Epigenetics – Could the central dogma be in danger?

DNA moleculeIn 1859, Charles Darwin set out his theory of evolution by natural selection, a theory that consists of three vital components – variation, inheritance and differential reproductive success. We are not all as beautiful as Angelina Jolie, for example (number one on the Official Top 30 World’s Most Beautiful Women of 2013), but her biological children likely will be, and no doubt many a man would be willing to father those children. Parents and offspring can share more than looks, however, and we can only hope that Angelina’s biological daughters are not also at risk of developing breast cancer. Without inheritance, adaptations (such as good looks), and maladaptations (for example heritable cancer risk) alike, could not be passed on from one generation to the next.  A century’s worth of work aimed at understanding this process of inheritance, including experiments with peas and bacteria viruses, finally culminated in 1953, when James Watson and Francis Crick revealed the structure and properties of DNA, the molecule that carries genetic information from generation to generation.

Eight years later in 1961, a young biochemist Marshall Nirenberg made a breakthrough discovery that allowed the genetic code – ‘the blueprint for life’ – to be deciphered. According to the code, the great diversity of life on our planet is generated in a remarkably simple manner – a 5-letter alphabet (the bases or nucleotides A, C, G, T and U), written to form 64 three-letter words (codons, such as AGG), codes for twenty amino acids that serve as the building blocks of proteins, and in turn the building blocks of life. Discovering the genetic code allowed us to understand how the variation essential for Darwin’s theory of natural selection could arise. Mutations that cause a change of a base from an A to a C, for example, can cause a different amino acid to be produced and a different protein to be built. This might sound trivial, but such minor changes in the genetic code can have dramatic impacts on an organism – how it appears physically, how it behaves, how likely it is to develop cancer.  Who we are as humans and our uniqueness relative to others appeared to be controlled quite tangibly and inflexibly by what is written in our DNA.

It almost seems foolish to have believed it so simple. The burgeoning field of epigenetics has more recently forced us to see the DNA world in a completely different light. Epigenetics (‘epi’ = ‘on top of’ or ‘above’) is the study of changes in gene activity that are not caused by changes in the DNA sequence. You can see the dilemma here – modification of gene function without change in the nucleotide sequence surely breaks the previously accepted rules. If DNA is the blueprint for life, how can we explain changes to ‘life’ that are not prewritten in the code? The term ‘epigenetics’ was first coined in 1942 by Conrad Hal Waddington, a man interested in bridging the gap between genetics and embryology (the science of the development of an embryo). Waddington considered development to be an ‘epigenetic process’ – a phenotype (such as Angelina’s looks) results not only from genetic processes but also from interactions with the external environment (such as diet or stress). Whilst Waddington’s work expanded the classical genetic vision on the phenotype, his concepts were accused of being ‘rather fuzzy at the edges’.

The definition of epigenetics has since been refined, and we now know that although epigenetic modifications can arise through various different mechanisms, they usually involve chemical changes that affect gene expression (gene expression is the process by which the information contained within a gene is translated into a functional gene product). The most studied epigenetic modification is DNA methylation. Along the human genome there are millions of sites (known as CpG sites) where methyl groups (a carbon atom bonded with three hydrogen atoms) can attach and affect the expression of nearby genes. These methyl groups act as tags on the DNA, controlling how strongly the genes are switched on. This methylation process forms an integral part of our development as human beings. When sperm and egg collide, the process of cell division and specialisation begins through the activation of certain genes and the inhibited expression of others. In this sense, epigenetics can be seen as the study of the chemical reactions that switch on and off certain parts of the genome at strategic times, and the factors that influence these reactions.

Epigenetic changes may last through cell divisions for the duration of a cell’s life. For cell specialisation to occur, as during development, any previous epigenetic tags added to the cell’s DNA need to be erased through a process of ‘reprogramming’, returning the cell to a genetically ‘blank state’.  It is possible, however, for some of these tags to escape reprogramming and pass unchanged from parent to child. Recent debate over the definition of epigenetics has in fact related to whether or not epigenetic modifications are heritable, and whether they are required to be so. If epigenetic modifications were to occur in sperm, for example, these could potentially be transmitted from father to offspring. A recent study published by researchers at McGill University has shown that a male mouse’s diet can affect the methylation in sperm of genes implicated in the development of chronic diseases such as cancer and diabetes. Although only two of these differentially methylated genes were differentially expressed in the placenta of the male’s offspring, the study nevertheless highlights the importance of understanding the potential mechanisms underlying inter-generational disease transmission.

If parents are able to pass environmental information, in the form of epigenetic modifications, on to their offspring as well as their genetic code, epigenetic inheritance adds a whole new dimension to the modern picture of evolution. For over a hundred years we have accepted that the genetic code changes slowly, through the processes of random mutation and natural selection. Epigenetics creates the possibility for a much more rapid response to signals from the environment. It requires a completely different concept of information transfer – experiences had generations ago, such as a famine during your grandmothers time, could influence the way that your body develops, even in today’s more plentiful western world. Having said this, the epigenome (the combination of DNA plus epigenetic tags) has the potential to remain flexible as your environment continues to change, and may allow continual adjustment of gene expression accordingly. All this could happen without a single change in the DNA code. Could nurture have finally gained a place over nature? Perhaps there is hope for those on the quest for world-renowned beauty after all.

Emily Brown PhD

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