Spanish researcher reveals basis for differences between identical twins

Brussels, 12 Jul 2005

A mystery has been puzzling geneticists for decades: how it is possible that the identical twins - those that are genetically identical - nevertheless display genetic differences? A new study by a research team at the Spanish National Cancer Centre has thrown light on this enigma.

Twins are multiple babies who are conceived together, develop in one womb, and then are born at the same time. There are two types of twins: fraternal and identical. Fraternal, or dizygotic, twins are different in their genetic make-up whereas identical, or monozygotic, twins are genetically the same.

Monozygous twins develop from the same ovum, therefore they share identical genetic information. They are always of the same sex and have the same arrangement of genes and chromosomes. They are usually alike in both physical and mental characteristics.

How it is then possible, scientists asked, that in identical twins with common genetics, one sibling can develop bipolar upheaval or schizophrenia, for example, and the other doesn't? Or between two twin sisters with the same alteration in gene BRCA1, how it is possible that one develops breast cancer at 25 and the other not until she is 70?

In fact, most monozygotic twin pairs are not identical - they present what is known as phenotypic discordance, i.e. differences in physical appearance and constitution, or a specific manifestation of a trait. Examples of these are differences in susceptibility to disease and a wide range of anthropomorphic features.

There are several possible explanations for these observations: one is the existence of 'epigenetic' differences - that is, differences in how the genome is expressed.

DNA does not exist as naked molecules in the cell: it is associated with proteins called histones to form a complex substance known as chromatin. Chemical modifications to the DNA or the histones alter the structure of the chromatin without changing the nucleotide sequence of the DNA. Such modifications are described as epigenetic.

To find an answer to this enigma, Mario F. Fraga and his colleagues at the Epigenetics laboratory of the Spanish National Cancer Centre (CNIO), studied 160 monozygous twins ranging from three to 74 years of age. To carry out the study, the Spanish team cooperated with research institutes in Denmark, Sweden, Great Britain and the United States.

The research focused on two biological mechanisms that influence gene activity. In one, called 'DNA methylation', enzymes inside a cell attach a minuscule molecular decoration to a gene, deactivating that gene. In the other, called 'histone acetylation', a dormant gene is made active again.

These altered genetic settings can last a lifetime - though they are not passed down to a person's offspring - and can be important if, for example, the turn-off gene is one that protects against cancer. Until now, the extent to which epigenetic changes are pre-programmed from birth or triggered by factors outside the body has been unclear.

The research team determined that early in life, twins were indistinguishable in the manner in which their genes were expressed. Among older sets of twins, however, significant differences in the gene-expression portraits were apparent for 35 percent of the study group.

In addition, a finding that scientists said was particularly groundbreaking, the epigenetic profiles of twins who had been raised apart or had especially different life experiences - including nutritional habits, history of illness, physical activity, and use of tobacco, alcohol and drugs - differed more than those who had lived together longer or shared similar environments and experiences.

Researchers say the results support the theory that environmental factors, including smoking, diet, and physical activity may affect a person's gene activity and explain some of the differences in disease risk found among identical twins.

Small epigenetic events before birth probably account for many of the minor distinguishing differences in the appearance, personality and general health of young twins. A lifetime of further epigenetic changes gradually increases individuality.

Beyond its potential importance for understanding differences in identical twins, epigenetics could explain many of the twists of fate that affect ordinary people -- why one person may be struck by cancer, for example, while another is spared, even though neither's DNA harbours a cancer-causing mutation.

These findings could lead to far-reaching revelations about how our environment breeds predispositions for lots of diseases, like diabetes, cancer and heart disease. Epigenetic changes do not alter genetic spellings but may account for as many cases of cancer and other diseases as full-blown gene mutations.

Scientists now want to identify the epigenetic changes wrought by specific environmental exposures - whether dietary factors, environmental toxins or more nuanced influences such as persistent stress - and develop drugs that can reverse those alterations.

For further information, please consult the following web address: http:///groups.cnio.es/epigenetica/ indexe ng.htm
Remarks: Peer reviewed publication and references: The Scientist 7-7-2005 'How epigenetics affects twins in genetically identical siblings, DNA methylation and histone acetylation correlate with age and lifestyle'

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