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© International Epidemiological Association 2003 Printed in Great Britain International Journal of Epidemiology 2003;32:29–31 DOI: 10.1093/ije/dyg015 The genome sequence is a jazz score Miquel Porta Keywords Gene expression, gene–environment interactions, penetrance, low-penetrant genes, highly penetrant mutations, phenotype, oncogenes, mutation, environment, metaphor, music, polymorphism genetics, DNA/genetics, screening, number needed to screen (NNS), genetic testing, jazz, musicians La Nature est un temple où des vivants piliers Laissent parfois sortir de confuses paroles; L’homme y passe à travers des symboles Qui l’observent d’un regard familier. individual organism. Penetrance is the percentage of individuals with a particular genotype that display the genotype in the phenotype; for example, a dominant gene for baldness is 100% dominant in males and 0% penetrant in most females, because the gene requires high levels of the male hormone for expression.3 Single, highly penetrant mutations in so-called cancer genes cause only a small proportion of cancers.1,4,5 Furthermore, once a gene shows penetrance it may show a range of expressivity of phenotype. Expressivity is the degree to which a particular gene exhibits itself in the phenotype of an organism, once it has undergone penetrance. Thus, for example, a penetrant baldness gene in man can have a wide range of expressivity, from thinning hair to complete lack of hair.3 The other main points made by Vineis and colleagues1 were as follows: the proportion of diseases attributable to specific low-penetrant genetic traits is probably much lower than the burden of disease attributable to certain environmental agents; to credit genes with a major independent role in the causes of complex diseases is scientific misjudgement of the way genetics affects disease risk; to assess the role of a gene–environment interaction and screening in a population we need to know the penetrance of the genetic trait and its frequency; a useful approach is to combine penetrance and frequency by computing the number needed to screen (NNS) in order to prevent one case of the target disease; a reasonable (i.e. low) NNS is achieved only by screening for highly penetrant mutations in high-risk families, not for such mutations in the general population or for low-penetrant polymorphisms; we need to temper enthusiasm for genetic testing in populations.1 Correspondances [fragment] In: Les fleurs du mal (1957) Charles Baudelaire It is not possible to do the work of science without using a language that is filled with metaphors. In: The Triple Helix (2000) Richard C Lewontin The main purpose of this paper is to suggest a metaphor— among many possibly valid and evocative—for the role of genes in complex chronic diseases. It is based on the inherent role of host-environmental interactions on the expression of lowpenetrant genes. The relationship between an individual’s genetic makeup and its phenotypic expression can be likened to the relationship between a jazz score and the performed music. I think one of the most inspiring papers published in the last couple of years was the one published by Paolo Vineis, Paul Schulte, and Anthony McMichael in The Lancet.1 Three most important facts that the paper addresses are: (1) gene– environment interactions are intrinsic to the mode of action of low-penetrant genes; (2) only highly-penetrant (e.g. highly deleterious) mutations in cancer genes may act with no interaction with external factors; and (3) the relation between the frequency of a variant and its penetrance is almost inverse: the more penetrant a mutation, the less frequent it is in the population. Penetrance of a gene describes the frequency with which the characteristic it controls (the phenotype) is seen in people who carry it.2 Phenotypes are the observable features of an Misleading and inspiring metaphors of the expression of DNA To explain to non-specialists—and to ourselves—the abovesketched notions and the potential wider meaning of research findings on the human genome sequence,1,4–9 metaphors are being used. Some are misleading, others are like foghorns and lighthouses.10–12 While reminding us that the emphasis on genetic testing often has an unmistakable commercial motivation, Vineis and colleagues remark that such emphasis is often based on and promoted by false metaphors of the role of DNA. For instance, one common set of metaphors likens the genome to computer programs or to instruction manuals. However, a computer program merely executes the instructions, Institut Municipal d’Investigació Mèdica (IMIM-IMAS), Universitat Autònoma de Barcelona, Spain and University of North Carolina at Chapel Hill, USA. Correspondence: Prof. Miquel Porta, Institut Municipal d’Investigació Mèdica, Universitat Autònoma de Barcelona, Carrer del Dr. Aiguader 80, E-08003 Barcelona, Spain. E-mail: [email protected] 29 30 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY without changing them on the basis of context.1,11 The authors prefer ‘a much better metaphor’ proposed by Jeffrey Lewis: If the genome can be seen as a text or a script, then its phenotypic expression can be seen as a performance of that script, bringing the text to vibrant and unique life just as actors on a stage bring life to the words on a page.12 Not that I do not see (and like) the point but, with due respect for actors and theatre people at large, let me suggest that we go one step further. The genome nucleotide sequence is the score of a jazz composition. First, the jazz musician learns how to read and to play the score, and does so embedded in a sociocultural environment, and grows with music and musicians and partners of all sorts. Though her endowment and talents count, so do her colleagues, experiences, and intuition: the result of such interaction is seldom predictable. Then, all over her life she continues to learn: to master technique—certainly—but above all, to express her emotions and ideas among the many treasures that music holds. The genome is thus like the innumerable scores that a jazz aficionado would play during all her life, some with great fidelity to the original musical text, many just—but deeply—inspired by it, still many others almost totally invented, whether improvised or consciously crafted. Surely the music that she expresses stems from the scores (through a marvellously complex process); but well beyond technique and script, every instant the unique music expresses what the musician knows, feels, and wishes to play. (Once, the origin of the music is a scent she smelled in infancy; once, a recent love loss; often the ‘source code’ is unknown.) And the music grows and evolves: with time—and, much more, with the people and places where it swells and flows. Stemming from the score. Sensitive to the other musicians with whom she plays. Delicately responsive to the audiences to whom and with whom she feels, every time of her lifetime. Remember: gene–environment interactions are intrinsic to the mode of action of the highly prevalent low-penetrant genes; once a gene shows penetrance it may show a range of expressivity (the degree to which the gene exhibits itself in the phenotype, based on the interaction between the gene and the local environment); to credit genes with a major independent role in the causes of complex diseases is to misjudge how genetics affects disease risk. Methods now exist to measure the ‘order state’ of sequences of symbols, and they are applied to DNA sequences. Schmitt and Herzel13 studied ‘higher order entropies’ for various DNA model sequences whose exact entropies are known, including a real DNA sequence, the complete genome of the Epstein–Barr virus, which they compared with the entropies of other information carriers (i.e. texts, computer codes, music). They conclude: ‘It seems as if DNA sequences possess much more freedom in the combination of the symbols of their alphabet than written language or computer source codes.’13 We may hence ask: is the jazz metaphor still too reductionist? Be it or not, focusing only on the score/genome sequence may be an error. In The Misunderstood Gene,11 Michel Morange argues that proteins, not DNA, are the category of molecules essential to life. And that there is far more richness and meaning in the structure, functions, and interactions of proteins than in the sequence of genes. Surely: what the jazz musician expresses stems from the score, but that is just the beginning of the story: the process through which music ultimately emerges is incredibly rich. Multifaceted and mysterious as music is, for a long time we will know much better how to make a good musician than about the making of complex diseases—if we focus too much on the genome nucleotide sequence. Metaphors and jazz and genetics: three words of caution Firstly: there are many ways to understand the nature, attributes and functions of metaphors; I here use just one. A renewed discussion on the uses of metaphors in ‘public health genomics’ could be of interest.14,15 Secondly: no single metaphor could even dream to grasp the multiple realities, meanings and implications that the human genome sequence holds;10 I here emphasize just a couple. Obviously, the relationship between genotype and phenotype is highly complex, and it is certainly not a simple function of environmental interactions (I do not think the metaphor contradicts that, for it alludes to many internal host factors). Gene–gene interactions, for instance, are important; you may think that the metaphor does or does not capture such possibility. Redundancy and robustness (in the biological sense) are common in genetics and uncommon in many simple jazz scores. Also ‘against the metaphor’ may be the fact that the DNA has the ‘instructions to make’ the musician and the instrument; or the fact that proteins have little capacity to improvise; etcetera, etcetera ... We just cannot expect any single metaphor to capture every dimension of the human genome. Furthermore, as the field of proteinomics evolves, as knowledge accrues on the interrelationships between genes and human health, new metaphors will also be crafted. Of course, other metaphors, figures, and analogies on the human genome sequence may also be true, provocative, and fun.10,12 Any of them is bound to have limitations. If a metaphor did not have ‘technical limitations’ it would also lack the power to evoke, to persuade, to teach, to stimulate inquisitive minds ... I am also aware that particular sequences of the human genome have directly been used to produce music—among others, by Prof. Ernesto di Mauro (in Rome, Italy). But that is just one among many other stories. And thirdly: jazz is so diverse ...! and it awakens such a variety of feelings, images, and meanings, that it would be no wonder if those in the reader’s mind differed radically from what I try to evoke. Many jazz musicians do not even use scores! I just hope that a true clash does exist—between jazz and genome—in my text. For—beyond musical metaphors—there is something quite important at stake: the part of epidemiology and public health in the social construction of health-related risks and metaphors. The social construction of risks and the epidemiological construction of metaphors We appear to lack a comprehensive analysis of the roles played historically and currently by epidemiological evidence and by epidemiologists in the social construction of risks to health. In THE GENOME AND JAZZ some instances, such roles seem to be rather minor (in comparison, for instance, with the role of the chemical industry, or of the mass media and public relations industries).16,17 Furthermore, the part of epidemiology may have been similarly minor in influencing the emergence of health-related metaphors; in particular, epidemiology has barely affected the downloading into the collective imagery of reductionist and deterministic metaphors on the relationship between genetic characteristics and disease risk. 6–9,14,15,18 Changing this situation could modestly contribute towards the prevention of ‘genomic iatrogenia’. Among other reasons because, in the end, one of the few fundamental issues that the jazz metaphor raises is: how freely can the musician play her own score/genome? Many of us think that—in a favourable environment ...—very freely. But are we right? 31 3 Hale WG, Margham JP. Biology. Collins Reference Dictionary. London & Glasgow: Collins, 1988. 4 Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000;343:141–44. 5 Willett WC. Balancing life-style and genomics research for disease prevention. Science 2002;296:695–98. 6 Porta M, Álvarez-Dardet C. How is causal inference practised in the biological sciences? J Epidemiol Community Health 2000;54:559–60. [Erratum appears in J Epidemiol Community Health 2000;54:720.] 7 Davey Smith G, Ebrahim S. Epidemiology—is it time to call it a day? Int J Epidemiol 2001;30:1–11. 8 Vineis P, Malats N, Porta M, Real FX. Human cancer, carcinogenic exposures and mutational spectra. Mutat Res 1999;436:185–94. 9 Bobrow M, Grimbaldeston AH. Medical genetics, the human genome project and public health. J Epidemiol Community Health 2000;54: 645–49. 10 Avise JC. Evolving genomic metaphors: a new look at the language of Acknowledgements I am obviously (and gratefully) indebted to Paolo Vineis, Paul Schulte, and Anthony McMichael: for the above-mentioned paper and for many other wonderful scientific exchanges along similar scores. For their comments to this paper and their teachings on genetics, epidemiology, metaphors, and jazz—or all of the above—, warm thanks are also due to Alfredo Morabia, Lluís Quintana-Trías, Miguel Valverde, Miguel Beato, Miguel Hernán, Antoni Sitges, Roderic Guigó, Yoav Ben-Shlomo, Carlos Álvarez-Dardet, and two excellent reviewers (unfortunately, anonymous). To all of them I apologise for not having been able to better integrate their multiple suggestions. DNA. Science 2001;294:86–87. 11 Morange M. La Part des Gènes. Paris: Odile Jacob, 1998. English trans- lation: The Misunderstood Gene. Cambridge, Mass.: Harvard University Press, 2001. 12 Lewis J. The performance of a lifetime: a metaphor for the phenotype. Perspect Biol Med 1999;43:112–27. 13 Schmitt AO, Herzel H. Estimating the entropy of DNA sequences. J Theor Biol 1997;188:369–77. 14 Castiel LD. Apocalypse ... now? Molecular epidemiology, predictive genetic tests, and social communication of genetic contents. Cad Saúde Pública 1999;15(Suppl.1):73–89. 15 Lippman A. Led (astray) by genetic maps: the cartography of the human genome and health care. Soc Sci Med 1992;35:1469–76. 16 Porta M. Bovine spongiform encephalopathy, persistent organic References 1 Vineis P, Schulte P, McMichael AJ. Misconceptions about the use of genetic tests in populations. Lancet 2001;357:709–12. 2 Vogelstein B, Kinzler KW. The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998. pollutants and the achievable utopias. J Epidemiol Community Health 2002;56:806–07. 17 Porta M, Zumeta E. Implementing the Stockholm treaty on POPs [Editorial]. Occup Environ Med 2002;59:651–52. 18 Porta M, Ashton JR, Álvarez-Dardet C. Genes as causes: scientific fact or simplistic thinking? J Epidemiol Community Health 1999;53:385.