The results of the Human Genome Project show unexpected layers of complexity in our
genes, says Clive Cookson
Published: February 11 2001 20:42GMT | Last Updated: February 11 2001 20:45GMT
Eight months ago, Bill Clinton and Tony Blair linked up to proclaim one of science's
greatest achievements: decoding the human genome or "book of life". But that public
relations spectacular was not supported by research data or conclusions. This week
scientists get their first look at the evidence, with the official publication of
the human genome sequence in the journals Nature and Science.
The two rival sequencing organisations - the public Human Genome Project and Celera,
the US biotechnology company - have produced scores of scientific papers. Their most
striking conclusion is how few genes we have: around 30,000. That is about the same
number as a mouse and only twice as many as a fly or a worm. Most scientists had
expected to find about 100,000 human genes and some estimates ran to 140,000 genes.
Our low gene count will disappoint those who think more is better. Eric Lander,
director of the Whitehead Centre for Genome Research in the US, says: "It seems to
be some kind of affront to human dignity."
But you can look at it another way: if the number of genes required to specify a
person is similar to that for other animals, then human biology attains a glorious
new level of richness and complexity.
Biologists will have to stop thinking of individual genes giving the body
instructions to make individual proteins (proteins are the molecules such as
hormones and enzymes that control biological processes). Instead, all our DNA - the
genome - must be seen as one immensely complex system.
As Craig Venter, president of Celera, puts it, "There are no 'good' genes or 'bad'
genes, merely networks that exist at various levels and various connectivities, and
at different states of sensitivity to perturbation. The notion that one gene equals
one disease, or that one gene produces one key protein, is flying out of the
window."
No one knows how many proteins there are. The answer will be revealed over the next
few years by the emerging field of proteomics, successor to genomics. But Dr Venter
estimates that we have 250,000 different proteins - about 10 for every gene - to do
the essential work in our bodies.
John Sulston, of the Sanger Centre near Cambridge, where one-third of the human
genome was sequenced, says the results show that we achieve our human complexity not
so much by adding new protein-making instructions as by "increasing the variety and
subtlety of genes that control other genes." Many human genes can be read in
alternative ways, and many proteins can be modified by other proteins without the
intervention of genes.
"This builds into a picture of exquisite control of genes and proteins, with genes
being turned on and off, up and down, with extraordinary subtlety - driving our
development from fertilised egg to adult, and maintaining and repairing our bodies
during the rigours of daily life," says Richard Gallagher, publisher of Nature.
Some experts were saying yesterday that the unexpectedly low number of human genes
would be good for medicine, since there are fewer genes to understand. But it could
work equally well in the opposite direction: the complex interactions between genes
may make it harder to cure disease by changing one or two of them, for example
through gene therapy. This may explain partly why gene therapy has given
disappointing results in clinical trials over the past 10 years. The emerging
technology of stem cells - replacing failing cells with potent new cells - may
produce better results because the patient is receiving the whole genetic system at
once.
The genomes published this week are composite sequences, derived from five
volunteers in the case of Celera and a dozen people for the public project. All the
main racial groups are represented. The results show that DNA from two unrelated
individuals is 99.9 per cent identical - on average, about 3m of the 3bn chemical
'letters' in their genetic code will be different.
But the real biological differences are far less even than this figure would
suggest, according to Dr Venter. The majority of variations in the human genetic
code have no effect and "only about 10,000 genetic differences between unrelated
humans will be biologically significant," he predicts.
Discovering the DNA differences that matter is one of the most important pieces of
unfinished business for the human genome project. It will be the basis, for example,
of pharmacogenomics - understanding why some people with a particular disease
respond better than others to drug treatment.
"If you could identify those patients where the drug was toxic versus those patients
where the drug would have its desired effect, then there is a potential treasure
chest out there of medicines already discovered and partially developed but which
cannot yet be used," says Mike Dexter, director of the Wellcome Trust, the British
charity that has contributed #210m to the public project. "The information we are
now accumulating will provide us with an ability to carry out diagnostic tests, to
use existing medicines better, and the ability to develop new medicines because we
have new targets."
Another important avenue of research will be to compare the human genome in detail
with other animals. Differences will help to reveal the functions of the genes, most
of which are still unknown. Mouse DNA is being sequenced both by Celera and by a
independent public-private sector consortium and, Dr Venter says, "we already know
that there only 300 genes in the human genome that do not have a counterpart in the
mouse."
Meanwhile, technologists are working to drive down the costs of DNA sequencing so
individual human genomes can routinely be read out on gene chips. If miniaturisation
and automation continue to cut costs by a factor of 10 every decade, Dr Gallagher
says, it will be possible by 2020 to sequence individual genomes for a few thousand
pounds each.
George Church, director of the Lipper Centre for Computational Genetics at Harvard,
points out that the information content of an individual genome can fit on a
computer DVD disk. He is confident that affordable technology will be soon developed
to read it.
Researchers warn such information must be used wisely as health, behaviour and
characteristics are influenced by many factors. As the Celera scientists conclude in
Science: "there are two fallacies to be avoided: determinism, the idea that all
characteristics of a person are 'hard wired' by the genome; and reductionism, that
now the human sequence is completely known, it is just a matter of time before our
understanding of gene functions and interactions will provide a complete causal
description of human variation."
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