genes and upbringing, that even if we were just one of thousands of clones we would still all end up different in some ways. Put another way, creating a clone army may be harder than the movies suggest.
“There is more to our uniqueness than genes and upbringing: even clones will all end up different”
Where does this leave the nature versus nurture debate? It is clear that some traits, such as hair colour, are mostly down to genes, whereas others, such as the language we speak, are due to the environment. But you could argue that there’s a third factor too – call it chance or serendipity – in the form of random events occurring in our bodies or in the environment. That may be why the two Dutch twins were so different.
What’s more, many aspects of our bodies and behaviours seem to be the result of complex interactions between genes and the environment, mediated by epigenetics and with a large dash of chance thrown in. In these cases it seems pointless arguing about nature versus nurture. “The debate is outdated,” says epigeneticist Manel Esteller of the Bellvitge Biomedical Research Institute in Barcelona, Spain. “It doesn’t make sense any more.”
This article appeared in print under the headline “Beyond nature and nurture”
