Download The genome sequence is a jazz score

© 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]
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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?
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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.