Under the Microscope: The classical understanding of molecular genetics is that biological traits are specified by information encoded in DNA in the linear sequence of its sub-units.
This DNA information is translated into proteins, the agents responsible for effecting most of the cell's activities. Most traits are transmitted by DNA genes operating in this manner, but we now also know of a separate code written in chemical notation outside the DNA sequence that has significant effects on the health and appearance of organisms. This separate information system is called the epigenetic code.
DNA is a large molecule made of 4 different types of nucleotide sub-units termed A, T, G, C for short. The information content of DNA resides in the linear sequence of these four sub-units and the code is read in groups of three successive letters.
Proteins, the active agents in the cell, are large molecules made of units called amino acids joined together in a long string. There are 20 different kinds of amino acids and the identity of a protein is determined by the sequence of amino acids linked together in its long chain. This amino acid sequence in turn is specified by the sequence of nucleotides in the DNA gene that specifies the protein. A length of DNA code sufficient to specify a protein is called a gene. The unit of biological organism organisation is the cell and there are about 30,000 genes in every human cell.
A change in DNA nucleotide sequence in a gene changes the information content of the gene and such a change is called a mutation. Many factors can cause mutations - the cell can make a mistake during DNA synthesis, a foreign chemical can delete a nucleotide, radiation can damage DNA, and so on. Almost all heritable disorders are caused by mutations.
DNA does not occur in the cell as a naked molecule - it is associated with proteins called histones to form a complex substance called chromatin. Certain chemical modifications of the DNA or the histones can alter the structure of the chromatin without altering the nucleotide sequence in the DNA. Such modifications are said to be epigenetic.
Chromatin structure has a profound effect on gene expression. For example, if part of the chromatin is tightly bunched up, the genes in this region will not be translated into proteins. If the chromatin is stretched out, the genes in the region are available for expression.
Epigenetic modifications that inappropriately silence genes can cause a number of human diseases. For example, most cancers involve the epigenetic silencing of genes that control rate of cell division. The epigenetic chemical modifications in human tumours involve the addition of chemical groups called methyl groups to DNA and the removal of acetyl groups from histone proteins. These changes condense chromatin and silence certain genes.
Since epigenetic changes are so important in cancer, new therapies are under development to reverse DNA methylation and inhibit deacetylation of histone.
Only 2 per cent of our DNA directly codes for proteins. Over 40 per cent of the remaining "non-coding" DNA is made up of "junk DNA", analogous to "spam" e-mail.
All students of biology have heard of the French biologist Jean-Baptiste Lamarck (1744-1829) who is best remembered for a discredited theory of heredity, the "inheritance of acquired traits". For example, this theory held that, because giraffes had to stretch their necks to reach high leaves, they then give birth to progeny with similarly stretched necks. We know this explanation is wrong, but what was not appreciated until recently is that, in some cases, the environment can indeed cause changes in parents that are transmittable to offspring.
Take the case of Agouti mice whose coat colour is determined by the Agouti gene. This gene can be partly or fully silenced depending on the extent to which its DNA is modified by methyl groups. In a famous experiment some pregnant Agouti mice mothers were fed folic acid and other methyl-rich dietary supplements, whereas others were not.
Despite the fact that all offspring inherited the same Agouti gene (i.e. its nucleotide sequence was identical in all cases), mice who received supplements produced offspring with mostly brown fur, while mothers without supplements produced mostly yellow pups and these were more susceptible to obesity, diabetes and cancer. The effect appears to be solely due to increased methylation and reduced expression of the Agouti colour gene.
Epigenetic effects have also been noted in humans. A famine occurred towards the end of the second World War in German occupied western Holland and about 30,000 people died. Data collected at the time and subsequent follow-up research has correlated pre-natal exposure to famine with low-birth weight, and subsequent predisposition to diabetes, obesity, heart disease and breast and other cancers in the offspring of the women. Even more interestingly, one study correlated pre-natal exposure to famine with the subsequent birth of smaller-than-normal grandchildren. This suggests that a pregnant mother's diet can affect her health in such a manner that not only her children, but her grandchildren inherit the same health problems.
William Reville is associate professor of biochemistry and director of microscopy at UCC.