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Acknowledgements
33. Harris, E. E. & Hey, J. X chromosome evidence for ancient My work is funded by the Max Planck Society, the For over 90 years, the association between human histories. Proc. Natl Acad. Sci. USA 96, 3320–3324
Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft. I thank B. Cohen, H.
34. Yua, N. & Li, W.-H. No fixed nucleotide difference between Kaessmann, D. Serre, M. Stoneking, C. Stringer, L.
Africans and non-Africans at the pyruvate dehydrogenase Vigilant and especially D. Altshuler for helpful comments E1 Ȋ-subunit locus. Genetics 155, 1481–1483 (2000).
results from faults in the DNA double helix(see, for example, the Online MendelianInheritance in Man database at www.-ncbi.nlm.nih.gov/omim/, which pro- vides a catalogue of human genes and geneticdisorders). Is it then too extrapolative to Aravinda Chakravarti* & Peter Little†
suggest that all diseases and traits, each of *McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Jefferson Street Building, 2-109, Baltimore, Maryland 21287, USA †School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New SouthWales 2052, Australia (e-mail: p.little@unsw.edu.au) Is our fate encoded in our DNA?
Is Watson’s genetic aphorism of human dis-
What has been learnt about individual human biology and common diseases 50 years
ease really true? The excitement of genetics, on from the discovery of the structure of DNA? Unfortunately the double helix has
and the perceived medical importance of the not, so far, revealed as much as one would have hoped. The primary reason is an
inability to determine how nurture fits into the DNA paradigm. We argue here that the
environment exerts its influence at the DNA level and so will need to be understood
before the underlying causal factors of common human diseases can be fully
recognized.
approaches used successfully to identify single-gene diseases could simply be applied “We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes.” J. D. Watson, quoted in Time magazine, 20 March 1989 (ref. 1).
morbidity and mortality, such as cancer,heart disease, psychiatric illness and the like.
This would enable a boon for diagnosis, The double helix, in its simplicity and laws of inheritance. So far, human geneticists understanding and the eventual treatment of have been most successful at understanding single-gene disorders, as their biological basis, discovery provided the bridge between the and thus presumed action, could be predicted from inheritance patterns. Mendelian dis- been slow, and only recently have there been modern functional definition of genetics, eases are typically caused by mutation of a some successes6. It is now appreciated that single gene that results in an identifiable although genes are one contributor to the biochemistry, cell biology and physiology.
disease state, the inheritance of which can readily be traced through generations.
they contain must have properties that are different from the more familiar, determin- istic features of single-gene mutations.
about the role of genes in human disease.
Indeed, the underlying genes are likely to be Notably, mutations in specific genes lead to specific biological changes, and rarely do major role, and mutations within these genes mutations in multiple genes lead to an being common and imparting small geneticidentical set of characteristics that obey effects (none of which are either necessary or One gene, one disease
‘Mendelian inheritance’. Additionally, Recognition that genes have a role in human sequence diversity of mutations is large and, Moreover, there is a suspicion that these disease dates back to the rediscovery of the rules that govern the inheritance of genes by almost always rare, showing relatively and with the environment and lifestyle, Gregor Mendel — the so-called Mendelian although the molecular specificity of inter- NATURE | VOL 421 | 23 JANUARY 2003 | www.nature.com/nature 2003 Nature Publishing Group
actions is unproven8. To complicate matters, genetic variation and environment suggests population differences that have led to health ideas about genetics are simplistic; two in disparities and, as is becoming more evident, particular are the ‘bar code’ view of genetic the incidence of these disorders can show sig- diagnosis and the ‘right medicine for the Interplay of DNA and environment
tially binary — either an adenine or guanine The inability of geneticists to easily identify base, or a cytosine or thymine base — at a given position in the sequence. Unfortunate- vindication of the importance of nurture.
ly, this leads to a tendency to define genetic This is too simplistic; the influence of nature individuality as a binary pattern, a so-called and nurture cannot be neatly divided, as it is ‘bar code’ for each individual. Some genetic clear that nurture is important to biology variants convey susceptibility to a disease, through its actions on DNA and its products.
but they typically convey risk rather than The environment must affect the regulation certainty of being afflicted with a condition. of critical genes by some mechanism and so, seen another way, mutations are not the only have significant public health implications, research reveals that despite having hetero- intolerable, knowledge of likely outcomes, acquired — a specific tumour develops only with no certainty, only probabilities. Most from altering the expression (activity) of individuals, we suspect, are ill equipped to specific sets of genes10. That is, a variety of deal with the knowledge that they have a 50 per cent chance of succumbing to an ill- change the activity of specific genes and, ness; equally, society has had great difficulty consequently, interrupt precise aspects of in knowing how to respond to such informa- cell metabolism. The regulation of circadian tion, hence the concerns regarding genetic discrimination13. The reality is that the external environmental cues influence DNA genetic bar code is weakly predictive and individuals may find this threatening, life enhancing or just irrelevant; in any event, interacts with the environment, directly and much work is needed to enable the predictive indirectly, to predispose or protect us from disease. If perturbations of multiple genes contribute to a disorder, then the activities of the recognition that medicine has to refocus these genes can be affected by any combina- on the individual. This has been the rallying cry, particularly within the pharmaceutical exposure altering their function. It is our business, of pharmacogenomics (the applica- opinion that genes have a stronger, maybe tion of genome-scale understanding to the even a pervasive, role in all diseases and development of medicines), and there is no traits, with the understanding that it is the doubt that understanding of the variation collective action of genes and nurture that Figure 1 Studies of identical twins have revealed that
some conditions, such as psoriasis, have a strong genetic exploded in the past 20 years14. The underpin- Rather than dismissing the role of component and are less influenced by environmental and ning idea is enormously attractive — if genetic environment, our view embraces it directly, lifestyle factors — identical twins are more likely to share analysis of key DNA variations can be used to these diseases. But other conditions, such as multiple understand how individuals might respond to term ‘genetic’. It also emphasizes the work sclerosis, are only weakly influenced by genetic makeup drugs, then it could be possible to eliminate the that remains to be done to understand gene and therefore twins may show differences depending on difficult, sometimes lethal, hit-and-miss regulation and, in particular, how genes and their exposure to various environmental factors.
approaches to medication that are a necessary feature of present medical practice.
Unfortunately, the influence of lifestyle is human disease. Human beings are each to moderate in diabetes, heart diseases, just as much a feature of drug response as it is migraine and asthma, to high in disorders of any other genetically influenced condi- unique set of experiences. Both need to be such as psoriasis12. Critically, the discordance tion. The classic case of the influence of understood to intervene effectively in disease between identical twins — where twins show drinking grapefruit juice on the levels of different diseases despite being genetically many drugs15 illustrated that there can be no identical — illustrates the influence of exoge- such thing as ‘the patient’, because the Implications for medicine
nous factors, but does not prove the lack of patient is living in a complex world that What does this mean in practice? The assess- influence of genes: of course, environmental changes by the minute. Once again, predic- ment of the quantitative role of genes in factors over a lifetime affect an individual’s tions for the population do not have the same human traits is derived largely from studies on identical and fraternal twins (Fig. 1). By this measure, all common disorders have a ‘genet- that all of the relevant genetic and environ- Future challenges
ic’ basis, but the contribution varies from mental factors are identified that lead to a The challenges that lifestyle presents to slight in some cancers and multiple sclerosis, disease. Appreciating the relationship of genetic studies are considerable. We believe NATURE | VOL 421 | 23 JANUARY 2003 | www.nature.com/nature 2003 Nature Publishing Group
that the next 50 years will bring a genuine an appreciation of both genetic and 8. Sullivan, P. F. et al. Analysis of epistasis in linked regions in the revolution of far greater individual signifi- environmental individuality; only then will Irish study of high-density schizophrenia families. Am. J. Med.
Genet. 105, 266–270 (2001).
cance than that delivered by genetics over the individuals understand the meaning of their 9. Boyle, J. P. et al. Projection of diabetes burden through 2050: past 50 years. This is because lifestyle can impact of changing demography and disease prevalence in the conceivably be analysed, and in so doing, it United States. Diabetes Care 24, 1936–1940 (2001).
should be possible to develop a genuinely 10. Münger, K. Disruption of oncogene/tumor suppressor networks during human carcinogenesis. Cancer Invest. 20, 71–81 (2002).
1. Jaroff, L. The gene hunt. Time 20 March, 62–67 (1989) 11. Panda, S., Hogenesch, J. B. & Kay, S. A. Circadian rhythms from 2. Arcos-Burgos, M. & Muenke, M. Genetics of population isolates.
flies to human. Nature 417, 329–335 (2002).
Clin. Genet. 61, 233–247 (2002).
about how to identify lifestyle influences: 12. MacGregor, A. J. et al. Twins: novel uses to study complex traits 3. Aidoo, M. et al. Protective effects of the sickle cell gene against and genetic diseases. Trends Genet. 16, 131–134 (2000).
such studies will have to be on an unprece- malaria morbidity and mortality. Lancet 359, 1311–1312 (2002).
13. Wertz, D. C. Ethics watch. Nature Rev. Genet. 3, 496 (2002).
dented scale and one of the first of these, 4. Tishkoff, S. A. & Williams, S. M. Genetic analysis of African 14. Evans, W. E. & Johnson, J. A. Pharmacogenomics: the inherited proposed to comprise 500,000 individuals in populations: human evolution and complex disease. Nature Rev. basis for interindividual differences in drug response. Annu. Rev. Genet. 3, 611–621 (2002).
the United Kingdom, has already started16.
Genomics Hum. Genet. 2, 9–39 (2001).
5. Chakravarti, A. Single nucleotide polymorphisms: …to a future 15. Lown, K. S. et al. Grapefruit juice increases felodipine oral These kinds of studies are a bold venture of genetic medicine. Nature 409, 822–823 (2001).
availability in humans by decreasing intestinal CYP3A protein into relatively uncharted territory and face 6. Carrasquillo, M. M. et al. Genome-wide association study and expression. J. Clin. Invest. 99, 2545–2553 (1997).
substantial technical, biological and science- mouse model identify interaction between RET and EDNRB 16. Wright, A. F., Carothers, A. D. & Campbell, H. Gene- pathways in Hirschsprung disease. Nature Genet. 32, 237–244
environment interactions—the BioBank UK study.
Pharmacogenomics J. 2, 75–82 (2002).
Scientifically, it is necessary to under- 7. Cox, N. J. Challenges in identifying genetic variation affecting 17. Stucker, I. et al. Genetic polymorphisms of glutathione S- susceptibility to type 2 diabetes: examples from studies of the transferases as modulators of lung cancer susceptibility.
calpain-10 gene. Hum. Mol. Genet. 10, 2301–2305 (2001).
Carcinogenesis 23, 1475–1481 (2002).
culty here is the uncertainty surroundingboth terms in the equation; ideally, one set of genetic factors will interact with one set ofenvironmental influences to produce The double helix in clinical practiceidentical outcomes, but it is unknown John I. Bell
whether this is always going to be the case. Afar more difficult relationship would exist if The Office of the Regius Professor of Medicine, University of Oxford, Oxford OX3 9DU, UK multiple genetic factors interacted with (e-mail: regius@medsci.ox.ac.uk)
multiple environments to achieve the same
outcome. The example of glutathione The discovery of the double helix half a century ago has so far been slow to affect
S-transferase mutations, smoking and medical practice, but significant transformations are likely over the next 50 years.
incidence of lung cancer17 shows it is possible
Changes to the way medicine is practised and new doctors are trained will be
to detect some interactions, but it is unclear required before potential benefits are realized.
how, or even if, statistical methods might bedeveloped for addressing the more complex “It is much more important to know what kind of patient has a disease than to know what kind of disease a patient has.” Caleb Parry, 18th century physician, Bath.
taking these projects is human psychology; theconsequences of smoking have been known This was despite the convictions of at least for many decades, but people still smoke.
one distinguished statistical geneticist who basic framework that would developinto the field of molecular genetics. The argued against the causality of this observa- turn knowledge into practical outcomes must tion, implying that a common genetic factor be an increasing focus of attention for both caused both lung cancer and a predilection influence on our understanding of biological Psychology is also in play in the initial significant heritable component, it was soon researchers, funding agencies and politicians recognized that the characterization of the health care at the time of their fiftieth there is great risk implicit in undertaking a anniversaries than has the double helix, its hugely expensive project with complex out- provide remarkable opportunities for clinical slower transition from discovery to clinical come. People would like to live in a simpler medicine, potentially altering the way disease world, with simpler decisions, but the vision was understood, diagnosed and treated.
medical disciplines. Progress has been slow, complete, as much will be known about the cations to medicine, the development of but mounting evidence suggests that, while origins of human disorders as can be discov- significant genetic advances relevant to public health and antibiotics produced clinical practice could take generations. This important healthcare outcomes in the past genetic studies. Perhaps more important, the is in marked contrast to many other medical- 50 years, the next 50 are likely to belong to beginnings of a new medicine will emerge, ly related discoveries that occurred around The potential impact of genetics on clini- rapidly into clinical practice. For instance, genetic uniqueness and personal choices that the development of penicillin by Ernst Chain observers5 who believe that the positive are the very essence of individual lives.
and Howard Florey in 1941 was saving predictive value of genetic testing for most If we are collectively bold in our present thousands of lives within months of their common disease genes will be insufficient to decisions and accept the risk of action, a discovery of how to efficiently produce the provide the beneficial effects seen with antibiotic2. Discoveries relating to disease single-gene disorders, which affect only a guide, not a place of last resort. If the past aetiology, such as the recognition in 1950 of a 50 years has seen the revolution of DNA, then relationship between smoking and lung can- advocates of genetics argue, on the other the revolution cannot be completed without cer, have had a profound effect on mortality3.
hand, that our understanding of disease is NATURE | VOL 421 | 23 JANUARY 2003 | www.nature.com/nature

Source: http://monod.biomath.nyu.edu/index/course/hw_articles/nature6.pdf