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 Research & Giving News Article  For many years the prevailing wisdom governing heredity was that DNA alone was responsible for inheritable characteristics. Early on, however, scientists noted anomalies that were inexplicable using the DNA-only approach. For example, often one of a pair of identical twins will develop schizophrenia – a disorder believed to have a strong genetic component – while the other twin will not. If the condition were dictated purely by DNA, then the second twin – a genetic mirror image of the first – should always have it, too. The science of epigenetics seeks to understand the mechanisms of inheritance whereby this and other variations occur. Traditional genetics describes inheritance on the basis of DNA sequence, whereas epigenetics studies inheritance on the basis of how the gene is expressed. These are not conflicting, but complementary areas of study, as epigenetics examines the chemicals and proteins that act on DNA. DNA methylation is the mechanism for turning genes “off”, and altering gene expression in a cell. Therefore, aberrant methylation is increasingly recognized as playing a critical role in certain diseases. DNA Methylation The master code that contains the genetic information for all living creatures – from microbes to mammals – is contained in each cell’s DNA. DNA is comprised of four bases which have been abbreviated as G, A, T, and C, which are organized in a ladder-like formation, with pairs of these bases making up the rungs. The letter G pairs with C, and A with T. Strings of these pairings store information, with the information to make specific molecules grouped together in regions called genes. Every cell in the body contains two copies of our genes, with one copy from our mother and one from our father (with the exception of the genes that determine whether we develop as a male or female). There are a limited number of genes that change sequence during our lives. These are the specialized genes for antibodies, which need to be able to change to enable us to fight off new infections. Not every gene should be expressed in each cell of our bodies, however – we don’t want our skin cells manufacturing brain tissue, for example. But if all cells contain the whole genetic code, what prevents our skin from doing just that? Or, for that matter, from our brain cells producing skin? Clearly there must be processes that control which genes are expressed in each cell, so that cells can perform their appropriate tasks within the body. These controlling processes actually determine each cell’s type, whether, brain, kidney, skin, liver, etc. To regulate the levels at which genes are expressed, sets of regulatory proteins bind to parts of DNA encoding each gene. In complex organisms such as humans, many control factors must act together to achieve the degree of power and refinement needed for gene regulation. One of these levels of control is provided by the addition of a small “tag” called a methyl group onto the DNA base C. Methyl group tags in mammalian DNA play an important role in normal development and functioning, by determining whether certain genes are or are not expressed. Genes unnecessary for a cell’s function can be tagged with the methyl groups, and the number and placement of the tags produces a signal saying that the gene should not be expressed. There are proteins in the cell that specifically recognize and bind to the tagged gene, preventing its expression. In addition, some of these proteins determine how tightly folded that section of DNA becomes which also influences which genes can be used, as genes in tightly compressed DNA are typically not well expressed. Abnormal DNA methylation plays a central role in certain diseases as well. Generally it does not matter if both copies of a gene (from the mother and father) are active; however, with certain genes only one copy is normally active. Children are born with abnormalities when both copies of these particular genes are active, which occurs when the methyl group tag that usually blocks one of the gene group’s expression fails to do so. There is also evidence that in some cancers methyl tag groups inappropriately silence genes that control runaway cell proliferation, which results in uncontrolled cell division. Conversely, other diseases are caused by genes, normally inactivated by methylation, that are inappropriately allowed expression. Epigenetics in Schizophrenia & Bipolar Disorders In a 2003 report, Dr. Petronis noted that silencers are normally present on the gene for producing the neurotransmitter dopamine. One characteristic of schizophrenia is an excess of dopamine in the brain. Dr. Petronis investigated the epigenetic gene modification in a section of the dopamine-2 receptor in two pairs of identical twins. In the first set of twins – one with schizophrenia and one without, he discovered that molecular silencers for this gene were almost absent from the twin suffering from schizophrenia. In the second pair of identical twins, both of whom were suffering from the disorder, he found that both were missing this silencer. According to Dr. Petronis, “the twin with schizophrenia [from the first pair] was closer to these unrelated men than to his own twin brother.” Dr. Petronis has undertaken a new study of chromosome 22 genes (chr 22), which have been implicated in major psychosis, but with inconsistent data results. He believes that epigenetics may help us understand the existing chr 22 clinical and molecular findings. Dr. Petronis will perform a large scale analysis of chr 22 in schizophrenia and bipolar disorder; the microarrays he will use will provide for thousands of measurements in a single experiment. His research may lead to a better understanding of gene regulation in major psychosis, and may also begin to explain why the same gene sequence may or may not predispose an individual to schizophrenia or bipolar disorder. Finally Dr. Petronis’ investigations may shed additional light on how – on a molecular level – environmental factors can interact with, and cause changes to, the human genome. |
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