Editorials

Waiting for the working draft from the human genome project

A huge achievement, but not of immediate medical use

See also p   1257

Hyped as biology's holy grail, the generation of a consensus sequence of the entire human genome is the flagship endeavour of the human genome project. ^{1 2} About 1.7 billion base pairs have been sequenced so far in publicly funded projects, representing just over 50% of the genome and including the complete sequence of one full chromosome.³ By June 2000, another one billion base pairs are expected to be sequenced, completing 90% of the genome at what is called fivefold sequencing coverage (this being the number of times each part of the sequence is read in order to eliminate errors).⁵

The aim of the project, 99% completion of the genome at tenfold coverage, seems on track for its deadline of 2003.⁴ By any standards, an effectively complete sequence will be a remarkable achievement.⁶ However, the hyperbole that surrounds it may reflect the scale of the undertaking rather than its immediate impact. A consensus sequence will make it possible to carry out a wide variety of studies involving gene content (even the number of genes remains contentious), comprehensively classify gene or protein families that may predict function, and understand how genes are organised and controlled. However, a single consensus sequence represents a collection of different fragments assembled together, so there is no information about the genetic differences that may explain who gets which disease and why. Thus, knowledge of the consensus sequence is unlikely to revolutionise medical understanding, let alone practice, in the near future.

The greatest immediate benefit for medicine will derive from sequence differences rather than consensus. This fact is relatively underappreciatedonly recently has sequence variability been formally included in the project's goals. ^{2 7} Firstly, evaluating sequence differences is the only direct means by which the overstated goal of personalised medicine may be achieved. There is much expectation that specific relations between sequence variability and individual differences will allow predictions to be made, based on DNA, of a person's risk of a given disease and response to particular treatments.⁸ Potentially this may indeed lead to new diagnostics, new ways of conducting clinical trials, and conceivably a more rational approach to therapy in common multifactorial diseases. However, even the simplest single gene disorders behave in complex ways, and the extent to which multiple susceptibility genes (which can have only modest effects) may be analysed to predict individual risk is unclear.

A more realistic and important goal of the genetics of complex traits may be the identification of novel pathways and mechanisms of disease through characterising the sequence variants that increase susceptibility to disease. Some risk factors for common diseases, such as atherosclerosis, are known to be genetically determined, but these do not account for the total genetic contribution. Thus, novel disease genes may implicate previously unsuspected aspects of pathogenesis and lead to new targets for drug discovery. Even if such targets are identified through studies in a subset of patients with a strong inherited tendency to a given disease, new treatments are likely to be broadly applicable. For example, understanding the regulation of the receptor for low density lipoproteins which came from genetic studies in familial hypercholesterolaemia led to the development of HMG-CoA reductase inhibitors (statins) which are now a mainstay for the prevention of coronary disease.

There is now a growing need for an extensive catalogue of human genetic variation. A non-profit consortium of the Wellcome Trust and 10 international pharmaceutical partners was formed in April 1999 to identify 300 000 random DNA variants distributed throughout the human genome.⁹ Hopefully many of these variants will be within or close to functional coding regions, so correlations can be made between sequence variability and individual differences in outcomes.

The most imminent milestone of the human genome project is the publication of a working draft of the human genome. The working draft was initially conceived as a pre-release of an incomplete and prone to error version of the genome at the end of 2001.² However, pressures from the commercial sector have accelerated this goal. In particular, the extensive capacity for sequencing of specific biotechnology companies, most notably Celera Genomics, Inc, has raised concerns about free public access to human genome sequence, which has been a key feature of the project. ^{2 10} The lack of transparency of the efforts of the private sector have made it hard for scientists to assess progress and the impact of this unexpected competition remains uncertain. Either way, the working draft is, as a result, now expected to be released in spring 2000.¹¹

However, while the draft will be valuable for identifying gene and polymorphism, the relaxed error rate means that much work will be needed before the most basic sequence information can be put to practical use. For example, novel cytochrome P450 enzymes involved in drug metabolism are likely to emerge in the working draft, giving new targets for pharmacogenetics research. However, the new genes will need to be verified first, so that accurate assays can be developed to assess the genotype composition of patients with specific disorders or undergoing trials of different treatments. The working draft provides a framework but remains just a map, one that is still too crude for clinical use. As with any map, its utility lies in specific applications to specific circumstances. For the human genome project, this specificity requires application at the level of the patient or research participant, rather than the abstract level of consensus. While not wanting to begrudge a historic scientific achievement, it is best to acknowledge that we will have to wait for more than the working draft to see a real impact on medicine.

Lon R Cardon, head of bioinformatics. 

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN (lon.cardon{at}well.ox.ac.uk)

Hugh Watkins, professor. 

Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 9DU (hugh.watkins{at}cardiov.ox.ac.uk)

1.	Collins F, Galas D. A new five-year plan for the US Human Genome Project. Science 1993; 262: 43-46[Free Full Text].
2.	Collins FS, Patrinos A, Jordan E, Chakravarti A, Gesteland R, Walters L. New goals for the US human genome project: 1998-2003. Science 1998; 282: 682-689[Abstract/Free Full Text].
3.	Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, et al. The DNA sequence of human chromosome 22. Nature 1999; 402: 489-495[CrossRef][Medline].
4.	Smaglik P. Genome leaders told to keep their eyes on the main prize. Nature 2000; 404: 111[CrossRef][Medline].
5.	Zimmern RL. The human genome project: a false dawn? BMJ 1999; 319: 1282[Free Full Text].
6.	The Human Genome Project. Curr Biol 1999; 9: R908-9[Medline].
7.	Collins FS, Guyer MS, Chakravarti A. Variations on a theme: cataloging human DNA sequence variation. Science 1997; 278: 1580-1581[Free Full Text].
8.	Drews J, Ryser S. The role of innovation in drug development. Nat Biotechnol 1997; 15: 1318-1319[CrossRef][Medline].
9.	Woodman R. Wellcome trust and drug giants fund gene marker database. BMJ 1999; 318: 1093[Free Full Text].
10.	Butler D, Smaglik P. Celera genome licensing terms spark concerns over "monopoly". Nature 2000; 403: 231[CrossRef][Medline].
11.	Collins FS. Shattuck lecturemedical and societal consequences of the human genome project. N Engl J Med 1999; 341: 28-37[Free Full Text].