John Parrington, The Deeper Genome: Why There is More to the Human Genome than Meets the Eye (Oxford University Press, 2015), £18.99
John Parrington has written a lively and engaging popular science book about the history of genetics or what is increasingly referred to as “genomics”.
The history starts towards the end of the 19th century with Gregor Mendel who first showed, in pea plants, that characteristics like height and colour can be passed to offspring according to precise mathematical rules. Mendel’s work implied that for sexually reproducing organisms there are two copies of what would become known as genes, one inherited from the father and one from the mother. In “dominant” situations only one copy of a gene variant is needed to help produce the characteristic whilst in “recessive” situations two copies are required.
If characteristics like height and colour can be passed on to offspring how do genes help produce these characteristics? A key insight was provided by Jacques Monod and Francis Jacob who began their research around the start of the Second World War. Monod and Jacob argued that there are in fact two types of genes: “structural” genes and “regulatory” ones. Structural genes “code” for ribonucleic acid or RNA which has a similar structure to deoxyribonucleic acid or DNA. RNA in turn produces proteins including enzymes. Regulatory genes “code” for RNA whose protein products act as switches to turn these structural genes on or off. It should be noted that recent research paints an even more complex picture than this distinction suggests and this is in part the source of the “deeper” genome of the book’s title.
Perhaps the most familiar part of the history conveyed in the book is Francis Crick’s and Jim Watson’s discovery of the double helix structure of DNA in the early 1950s. Although the contribution of Rosalind Franklin was overlooked at the time she played a key role in solving the problem of how the molecule was able to replicate. As their full names suggest, both DNA and RNA are nucleic acids, the subunits of which—nucleotides—come in four varieties, defined by the bases. The four bases of DNA are: adenine, cystosine, guanine and thymine. The key insight Crick and Watson proposed was that the two strands of the double helix are held together by an attraction between adenine and thymine on the one hand and guanine and cystosine on the other. When the strands split apart during cell division they form the template for another mirror-image strand to be formed. The importance of the aforementioned discoveries is shown by the seemingly never ending flow of Nobel Prize winners that Parrington mentions.
In the 1960s Roy Bitten and David Kohne made the surprising discovery that over half of the genome of a mouse is made up of sequences that do not code for proteins. It was not at all clear what if anything they did do. This seemed to lead to the picture of islands of genes in a sea of repetitive sequences or “junk” DNA. This also raised the question of why our bodies would spend vital energy replicating and storing something with no apparent function.
More recently, the Human Genome Project set out to map the 3 billion or so nucleotides in the human genome. This was and still remains the largest and most costly biological project ever known. It was completed to much fanfare in 2003. Another aim of the multi-billion pound project was to work out the number of genes humans have. This was a surprisingly small 22,000 (a common estimate before the start of the project was 100,000). Even more surprising is the fact that grapes have over 30,000! Among other things, this clearly shows that genes alone cannot account for the differences between humans and other organisms.
In 2012 the Encyclopedia of DNA Elements or ENCODE was published. Its aim was to provide detailed information about each gene and its relationship to the rest of the genome. Perhaps ENCODE’s most surprising claim was that as much as 80 percent of what had been considered to be “junk” DNA actually had an important function. Parrington is clearly excited by the findings of ENCODE but he is equally clear that those findings have not been universally accepted. For example, one critic lambasted the claims of ENCODE as “absurd”, its statistics “horrible” and that it was “the work of people who know nothing about evolutionary biology” (p4).
Much of the history contained in the book will be familiar to those with an interest in biology. However, everyone will learn something new. For example, not only does Parrington tell us that Monod was jointly responsible for the distinction between regulatory and structural genes (as noted above), we also learn that while he was carrying out this work he was active in the French Resistance, eventually becoming its chief of staff. Perhaps even more amazing is that Monod helped smuggle the dissident scientist Agnes Ullman out of Hungary following her support for the failed Hungarian uprising.
Francis Crick, one of the discoverers of the double-helical structure of DNA, famously contended that life is a one-way flow of information from DNA to RNA to protein, something he dubbed the “central dogma of molecular biology”. An interesting aspect of the book is Parrington’s contention that this is not in fact always the case. For example, it turns out that the position on a chromosome of some genes is not fixed but rather highly mobile. Furthermore, the source of some gene’s mobility is via an RNA intermediary which then turns back into DNA before it reinserts itself into the chromosome. The key point here is that RNA can code for DNA and, as a consequence, the flow of information, contrary to Crick’s claim, is not one-way but two-way.
Such findings appear to lead to one of the more unusual parts of the book, Parrington’s cautious support for “epigenetics”. This is the claim that gene activity may be altered in ways that do not involve changes in the DNA sequence. This is sometimes referred to as “Lamarckism” following the work of French scientist Jean-Baptiste Lamarck, who suggested 200 years ago that the environment directly influences hereditary material. Although Parrington cautiously supports epigenetics as an alternative to Crick’s central dogma, sometimes he uses language that seems to support the central dogma and is more in keeping with those who mistakenly hold that genes almost single-handedly make us who we are. For example, he writes of “how our genomes define us” (p4) and that “our human uniqueness must be based on genetic differences between ourselves and other species” (p172).
Parrington’s stated aim in the book is to find a middle way between two views. The first, he argues, holds that genes should be treated as abstract units or, little better, as discrete and isolated entities on chromosomes. The second recognises their complex and interconnected nature but holds that we have learnt nothing useful from the Human Genome Project. However, this way of framing the argument suggests that there is only one choice to be made when in fact there are two questions here. First, has the Human Genome Project given us a clearer idea of the nature of genes, the genome they constitute and the causal networks of which they are part? Secondly, have we learnt anything useful from the Human Genome Project about the diseases that afflict us? Parrington is correct that the answer to the first is “yes” but despite being convinced by much in the book I think that the answer to the second is a qualified “no”; qualified because, while much has been learnt, precious little has been achieved in terms of actually fighting disease and saving lives. To see this consider the following quote in Parrington’s book from Craig Venter: “We have, in truth, learned nothing from the genome other than probabilities. How does a one or three per cent increased risk for something translate into the clinic? It is useless information” (p152). Venter, as the leader of Celera Genomics’s rival efforts to sequence the human genome, would seem to have much to gain from a positive assessment of its importance.
However, overall Parrington has written a very good popular science book that can be read by all with profit. I recommend it.