Epigenetics: beyond DNA sequence
IDENTICAL TWINS are born with the same set of genes. Yet as they grow older, they begin to show subtle differences in their physiology and behaviour.
They differ in their susceptibility to diseases, or in their fertility, or the age of menopause. Why? Or, consider cloned animals like the famous Dolly. Dolly aged faster than we had anticipated and developed arthritis.
What are the reasons? The genotype or the genetic endowment of identical twins or clones is the same. Yet the phenotype — the physiology, the bodily functions and even some anthropomorphic features — are distinctly different. Why?
Emerging branch
Genetics is not all. An emerging branch called epigenetics is called in to explain the puzzle.
The Greek prefix `epi' has been used in a variety of contexts. In the word epilogue, it takes on the meaning of `after'; in epicentre, it means right above; in epicarp, it means around; and in epiphyte and epigenetics, it takes on the sense of `over' or `governing'.
While the term epigenetics has been around for over 100 years, it was given a precise definition by the biologist C.H. Waddington, who wrote in 1942: "epigenetics is the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being."
Contemporary research in biology shows that Waddington was on the right track. It has become clear that the genome does not have just the sequential information stored in the arrangement of the four bases A, C, G and T in its DNA chain.
These are of course important in terms of the words (codons), sentences (genes) and paragraphs and books (chromosomes). But there are additional layers of information stored in the mammalian genome, and it is these that we refer to as the epigenome. Epigenetics is the study of this part of information carried in a cell, which is heritable during cell division but does not constitute part of the DNA sequence. Heritable, yet not part of the DNA sequence?
Yes. Epigenetic mechanisms involve chemical modifications of the DNA itself, or modifications of proteins that are closely associated with DNA, such as the histone proteins that bind to and compact the DNA chain into the package called chromatin.
Some others that closely interact with, and govern the function of DNA, are nuclear scaffold proteins and transcription factors.
Epigenetic modifications involve (a) chemically attaching a methyl group (-CH3) to the DNA base cytosine, particularly cystosines that come before the base guanine (the so-called CpG sequence; it is estimated that about 80 per cent of all CpGs in a cell are methylated); (b) chemicals attaching an acetyl group (CH3CO-) to the amino acid lysine at the end of two histone proteins that wrap around the DNA (causing the otherwise tightly folded DNA chain to open up a little); (c) remodelling of other chromatin-associated proteins; and (d) `jumping' or transposition of certain stretches of the DNA sequence itself within the long chain, leading to subtle changes in the way the genetic information is read or processed in the cell.
Each one of the above modifications acts as a signal that controls and modifies the expression of genes. As Nicholas Wade describes in The New York Times, they "act on a gene like a gas pedal or a brake, marking it for higher or lower activity".
Of course, quite besides these, life style habits such as smoking, long-term use of steroids and certain other drugs also influence gene functions by physically or chemically interacting with DNA. But unlike epigenetic markers, which are programmed in the same manner in clones or identical twins, life styles and environmental exposure may differ between individuals.
Epigenetic markers differ as identical twins grow older. It is this aspect of how epigenetic differences might arise during the lifetime of identical twins that has been reported in a landmark study by a group at the Spanish National Cancer Centre at Madrid (PNAS 102, 10604, 2005).
They analysed the various epigenetic markers in eighty identical twins from Spain (30 males 50 females, ranging in ages 3-74 years). How did these genetically identical pairs differ in their phenotype — even as the epigenetic markers in them were pretty much the same?
Environmental factors
The answer came as the twins grew older — their epigenetic markers began displaying differences. DNA methylation and histone modification markers were seen to be distributed throughout their genome, and grew more distinct in the twins who were older, had different life styles, and had spent less of their lives together.
These underscore the significant role of environmental factors in translating a common genotype into a different phenotype. These epigenetic differences also show up in the susceptibility to diseases such as cancer or arthritis.
What we have learnt in recent times is that while the genome is the same in every cell of our bodies, the epigenome is expected to be different for each of the 250-odd cell types we have.
So, would it not be worthwhile to initiate the Human Epigenome Project, just as the human genome project? Surely, say a number of biologists, among whom is Dr. Florian Eckhardt of the firm Epigenomics AG in Berlin, Germany (Eckhardt et al. Expert Reviews in Molecular Diagnostics, 4, 609. 2004). For a feel of what the epigenome project involves, go to the website www.epigenome.org.
D. BALASUBRAMANIAN
dbala@lvpei.org
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