How are identical twins made

LIFE MAKES THE DIFFERENCE

Gemini has always been surrounded by a special aura. In some ancient cultures they were revered as divine creatures and good luck charms, in others they were persecuted as the product of the devil and even killed. According to legend, Romulus and Remus founded the city of Rome. Hanni and Nanni made Enid Blyton one of the most successful children's book authors. And whether the Kessler twins would have achieved world fame individually is at least questionable. Science has long been fascinated by the doppelgangers. "Twins offer the ideal basis for researching the influence of genes and the environment on individual differences," says Heike Wolf, behavioral geneticist at Saarbrücken University. And thus to fathom a key question of human existence: What makes us what we are? Is it mainly the genes? Or the world we live in? With one in 250 births worldwide, parents can look forward to identical twins because the fertilized egg cell, the zygote, divided into two halves in the first days of pregnancy. It is unclear why this internal “cloning” occurs.

What is certain, however, is that such monozygous twins begin their existence with the same genetic makeup. So it's no wonder that they look so confusingly similar. Fraternal (dizygote) twins, on the other hand, only match half of their DNA, so, viewed from the genome, are nothing other than siblings born on the same day. What the two groups have in common: pairs of twins usually grow up in the same family and are therefore largely subject to the same external influences. From the mother's diet during pregnancy to the parents' hygiene, social status and financial circumstances, up to and including upbringing, cultural and social background - their living conditions are largely the same. “This is why twins are so valuable for behavioral genetic studies,” says Heike Wolf. The comparison between monozygotic and dizygotic twins with regard to a certain characteristic, such as body size or intelligence, is revealing. If monozygous twin pairs are more similar in this respect than dizygote, this difference must be genetically determined - and not due to external conditions, since these are the same in twin siblings.

DARWINS COUSIN HAD THE IDEA

That is the basic idea of ​​twin research. It was first expressed in 1875 by Francis Galton, a cousin of Charles Darwin. The two out of one egg are the means "to differentiate between the effects of tendencies that they received at birth and those that the circumstances of their later life imposed on them," said Galton. In other words, between “Nature” and “Nurture” (nutrition) - as the English summed up the contrast between heritage and the environment with a single rhyme. While his famous cousin was making history, Galton shot himself offside in the history of science. Because he founded not only twin research, but also eugenics, which found its gruesome application in Hitler's extermination of "life unworthy of life". The debate as to whether genes determine human nature or whether it is upbringing and the environment has endured into the 21st century. And twins are still the focus. Heike Wolf is happy that the nature-versus-nurture discussion is less dogmatic today than it was a few years ago. "Most scientists now recognize that there is actually no personality trait in which only nature or only living conditions play a role." What is more interesting today is which of the two is relevant and how.

From food preferences and sportsmanship to sexual orientation and aggressiveness to job satisfaction and political convictions - twin researchers have now scrutinized almost every human trait and found a significant influence of genetic makeup. According to a study by the University of Minnesota, even belief is largely determined by genetic factors. "Religiousness is inherited", is the conclusion of the US scientists from the comparison of 104 dizygoti and 169 monozygotic twins. Gavin and Jason, two bearded people in their late twenties, are identical twins. Your photo adorns the information brochure and the website of the European Epigenome Network of Excellence "Epigenome NoE". This makes them the figureheads of what is currently arguably the hottest research area in biology - epigenetics. Our genome has 20,000 to 25,000 genes. They provide the blueprint for life. But it takes more than this plan. Because although all cells in the cell nucleus have the same genetic material, there are hundreds of cell types in the human body: for example nerve cells, skin cells and liver cells. Cell types that have completely different properties and perform completely different tasks. The fate of human cells depends on which genes are active and how active they are in the course of their development.

This is partly regulated by control genes that are integrated into the DNA strand distributed over 46 chromosomes and a total of two meters long. But for some years now it has become increasingly clear that decisive influences on gene activity come from outside, from molecular control mechanisms that are not in the DNA itself, but rather on it. Such epigenetic factors control genome function, for example by switching genes on or off. Bryan Turner explains that DNA is like a tape on which information is stored. “But a tape is of absolutely no use to us without a playback device,” says the geneticist from the University of Birmingham. "Epigenetics deals with the playback device."

THE EVIDENCE FROM MADRID

Turner's Institute of Biomedical Research is one of the 25 permanent members of Epigenome NoE. There are good reasons why Gavin and Jason act as the “faces” of the network. On the one hand, twins can provide epigenetics with deep insights. Conversely, epigenetics has what it takes to turn previous views on the equality and differences of genetic doppelgangers on their head. This is impressively demonstrated by a study by Spanish scientists: The researchers led by Manel Esteller from the National Cancer Center in Madrid analyzed the genome of 40 monozygous twin pairs between the ages of 3 and 74, focusing on the two central epigenetic processes: on the one hand, DNA methylation, the genes inactivated, on the other hand the so-called histone acetylation, which awakens dormant genetic material (see graphic “The switches of the genes”).

Result: The number and distribution of these switching elements differed significantly between the twin siblings - and with it the activity pattern of their genes. It was noticeable that these differences were particularly evident in older twins. In the case of very young twin pairs, however, the epigenetic profiles were largely identical. There are two possible explanations for Esteller's discovery. One is the "epigenetic drift": modifications and defects in the epigenome accumulate over time. Because these changes happen by chance, they are not the same in the two parts of a pair of twins. The other explanation is that personal experiences and environmental factors are reflected in the epigenetic pattern. Manel Esteller sees both forces at work, but he has found solid evidence for the second thesis.

A MATTER OF LIFESTYLE

The researcher not only analyzed the genetic makeup of his subjects, but also asked them about their lifestyle and biography. And found: the twins who had lived apart the longest were epigenetically the least similar. The more different their experiences and habits - from diet and sporting activity to medical history and social status to tobacco and alcohol consumption - the greater the deviations in their epigenome. “Both their innate nature and environmental conditions have an impact on the twins,” says Esteller. "Epigenetics is the bridge between them."

Does the environment shape a person biologically by changing the activity of his genes? Jörn Walter, genetic researcher at Saarland University, admits that much of the evidence still comes from animal experiments, but one thing is for him: food, toxins, climate, stress, behavior, personal experiences - everything we experience can be epigenetic precipitate and thus influence genome function. “By activating and deactivating genes, we adapt to certain living conditions,” says Walter, whose working group is also part of the European research network Epigenome NoE. "While genetics work for millions of years, epigenetics change organisms within a generation."

It is becoming increasingly clear that the genetic makeup is a much more open system than was long thought. The DNA provides the basic blueprint for life, but epigenetic processes work from the outside into the cell nucleus, switching genes on and off and at least helping to determine what becomes of an individual and how it becomes. Researchers working with epigenetics pioneer Moshe Szyf found that newborn rats that are neglected by their mothers are more anxious and more prone to stress in adulthood. Investigations of their brains showed: In the hippocampus, a region that is central to memory and processing of emotions, the activity of important genes was reduced in the neglected animals. Last year, Szyf found similar epigenetic changes caused by methyl groups that prevent reading in the brains of suicides who had been abused in their childhood. They could be the reason these people took their own lives, speculates the researcher from McGill University in Montreal.

THE PLAYGROUND OF GENETICS

Jörn Walter does not like the fact that the epigenome is often viewed as “the true genome that decides everything” on the basis of such findings. Rather, he sees epigenetics as a "playground for genetics" that allows rapid adaptations to certain states and conditions. And in all directions, because unlike genetic mutations, the molecular signal generators on the DNA can be modified at any time. “Epigenetic changes are metastable,” says the researcher. This means that they arise faster and are easier to reverse than changes in the genes themselves. “The ability to react so flexibly is of great advantage for the organism.” How the DNA methylation machinery works, what influences it and which If the methylation patterns have an impact on the appearance and nature of a person - scientifically speaking: on their phenotype - Jörn Walter's working group in Saarbrücken is not the only one who wants to clarify. Researchers around the world are trying to unlock the secrets of the epigenome. Twins could become the most important subjects of study, says Andreas Busjahn: "Since identical individuals have the same base sequence, you will find the optimal conditions in them to investigate phenotypic effects of epigenetic effects - as well as the effects of environmental factors on epigenetics." -Year-old worked for a long time as a twin researcher - at the Berlin Charité and at the Max Delbrück Center for Molecular Medicine. Busjahn has been running HealthTwiSt since 2002. From four offices in Berlin-Buch, he and his four employees organize twin studies for genetic research. Orders come primarily from universities. HealthTwiSt's working capital is a database that has registered over 1700 pairs of twins, monozygotic and dizygotic. Some of the double Lottchen and Hänschen have already participated in umpteen projects, says Busjahn. “Twins are usually happy to make themselves available to science because they know that they are genetically something special.” The trained psychologist cannot complain about a lack of demand for his services. And he expects to be even more sought after in the future. "The potential of twin studies in epigenetics is only just being recognized."

STRANGE OBSERVATIONS

Tim Spector, Head of the Department of Twin Research at King’s College, London, is also convinced that investigating epigenetic processes with the twin model will "make twin researchers happy for the next fifty years". Conversely, epigenetics could also explain some strange phenomena in twins. Gavin and Jason, the identical ambassadors of the Epigenome Network of Excellence, can hardly be distinguished visually, share hobbies such as surfing and both have an inherited predisposition for type II diabetes. But only Jason had to be treated by a doctor for high blood sugar. Brother Gavin, on the other hand, has no problems with the pancreas. They have exactly the same DNA. But that out of two genetically identical twins only one gets a disease with a hereditary component is - contrary to what one might think - not that rare.

EXOTAS IN THE GENOME

The reason could be a phenomenon that geneticists call monoallelic expression. In addition to the germ cells, there are two copies of every gene in the nucleus of human cells, one inherited from the father and the other from the mother. According to the doctrine, both copies (alleles) of a gene are always read and converted into the corresponding gene product - apart from a few individual cases. The best known exception is the second X chromosome in women, which is always shut down. But also genome segments for certain messenger substances of the immune system and olfactory receptors belong to the exotic species in the genome, which are implemented monoallelically.

But these exotic species are apparently not that exotic at all. Alexander Gimelbrant from Harvard University screened around 4,000 human genes and found more than 300 in which one allele, sometimes the other and sometimes both were used. And this despite the fact that the DNA sequence of the cells tested was identical - they were clones of human immune cells that had grown in laboratory vessels. Whether the maternal or paternal variant is chosen seems to be random and can vary from cell to cell. So far, the Harvard researchers only suspect that epigenetic effects activate and deactivate the respective alleles. But Gimelbrant is convinced: "Even with identical twins there will be the observed differences." This may be why Jason has high blood sugar and Gavin does not. Because if Jason only has one allele switched on for a gene, smaller quantities of the product encoded by this gene are also produced. If this gene product is in turn important for the sugar metabolism, the development of diabetes is favored. And not just the development of diabetes or other ailments, says the Berlin twin researcher Andreas Busjahn: "The monoallelic expression can also have phenotypic consequences that affect personality and character."

THAT'S WHY EVERYONE IS UNIQUE

If the results from Harvard are extrapolated to the entire human genome, of over 1000 genes, sometimes the maternal copy, sometimes the paternal copy and sometimes both are used. The almost infinite number of combinations that result from this is a factor that makes every individual unique, according to Gimelbrant, even with the same basic genetic makeup. Identical twins are like two musicians who play the same score but interpret it differently. How the notes are interpreted changes a lifetime, as Manel Esteller's study shows. The conductor is obviously the epigenome, which also determines when a gene has to sound and when it has to be silent. Environmental factors can intervene in genome regulation via epigenetics, which in turn affects the nature of a person with all its facets.

This closes the circle and makes the question “Nature or Nurture?”, Which has dominated Andreas Busjahn's research area for so long, no longer necessary. “Genes and the environment cannot be viewed separately because they are in constant interplay. Twin research should concentrate on understanding this interplay. ”He is still amazed at how much the natural clones often look alike, even if their life paths are far apart. But that, according to Busjahn, is probably due to the fact that you pay particular attention to similarities, because that's what makes twins so fascinating. On closer inspection, however, you notice "that despite all the similarities they are two independent personalities, with their individual preferences, peculiarities and character traits."

The research team headed by Carl Bruder from the University of Alabama had definitely expected deviations when they compared the genomes of 19 monozygous twin pairs last year. However, only in the epigenetic profile. But what the scientists found shakes twin research to its very foundations. Because there are also differences in the DNA itself.In terms of the number of copies of a genome segment. Such so-called Copy Number Variants (CNV) are not inherited, but arise in the course of life when dividing cells copy the genetic information. That means: Identical twins are not genetically identical at all. “A really exciting result,” says Andreas Busjahn.

THE DIFFERENCES MATTER

CNVs were only discovered a few years ago. As we now know, they are involved in the development of various diseases, including neuropsychiatric conditions such as autism and schizophrenia. Jörn Walter thinks it is very conceivable that Copy Number Variants also influence the development of healthy psychological characteristics. The discrepancies in the DNA sequence discovered by Carl Bruder for the first time “could be one reason why monozygous twins do not resemble each other in terms of personality and character traits like one egg to another.” The epigenetic from Saarbrücken University criticizes the behavioral twin research has put the similarities too much in the foreground. It is much more revealing to examine which environmental factors and which interpretations of the genetic material have led to differences between identical individuals. “In this way you can really get closer to the age-old question of what shapes people,” says Walter. In any case, twins can be happy. After all, they don't want to be perceived as a strange double pack, but as two independent people. And that's what they are - also biologically. ■

bdw author ULRICH KRAFT happened upon a twin meeting last year. That made him curious about the highly topical topic.

by Ulrich Kraft (text) and Claudia Hentrich (photos)

COMPACT

· In the course of life, the genetic makeup of identical twins also differs from one another.

· Depending on the lifestyle, genes are switched on or off. But chance also plays a role.

· Further variations arise from the duplication of genes.

The switch of genes

The DNA is structured like a rope ladder, with each rung representing a letter of the genetic code. So-called epigenetic switching elements decide whether the code can be read or not.

The acetyl groups act as “switches”. They hang on the tails of the histone proteins (green). Eight histone proteins each form a complex around which the DNA thread is wrapped like hair around a curler, a winding is called a “nucleosome”. If the histones are acetylated (provided with acetyl groups), the nucleosomes separate from each other and release the DNA for reading. If the acetyl groups are missing, the genetic material is compactly twisted - especially in the short phase of cell division when it becomes visible as a chromosome.

Methyl groups act as epigenetic "switch-offs". They bind to certain rungs of the DNA rope ladder and prevent the genes there from being read. Both types of gene switches ensure biological individuality even in identical twins.

July 21, 2009

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