Epigenetics
Epigenetics refers to alterations in gene expression that cannot be explained by changes in the sequence of deoxyribonucleic acid.
Epigenetic traits have significant economic and medical relevance. For example, during the last few years it has become clear that epigenetics has an essential role in the mechanism by which the expression of genes is turned on and off. Selective temporal gene expression is vital for the normal development of cells and organelles in both animals and plants, and the response of genomes to environmental stress. In addition, expression of certain genes at an inappropriate time is known to play a critical role in certain human diseases. The increased understanding of epigenetic mechanisms should reveal more of the functioning of genes.
The concept of epigenetic arose with the increased awareness that active and inactive genes having the same DNA sequence can be passed from parent cells to progeny cells. Thus, the transmission of genes from generation to generation - the inheritance of DNA base sequence - is distinct from the mechanisms involved in the transmission of alternative states of gene activity following cell division.
The turning on and off of genes is also called genomic imprinting. The differential expression of genes of identical DNA sequence is accomplished by a mechanism called gene silencing. Gene silencing is an epigenetic phenomenon, involving the addition of a methyl group to certain of the bases, particularly cytosine, which comprises DNA. Methylation is the most widely studied epigenetic characteristic. Methylcytosine was first recognized in 1948. Its significance has been controversial, not least because in some cases its existence violates the principles of Mendelian genetics.
Epigenetic changes acquired by cells over their natural lifespan are passed on from mother to daughter cells--for example when a liver or skin cell divides, or a malignant cells grows into a tumor--but they are normally eradicated from the cells that produce the next generation. This is in line with Mendel's genetic laws. However, new evidence from experiments on plants, fruit flies, and mice suggests that this is not always the case. Some of the epigenetic changes are passed onto the offspring, raising the possibility that epigenetics could play a role in evolution.
The connection between DNA methylation and gene expression was first shown two decades ago. It is now clear that methylation of cytosine acts to alter the three dimensional structure of the DNA in that region of the DNA. Transcription is blocked, preventing expression of the gene and so the production of the protein it encodes. This may be important in regulating the expression of an organism's own genes, or in defending itself from invaders, through the methylation of the invader's DNA.
Clinically, malfunctions in gene expression due to methylation are the cause of Prader-Willi syndrome and Angelman syndrome, both of which manifest as mild retardation, weight imbalances and behavior abnormalities. An estimated 100-200 human genes are transcriptionally affected by methylation. In addition to the above maladies, others include defects in vitamin and human growth factor VIII production, fragile-X syndrome (a common form of mental retardation) and ICF syndrome (characterized by immunodeficiency and facial abnormalities), diabetes, myotonic muscular dystrophy, Huntington's disease, developmental defects such as neural tube formation and tumor formation. It has been shown that cancerous cells have enhanced cytosine methylation, and that this occurs early in cancer development. In the future safe drugs targeting the methylation machinery could be used to fight cancer and restore normal function to a cell.
Another manifestation of epigenetics is epistasis, a double mutation where one mutation masks the physical expression of another mutation. The underlying cause of epistasis is altered DNA transcription, again involving methylation. Epistasis is always a recessive characteristic. For instance, a mutant gene that causes complete baldness would be epistatic to a mutant gene that determines hair color. Likewise, a mutation preventing an early step in a biochemical pathway will be epistatic to a mutation that prevents a step later in the same pathway.
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