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‘It will lead to an understanding of who we are as a species and how we came
to be.’ These bold words, from Marie-Claire King, a geneticist at the
University of California, Berkeley, refer to a new and controversial
proposal to create a global map of human genetic variation. The aim of the
project is to analyse and compare thousands of DNA samples from hundreds of
different ethnic groups – an ambitious undertaking which is likely to
produce a rich seam of information on the origins and migration histories
of human populations and the genetic basis of their differing
susceptibilities to certain diseases.

Known as the Human Genome Diversity Project, the venture is awaiting
financial approval in the US and Europe. But if it goes ahead, it will
involve geneticists and anthropologists collecting blood from at least 25
individuals from each of some 500 ethnic groups worldwide. There is great
urgency, say the project’s proponents, because many ethnic groups are on the
verge of extinction, as small, isolated, aboriginal societies either die out
or are absorbed into larger populations.

The techniques central to the project – methods of collecting and preserving
human cells and, most important, of efficiently detecting variations in DNA
– have only recently become available. ‘It would be tragically ironic if,
during the same decade that biological tools for understanding our species
were created, major opportunities for applying them were squandered,’ the
project’s leaders wrote in an article in the summer of 1991 when trying to
whip up support for the initiative.

Initially, the response was uniformly enthusiastic, as many researchers
realised that the project would produce useful genetic information more
quickly than the much-vaunted Human Genome Project, the 15-year plan to map
and sequence all three billion bases of the human genetic blueprint. ‘The
diversity project gives us an unparalleled opportunity to apply genetic
techniques to important anthropological problems,’ said Ken Weiss, an
anthropologist at Pennsylvania State University.

More recently, however, criticism has begun to be voiced about the project’s
aims and underlying philosophy. Critics argue that the diversity project’s
approach is based on an outmoded notion of race. The project is
’21st-century technology applied to 19th-century biology’, says Alan
Swedlund, head of the anthropology department at the University of
Massachusetts at Amherst. Knowing about human genetic diversity is a
worthwhile goal, he admits, but the view that isolated populations can be
treated as genetically discrete is simplistic. This kind of ‘typological’
thinking – which underpins all notions of racial differences – has been in
retreat for years, argue the critics, and for good reason: it assumes not
only that human groups are defined solely by genetic characteristics but
that these vary from group to group in a distinctive manner.

In addition, Swedlund is angered by what he judges to be a colonial
attitude. The project’s leaders, he says, have hitherto ignored the plight
of aboriginal peoples but now want to swoop in, collect blood for their own
scientific goals, and then leave the people to their fate. This criticism is
shared by a growing number of anthropologists, who fear that their science
is becoming dominated by genetic determinism and is losing touch with
social and cultural issues. Anthropologists, they argue, have a duty to
attend to the real life circumstances of the people they study, in addition
to pursuing scientific questions.

The idea for the diversity project originated two years ago in the US, from
discussions between Luigi Luca Cavalli-Sforza of Stanford University, and
Kenneth Kidd of Yale University. European interest quickly followed, under
the guidance of Walter Bodmer, then president of the London-based Human
Genome Organisation (HUGO). The European and US initiatives, while being
closely integrated in planning and approach, were to be funded separately.

Funding for the US programme, which is estimated to cost some $25
million over five years, will depend heavily on the outcome of an imminent
review of the future of the Human Genome Project. Even though support for
the diversity project would require only a small proportion of the Human
Genome Project’s annual budget of more than $100 million, it would
divert funds from goals already set. If Human Genome Project officials don’t
look kindly on the diversity project, Cavalli-Sforza and his colleagues will
approach international bodies, such as the WHO and UNESCO. Funding for the
European programme, whose budget has yet to be determined but may reach
$5 million, is also to be settled within the next few months, at
least for the initial part of the project. An application to the European
Community’s 1994 fund for science is said to have been favourably
considered.

Cavalli-Sforza is among the world’s leading human geneticists, and has been
collecting genetic information from hundreds of populations around the world
for almost four decades. This information is based on analysing proteins –
the products of genes – and is in the form of so-called classical genetic
markers, such as blood groups. Because the vast majority of proteins vary
little, if at all, from one person to the next, the scope of such markers is
limited. Useful ones number less than a hundred.

During the 1980s the science of molecular genetics matured, with the result
that researchers extended their search for markers to include not only genes
but stretches of human DNA that do not encode proteins. This led to the
discovery of a wealth of polymorphisms – DNA sequences that vary from one
person to the next and which can be readily detected. Because there are
thousands of these polymorphisms, scattered around the human genome, they
represent a rich source of previously undetected genetic variation within
and between populations.

GLOBAL THINKING

In 1984, soon after the new source of DNA polymorphisms was first
identified, Cavalli-Sforza and Kidd began a collaboration to analyse genetic
diversity in some 250 aboriginal populations around the world. By 1991 they
had collected blood and established cultures of white blood cells from 13 of
those populations. Frustrated by the slow progress, and inspired by the
global thinking of the late Allan Wilson, Cavalli-Sforza realised that a
major effort was required.

Wilson, who died last summer, had long exploited genetic techniques for
studying human evolution. He is perhaps best known for his Eve hypothesis –
a theory, based on variations in DNA found in mitochondria (which are
inherited only in the maternal line), that all modern humans originated from
Africa (see ¿ìè¶ÌÊÓƵ, Science, 15 February, 1992). With King, Charles
Cantor of the University of California, Berkeley, and Robert Cook-Deegan of
the Institute of Medicine, Washington DC, Cavalli-Sforza and Wilson signed
an article titled ‘Call for a Worldwide Survey of Human Genetic Diversity’,
published in the journal Genomics in the summer of 1991.

The message was that, admirable though the Human Genome Project may be in
seeking a complete description of human DNA, it ignored genetic diversity.
‘The total absence of knowledge on individual variation would be
unacceptable,’ proclaimed Cavalli-Sforza. ‘The ‘Book of Man’ would be rather
shallow if it were written without consideration of the well-known fact
that everyone is different from everyone else.’

A series of meetings was soon planned to decide on strategy and techniques:
how many, and which, of the 7000 or so ethnic groups around the world to
include in the survey; how many individuals to sample in each population;
and how best to collect and preserve the DNA. Bodmer, a long-time associate
of Cav-alli-Sforza’s, initiated similar plans to study DNA variation in
European populations, calling the venture ‘a cultural obligation of the
Human Genome Project’.

Leaders of the US project were barely at the planning stage when they fell
out over the sampling strategy. Cavalli-Sforza wanted to sample aboriginal
populations that had long been isolated and were culturally and
linguistically discrete. Wilson, by contrast, pushed for a geographic-grid
strategy, where sampling would simply take place every 50 or 100 miles,
regardless of who was there.

The first approach focuses on populations, the second on individuals – a
difference in emphasis that flows from the techniques used by the two
protagonists. Working with DNA in the cell nucleus, Cavalli-Sforza has
always measured the frequency of certain genetic markers in populations, not
their absolute presence or absence. In mitochondrial DNA, by contrast,
sequence differences build up much more quickly, with the result that even
individuals living relatively close together can have unique polymorphisms.

It was clear that Cavalli-Sforza’s population-based approach would achieve
many of the project’s goals, producing information galore on genetic
variation among the selected ethnic groups. But in Wilson’s eyes, the grid
strategy promised something more radical. By eschewing traditional notions
about what constitutes an ethnic group in favour of a less biased sampling
strategy, he argued, researchers could amass a much more powerful set of
data – information about genetic differences that could be used to
reconstruct the history of modern people.

At the project’s first workshop, held at Stanford University a month after
Wilson’s death, Mark Stoneking, a molecular geneticist at Pennsylvania
State University, echoed Wilson’s con-cern. By sampling populations based on
linguistic and cultural uniqueness, he said, the outcome would be
predetermined: ‘You will find that the human species is made up of
well-defined ethnic and linguistic groups.’ By the end of the Stanford
workshop a compromise was achieved. The population approach would dominate,
but sampling would also be done between ethnic groups, wherever it was
feasible.

The workshop also tackled the practical issue of how many individuals should
be sampled in a population. The need for statistical significance had to be
balanced with the logistical difficulties of taking blood samples and
getting them to a laboratory within two days. In the end, delegates agreed
that 25 samples would be sufficient, provided numerous DNA polymorphisms
were subsequently analysed. The biggest costs would occur when the samples
reached laboratories, where they would have to be manipulated so as to
produce ‘immortal’ cell lines – a demanding and expensive process costing
$500 per sample.

At a second workshop, held last October at Pennsylvania State University,
the main aim was to draw up a list of target populations. Choosing 500 from
the 7000 extant ethnic groups was not easy. One criterion for inclusion was
imminent danger of extinction. This applies to about half of the selected
groups, including the Hadza of Tanzania, the Yukaghir of Siberia and the
Onge and Greater Andamanese of the Andaman Islands, Malaysia. Another
objective was to choose groups whose genetic make-up could shed light on
specific anthropological problems, such as how the Americas were first
colonised, or the history of the Bantu expansion in Africa, 2000 years ago.

Representatives of the European and American initiatives have formed joint
committees, so that strategies and techniques can be coordinated. This
month, participants of the European project will gather at the University of
Turin to select target populations. Because of the greater amount of
historical information available for European populations, and easier access
to laboratories, the number of individuals sampled in each population is
likely to be higher than in the US-run venture, perhaps as many as 100. The
mystery of the Basques and the spread of Indo-Europeans some 6000 years ago
are likely topics for investigation. There will also be a strong emphasis on
the genetics of susceptibility to disease and why it varies from population
to population.

A further European workshop, to be held jointly with the Americans in
Sardinia in September, will discuss ethics, among other things. The
Americans have already touched on the ethics issue, at a workshop at the
National Institutes of Health, in February this year. One of the
participants, Diane Paul, who runs a course on science and values at the
University of Massachusetts at Boston, was not impressed. ‘It seemed like
window dressing to me,’ she comments. ‘Issues were raised, but then not
addressed. Responses were defensive, with people saying ‘this can be dealt
with’ or ‘that won’t happen’.’

The thorniest issue was that of race: would the project’s spotlight on
genetic diversity among people encourage racism? (Leaders of the European
venture are already sensitive to this, and prefer to speak of ‘genetic
variability’ rather than the more politically-loaded term, ‘diversity’.)
There were two responses to the question. The first is exemplified by an
observation of Kidd’s. ‘There is no denying there is genetic diversity in
the world, but racism is based on cultural attitudes not on genetic
differences,’ he says. ‘You only have to look at what’s happening in Europe
to see that. Nothing we produce will affect that.’

The second response is more optimistic, and is based on a long-established
fact about human genetics: that there is more variability within populations
than between them. The diversity project will underscore this point, says
King, and help to undermine the popular belief that genetic differences are
always greatest between different populations. And as to the project being
based on outmoded ideas of racial differences? ‘No geneticist has done more
than Cavalli-Sforza to reveal that genetic variation between groups is
continuous, not discrete,’ says Weiss. ‘This has undermined typological
thinking, not supported it.’

But to many critics, such optimism appears naive. Indeed, Cavalli-Sforza
himself inadvertently upset anthropologists at a scientific gathering last
year by using the phrase ‘ethnic group’ for people in Europe and ‘tribe’ for
those in Africa. Weiss admits this was unfortunate but insists that
Cavalli-Sforza should be judged on his science not his language.

More practical ethical issues are still to be resolved in areas such as
informed consent and intellectual property rights, says Julia Bodmer, a
leader of the European initiative. It is all too easy, as history has shown,
for scientists to descend on a village or town, organise the collection of
biological samples (in this case blood) with the help of local contacts, and
sweep out again without even thinking about local consent. Will the same
happen with the human diversity project? For that matter, can anyone say
what constitutes true consent in the case of a venture which lies outside
the technical experience of many of the people concerned? And, thornier
still, who will own the rights to any commercial products that flow from the
project, particularly concerning the treatment of disease?

This last issue has already provoked bitter controversy in international
discussions on a closely related subject – animal and plant biodiversity. At
the Earth Summit in Rio de Janeiro last year, for example, delegates from
the US stuck to the traditional ‘First World’ view, that the genes of plants
and animals belong to a common international heritage. The rights to
financial benefits, argue proponents of this view, go to those who
manipulate the genetic repository to commercial advantage. People from
developing countries, where most of the world’s biodiversity is found,
properly challenge this position, says Paul. ‘Researchers will have to face
up to this issue in the genome diversity project,’ she says. It will be on
the agenda for the September meeting, says Julia Bodmer.

LOOMING CONFLICT

When it comes to the second main criticism of the diversity project – that
it will do nothing to improve the welfare of indigenous peoples – Weiss has
some sympathy. ‘We are concerned about the wellbeing of these people,’ he
says. ‘But let’s be clear about this: a group of geneticists isn’t going to
save them. Stop clear-cutting the Amazon rain forest. That will save them.’
All geneticists and anthropologists can do, says Weiss, is raise public
awareness. Many of the scientists behind the diversity project, he points
out, have been instrumental in publicising the plight of the Yanomami
people, who live on the border between Brazil and Venezuela. Their
population has plummeted in recent years as unrestrained mining for gold and
tin has devastated their environment – disrupting foraging territory and
introducing diseases such as malaria.

As the American and European diversity projects move towards
implementation, the scope for professional conflict will surely deepen. The
battle lines are already clear. One side sees an urgent project with
scientific and medical benefits; the other highlights practical,
humanitarian issues that are beyond immediate scientific goals but which
should concern scientists. So far the two sides have yet to clash head on.
But when they do, feelings will run high. This much was clear at an
anthropology conference in Mexico last year where some of the humanitarian
issues were highlighted. The conference was not anti-science, insists
Swedlund. ‘It was about doing better science – science that is not only
rigorous and interesting, and relevant, but also ‘humanised’.’

* * *

Making the most of a human genetic atlas

Four key areas of research will benefit from worldwide data on genetic
variability, predict leaders of the Human Genome Diversity Project (HGDP).

Human origins and prehistory

Genetic information from studies of DNA found in cell nuclei and
mitochondria has already changed conventional thinking about human
prehistory. The HGDP would strengthen such studies by collecting information
about many more genetic polymorphisms. One of the most important (and
controversial) questions concerns the origins of modern humans. Some
researchers believe that the ancestors of all modern humans lived in Africa
between 100 000 and 200 000 years ago; others say that modern humans evolved
simultaneously in many different parts of the world. Broadening the database
to include DNA other than that found in mitochondria – the principal source
of information at present – might help to resolve the controversy.

Information about genetic diversity would also give insights into the
movements of various populations since modern humans evolved. Especially
important here are questions concerning the colonisation of the New World,
Australia, and northern Asia. For instance, did humans first colonise the
Americas 35 000 years ago or much more recently, perhaps only 12 500 years
ago? Whereas the archeological evidence is still equivocal, genetic
information should be able to settle the matter. More recent migrations,
possibly linked with the spread of agriculture or pastoralism in Europe and
Africa are also likely targets of interest.

SOCIAL STRUCTURE

Anthropologists are interested in mating patterns, such as whether males or
females leave their groups to marry, or whether they marry within their
groups. Patterns of genetic variation, particularly from mitochondrial DNA
(passed only through the female line) and DNA from the Y chromosome (passed
only through the male line), could provide important clues. For example, the
absence in a local population of genetic markers present in surrounding
populations could imply that one or both sexes in the local population are
only marrying within their group. Alternatively, it could mean that the
population has only recently moved into the area.

ADAPTATION AND DISEASE

Anatomy, physiology and susceptibility to disease can all vary from one
population to the next. A key question is whether such variation is the
result of adaptation to local conditions or merely random changes in genetic
make-up. The genetic information collected in the HGDP could provide some
answers. Anthropologists are especially interested in diabetes,
thalassaemia, hypertension and sickle-cell anaemia.

FORENSIC ANTHROPOLOGY

Traditional genetic markers such as blood groups have long been used to
identify individuals and groups. The development of DNA fingerprinting has
increased the power of genetic identification techniques. But their accuracy
depends in part on knowing how the DNA markers detected in fingerprinting
vary from one population to the next. The HGDP will provide a full
inventory of such marker variations.