The Deeper Genome: Why there is more to the human genome than meets the eye
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Over a decade ago, as the Human Genome Project completed its mapping of the entire human genome, hopes ran high that we would rapidly be able to use our knowledge of human genes to tackle many inherited diseases, and understand what makes us unique among animals. But things didn't turn out that way. For a start, we turned out to have far fewer genes than originally thought - just over 20,000, the same sort of number as a fruit fly or worm. What's more, the proportion of DNA consisting of genes coding for proteins was a mere 2%. So, was the rest of the genome accumulated 'junk'?
Things have changed since those early heady days of the Human Genome Project. But the emerging picture is if anything far more exciting. In this book, John Parrington explains the key features that are coming to light - some, such as the results of the international ENCODE programme, still much debated and controversial in their scope. He gives an outline of the deeper genome, involving layers of regulatory elements controlling and coordinating the switching on and off of genes; the impact of its 3D geometry; the discovery of a variety of new RNAs playing critical roles; the epigenetic changes influenced by the environment and life experiences that can make identical twins different and be passed on to the next generation; and the clues coming out of comparisons with the genomes of Neanderthals as well as that of chimps about the development of our species. We are learning more about ourselves, and about the genetic aspects of many diseases. But in its complexity, flexibility, and ability to respond to environmental cues, the human genome is proving to be far more subtle than we ever imagined.
why this process seemed defective in some of his patients.126 This led him to try and identify all the cellular components required for generation of proteins. A major step forward came with his discovery that a ‘cell-free’ extract of rat liver could still generate proteins if supplied with amino acids.126 Plying this system with radioactively labelled amino acids or RNA in order to identify their respective roles in the synthesis process, Zamecnik noticed that, ‘strangely enough, the RNA
and this contact is sufficient to activate the polymerase. That transcription factors are themselves regulated by intracellular signals explains how information from the environment can influence gene action. This is one reason why, despite different cell types containing the same genomes, the proteins produced in such cells are very different. So heart cells typically contain proteins that regulate their contraction, while liver cells contain those involved in the metabolism of foodstuffs. The
crucial way in which the body fights infection is through its ability to generate antibodies against a seemingly unlimited number of foreign molecules, or antigens. Although some of this diversity comes from alternative splicing, a far greater role is played by a rearrangement of the DNA in the immunoglobulin genes coding for such antibodies. Immunoglobulins are composed of four protein chains, two heavy chains and two light chains. Together they form a ‘Y’ shape, and the tips of the Y constitute
of enzymes in the body, it was not surprising that one of the first tasks of geneticists, following the completion of the Human Genome Project in 2003, was to catalogue all the genes that code for enzymes in the genome. Yet what was surprising was how many of those identified seemed to be catalytically inactive, as defined by the presence of debilitating mutations in their active sites.425 So, of the 518 human kinases, enzymes which, as we saw in Chapter 3, activate other proteins by adding a