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Identical Genes, Individual Twins

Photo: Fotostudio Enjoy, Ingrid van Heteren (NL)

Identical twins essentially have the same DNA sequence, but the way they use their DNA can be vastly different. Photo: Fotostudio Enjoy, Ingrid van Heteren (NL)

By Marcel Coolen

Identical twins essentially have the same DNA sequence, but the way they use their DNA can be vastly different. Photo: Fotostudio Enjoy, Ingrid van Heteren (NL)

About once every 80 live births, a twin pair is born. The majority of these twins are fraternal, meaning they are derived from two separate fertilisations and are as similar genetically as brothers or sisters.

It is only once in every 250 deliveries that a single embryo splits after fertilisation. This event results in the formation of “identical” twins. As these twins are derived from the same fertilisation, they have identical genomes. Yet, somehow identical twins become increasingly different over time, with subtle differences in their personalities, how they look, how they act and even in their susceptibility to getting a certain disease, such as autism spectrum disorders, schizophrenia, bipolar disorder, epilepsy and diabetes.

The cause of this has to do with their “epigenome”, or how differently they use their DNA. But let’s start with some background.

The genetic sequence of an individual is more or less static over time. Still, the genome has the remarkable ability to dynamically respond to its environment. This is because DNA is only half the story.

Every living cell contains about 2 metres of DNA. To fit this DNA neatly into the tiny nucleus, it is wrapped around proteins called histones. Both these histones and the DNA itself can harbour chemical modifications that can activate or repress the underlying DNA sequence.

This additional layer of structure is called epigenetics, which is often defined as “changes in the functioning of the genome that occur without a change in DNA sequence”. It can be thought of as the interpreter of a poem that helps us to understand its meaning, but there is often more than one way to look at the text.

Epigenetics is the mechanism that the cell employs to help understand and interpret the DNA code in the correct space and time. For example, it makes heart and brain cells act very differently even though they have the same genetic information.

Moreover, epigenetic marks can respond to environmental signals, such as stress, diet, toxins and physical activity, and hence these external factors can influence gene expression. My research with Prof Susan Clark at the Garvan Institute of Medical Research has now shown that these epigenetic marks can be vastly different between identical twins.

Twin or no twin, each newly formed embryo contains two copies of every chromosome – except for the sex chromosomes in male embryos – one inherited from its father and one from its mother. For most genes both the paternal and maternal chromosomes are used by the cells to make protein products. However, a small set of about 80 genes behave differently and are predetermined to only use the copy passed down from either the father or the mother. This process is known as imprinting.

Imprinted genes are somehow stamped with a memory making it possible to tell which copy came from the mother and which copy was inherited from the father. This stamp is an epigenetic modification, where the DNA is methylated on only one of the chromosome copies.

It is not clear why imprinting exists, but it is evident that imprinting is essential for normal development. Improper imprinting can lead to severe developmental abnormalities, cancer and other health problems. It is also associated with an increased risk for developing colon cancer later in life.

We have just completed a large study in twins that focused on the DNA methylation profiles of imprinted genes that are important in the control of growth during early development. The study involved a detailed analysis of 512 adolescent twins (128 identical twin pairs and 128 fraternal twin pairs), making it one of the largest studies ever undertaken of this sort.

Our analysis aimed to determine what role genetics plays in determining who we are versus the role of environmental factors. By comparing genetically related people with genetically identical people, we could examine how closely their methylation patterns matched.

We were able to find differences in the DNA methylation profiles of imprinted genes in genetically identical twins. It is these changes that probably give rise to the differences observed in identical twins. These findings support the hypothesis that changes in DNA methylation reflect the interplay between the environment and genetics.

We also found that methylation patterns are exquisitely inherited, so the methylation patterns of identical twins are very similar to each other. This demonstrated that the DNA sequence does instruct the methylation pattern. When that methylation pattern changes, however, it gives rise to potential changes that determine who we are. The overall variability of DNA methylation patterns we observed in this study could be responsible for some of these differences between identical twins.

We now have evidence that changes in methylation patterns occur in genetically identical people, and therefore these changes can potentially change disease susceptibility. The next step will be to examine twins that are discordant for a particular disease, such as Type 2 diabetes. In these cases we will be looking for discordance in the methylation of key genes.

The impact of epigenetics on cancer and other diseases offers a golden opportunity to develop new treatments. While it is virtually impossible to change an inaccurate DNA sequence, it is potentially possible to change the epigenetic packaging of the DNA, allowing a proper interpretation of the genetic code.

In fact, clinical trials of epigenetic drugs are already underway. These drugs have been approved for use in critically ill patients and are having positive outcomes, although we are still at that early stage where they are not specific for the cancer. But they can change gene expression, and hopefully that will be enough for the cancer cell to resume normal cellular death processes.

Box: What Is Epigenetics?
Epigenetics is the study of changes in gene expression that are not caused by changes in the DNA sequence. Different cell types in a human body have different epigenetic profiles even though their DNA is the same. These epigenetic profiles are like a memory system for a cell, telling it what to do and which part of its DNA to use without the need for external signals to tell it how to act.

Several levels of epigenetic regulation exist:

• DNA methylation: DNA is built using four nucleotides: adenosine, cytosine, guanine and thymine. Cytosine can become chemically modified (methylated) if it is immediately followed in the DNA sequence by guanine, and this turns the gene’s activity off.

• Histone modification: DNA in the cell is wrapped around histone proteins that can be chemically modified in many ways (e.g. acetylated or methylated). These chemical modifications inform the cell how tightly to wrap the DNA around the histones. Different modifications can have activating and repressing roles on the DNA. To date, more than 100 different histone modifications have been identified, making this a complex level of gene regulation.

• Higher order chromatin structure: linear DNA is wrapped around histones and further folded and condensed to varying degrees, forming higher order chromatin structures. Inactive regions are tightly packed and no longer accessible for gene transcription, whereas active chromatin is more loosely packed. The position inside the nucleus is also informative on the activity of larger chromosomal regions.

The research described here was performed by Dr Marcel Coolen at the Garvan Institute of Medical Research’s Epigenetics group headed by Professor Susan Clark. Dr Coolen is currently group leader at the Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands.