Published online 17 October 2007 | Nature | doi:10.1038/news.2007.166

News: Q&A

The genetic map maker

Luigi Luca Cavalli-Sforza was one of the first to explore human genetic diversity as a geographer might. He talks to Alison Abbott about his new project to map the genetics of Italy.

Luigi Luca Cavalli-Sforza invented the concept of geographical genetics.

Luigi Luca Cavalli-Sforza, professor emeritus at Stanford University in Palo Alto, California, invented the concept of geographical genetics. He is most famous for demonstrating that the practice of agriculture spread not by word of mouth but as farmers migrated to different regions. But his attempt to systematically document the extent of human genetic diversity — by collecting cell lines from tribes and other populations — embroiled him in one of the major scientific controversies of the 1990s: the Human Genome Diversity Project was nearly crushed by charges of exploitation and racism. Now, at the age of 85, he has launched the Italian Genome Project in his home country.

You were probably the first geneticist to investigate human genetic diversity. What prompted your interest?

I switched from bacterial to human genetics in the 1950s. I wanted to try to quantify the role of chance in evolution, and distinguish its effects from that of natural selection.

I was living in Italy, where the Catholic church provided good demographic records going back to the sixteenth century. This allowed me to follow the migration of individuals and the sizes of local populations over time. I compared the frequencies of genes in small isolated villages in the mountains with those in larger towns of the valley of Parma, where my university was. Of course, back then we couldn’t look at genes directly, so we used the surrogate of blood groups. I was able to show that random genetic drift, then the Cinderella of evolution, could explain a great fraction of genetic variation, whereas — at least with the numbers I was looking at — the evidence for natural selection over the centuries was remarkably scanty.

Where did you look next?

I wanted to understand human genetic diversity in a more global way, and try to get a glimpse of the past. So I went to study the African pygmies, one of the few remaining hunter-gatherers whose environment had not been disturbed. I found that random genetic drift was also important in pygmy tribes and could also be used to follow the movements of migrating subpopulations.

I started a collaboration with a young archaeologist, Albert Ammerman, to study how the expansion and consequent migrations of populations could have affected the present genetic structure of Europe. This was the start of two decades of research which inspired the concept of the Human Genome Diversity Project and eventually it led me to the Italian Genome Project.

Were you taken aback by the opposition to the Human Genome Diversity Project?

Yes, because the objections came from strange, unexpected sources, motivated by politics rather than science. Some activists were really interested in self-promotion. People accused us of exploitation, but it was not generally the aboriginals themselves who said they felt exploited, but their self-selected representatives.

Then there were the people who thought we were paid by the pharmaceutical industry, even though we had prescribed that DNA could be distributed only to publicly funded research labs. I think that some fears had to do with the statements that DNA might be used to make claims of territorial rights.

Many of the objections seemed so absurd that they were hard to predict.

How did you feel about being accused of racism?

Well, many mistakes are made and that was a very curious one. I’d argued for decades that the concept of ‘race’ defined by external characteristics — such as skin colour, size variations or facial fat — is nonsense. These visible characteristics evolved under natural selection, mostly to cope with local environments, and have no deeper base.

I didn’t get angry or depressed, I only regretted how much time the objections cost to the project development.

Did the Human Genome Diversity Project suffer as a result?

It took me eleven years to get the project going, and that was far too long. As a result, it has so far obtained not many more than one-tenth of the planned 10,000 DNA samples, and some important parts of the world have still not been covered.

What exactly is the Italian Genome Project?

The idea emerged seven years ago, but it is only now taking off. We are collecting blood samples from about 100 people in each of Italy’s 100 or so provinces — 10,000 in all. The people are being selected from among regular blood donors on the basis of surnames that identify their local origin. We have generated a long list of such surnames. We collect them in villages and small towns, not in cities where you get complex admixtures.

We now have nearly 1,000 samples, from one province in each of Italy’s twenty regions. Their leopard-spot distribution will give us a basic knowledge of the country’s population from a genetic point of view.

The DNA samples will be analysed with a megachip, which can detect around half a million SNPs [single-point differences between genes]. Of course it would be better to be able to fully sequence each individual genome, but the cost is prohibitive at the moment. These massive new megachips allow analysis to be carried out at a cost of around $1,000 per sample and provide enough information for powerful studies.

What will the information be used for?

It’s mainly intended to provide control samples for medical genetics. These days medical geneticists mostly do ‘case control’ studies, in which patients are matched with a control population. Getting a good genetic match with healthy controls of the same origins allows you to do a statistically strong study with fewer people. Our collection will make it easier to find a close genetic match.

Of course the sample will also be used for studies of geographical genetics and evolutionary biology — after all this is my oldest curiosity.

Were you not concerned that the Italian Genome Project would face the same objections as the Human Genome Diversity Project?


Not really. I was helped by the national organization for blood donors in Italy (AVIS). This has more than a million members who are called on individually when a particular blood group is needed. Volunteer (unpaid) blood donors are already committed to helping medicine.

We have also developed a fool-proof method for protecting individual identity.

Should every country have its own genome project?

I believe every country with a substantial national health programme would gain from having its own genome project, given the effect of genetic disease and disease predisposition.

There are a lot of big projects in Europe — particularly in Iceland and Estonia, where very large proportions of the population are being tested. The Italian project is perhaps closest to the programme funded by the Wellcome Trust called ‘The People of Great Britain’. The European Union is planning to fund the coordination of national projects, and we will certainly consider collaborating in any Europe-wide plan that emerges.

In retrospect, do you think that the Human Genome Diversity Project can be considered a success?

I think so. At the last count 93 research laboratories have requested and obtained the project's DNA set, and many publications have already appeared. We have just finished the first megachip study on this data set and confirmed that there is a progressive loss of genetic diversity the farther you get from East Africa, from where we believe Homo sapiens emerged. The recent ‘Out of Africa’ theory is now on a very firm basis. 

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