Luigi Luca Cavalli-Sforza, a giant in population genetics and professor emeritus, dies at 96

Luigi Luca Cavalli-Sforza, MD, professor emeritus of genetics at the Stanford University School of Medicine, died Aug. 31 of natural causes in his home in Belluno, Italy. He was 96.

Cavalli-Sforza was among the first to use genetics to track human migration patterns. His blend of anthropology and genetics led to a new field he called genetic geography, in which he followed the spread of genetic variations to track how humans populated the world.

“Luca was one of the first scientists to use genetic information to understand the relationships between different human populations at the level of the DNA,” said Marcus Feldman, PhD, professor of biology at Stanford. “He was always ahead of the game. Luca wasn’t a follower; he was a pioneer in the true sense of the word. If other people were doing it, he didn’t want to touch it.”

A native of Italy

Born in Genoa, Italy, in 1922, Cavalli-Sforza earned his MD from the University of Pavia in 1944 and worked there as a physician for a year before becoming a genetics professor, teaching at Cambridge, Parma and Pavia. Although he began his genetics career studying microbiology, he quickly became interested in human genetics.

By the time Cavalli-Sforza arrived at Stanford in 1970, he had already begun developing new statistical tools for analyzing molecular differences between groups of people around the world. His earliest work involved looking at how the A, B and O blood types were represented in populations. From that, he devised the first of his many maps depicting human variation across the globe.

As technology became available to survey variations at the genetic level, Cavalli-Sforza began examining genetic changes on the Y chromosome in populations around the world. This chromosome is passed directly from father to son, preserving a clear paternal lineage. Using this technique, he traced the male lineage back to a single male ancestor, dubbed “Adam,” living roughly 70,000-100,000 years ago in sub-Saharan Africa.

According to Cavalli-Sforza’s data, Adam’s sons stayed close to home for about 23,000 years. At that time, small bands packed up and headed north to Europe, Asia and Australia. Years later, a second and third wave of travelers wandered off, some overlapping with past migrations and others staking out new territory.

These migration patterns have since been confirmed by researchers using different combinations of genetic markers. “Different genes have different histories. But when several genes are telling the same story, you’re more confident that you’ve got the history right,” said Cavalli-Sforza’s longtime Stanford collaborator Peter Underhill, PhD, senior research scientist in genetics, in Stanford Medicine magazine.

Cavalli-Sforza’s genetic work earned him accolades from those hoping to break down the barriers of race. He found that people from the same population are as genetically diverse as people from two different groups, essentially showing that at the genetic level, there is no such thing as race. Reviewing Cavalli-Sforza’s 2000 book Genes, Peoples, and Languages in The New York Review of Books, Jared Diamond praised the Stanford researcher for “demolishing scientists’ attempts to classify human populations into races in the same way that they classify birds and other species into races.”

Parsing the journey of humankind

In an attempt to extend his genetic analysis of people, Cavalli-Sforza began the Human Genome Diversity Project to gather and store genetic samples from populations around the world. Although Cavalli-Sforza and others saw the project as a way to safeguard DNA from dwindling populations and to learn about human history, others saw it differently. He was accused of biopiracy, exploitation and of enabling biological weapons that could attack the genetics of particular ethnic groups. In the end, the group collected samples from more than 50 populations that are now stored at the Center for the Study of Human Polymorphisms in Paris.

“The HGDP was a huge contribution. It was really one of the first projects to create a comprehensive view of worldwide genetic diversity,” said Jonathan Pritchard, PhD, professor of genetics and of biology at Stanford and a longtime collaborator of Cavalli-Sforza’s. “Since then, many large international projects have built on that idea, recapitulating aspects of HGDP — but the fundamental idea came from Luca.”

Based on those samples, a Stanford research group, including Cavalli-Sforza, published a 2008 Science paper providing a detailed look at human genetic diversity. What they found backed up much of what Cavalli-Sforza had learned from more than 40 years of studying blood groups, the Y chromosome and collections of genetic markers: People can’t be divided into racial groups based on DNA.

“It was a watershed paper and, in many ways, a vindication of Luca’s work,” Feldman said. “There’s no doubt that paper stimulated and set up the whole field of DNA population genetics, and Luca was really the father of that field.”

Despite the prevailing scientific interpretation that his work demolished the idea of race, Cavalli-Sforza’s findings remained controversial. White supremacists have argued that because genetic variations are associated with particular geographical locations, that’s as good as providing a genetic basis for race, an argument that Cavalli-Sforza rejected.

Cataloging human variation

Not all of Cavalli-Sforza’s findings were so contentious. He and Feldman founded the field of cultural evolution, a theory that social change resembles a Darwinian evolutionary process. Among the mysteries addressed by their work was the question of how agriculture spread. Archeologists had learned that the trappings of agriculture traveled at the rate of about 1 kilometer per year. What they didn’t know is how those artifacts had spread. Did stationary populations disperse agriculture by word of mouth, or did new agricultural groups migrate, taking their new knowledge with them? Cavalli-Sforza led work that revealed the new farmers had slowly migrated into hunter-gatherer territories, likely through intermarriage.

The genetic topography maps Cavalli-Sforza produced also helped clarify the factors that were most important in influencing gene frequencies within a population. These include natural selection, migration, mutation and drift. Although all factors play a role in determining what genetic traits become common in a given population, random chance turns out to be a major driving force in human history. Among the most important random events is the bottleneck effect, in which a small group of people containing an uncommon trait populate an area. Because of the genetic makeup of the founders, that trait becomes common in the new population despite carrying no evolutionary advantage.

Based on his lifetime of work, Cavalli-Sforza wrote what is considered a landmark description of human genetic variation. Originally published in 1994, The History and Geography of Human Genes is a 1,000-page tome of genetic information about human history.

“He’s one of the greatest minds I’ve ever come across,” said Feldman, who is also the Burnet C. and Mildred Finley Wohlford Professor at Stanford. “He had such a breadth of interest and depth of knowledge in so many fields. When I was a young assistant professor, whenever I was around Luca, it was like opening your eyes to a world of scientific possibilities.”

Cavalli-Sforza’s life’s work culminated with a call to analyze the world’s populations in even finer genetic detail. The information about human history that comes from these studies will be built on the research of Cavalli-Sforza, who pioneered the idea that we can learn about our past through our DNA.

He is survived by his sons Matteo, Francesco and Luca Tommaso Cavalli-Sforza, and by his daughter Violetta Cavalli-Sforza.