Lessons from the Human Genome Diversity Project – Gene to Genome

As the Human Genome Project began to take shape in the 1990s, Luca Cavalli-Sforza, the renowned scholar of human evolution, was already envisioning a different kind of genomic map: one constructed from worldwide human populations.

“Luca had always been interested in migration. He thought that when the Human Genome Project was going to become a reality, it would provide a great opportunity to study ancient migration…how the world’s current population-genetic order came about,” recalled population geneticist Mark Feldman, a longtime collaborator of Cavalli-Sforza’s coevolution with Huygen. It became clear that there wasn’t much point in that—that you needed that other thing, too.”

At a time before large research consortia, the idea was extraordinarily broad: a coordinated effort to collect genetic data globally, alongside emerging reference genomes.

Early discussions between Cavalli-Sforza and his colleagues formed the basis of the Human Genome Diversity Project (HGDP)—a project that drew on samples from the collaboration of many investigators, culminating in 2002 in a global panel of 1,064 cell lines maintained by the Center d’moriséde and the Human d’Moriseme Dumainétude. In thousands of research studies.

When Cavalli-Sforza passed away in 2018, he reflected anew on the project. In their recent Genetics paper, population geneticists Noah Rosenberg and Sohni Ramachandran, who worked on the HGDP early in their careers, talk with Feldman, Hank Greely, and Marie-Claire King, three of the project’s early leaders, to reflect on its inception, the challenges it faced, and its lasting influence on the field of human genetics.

“It reinforced for me the importance of incorporating evolutionary thinking into biological research,” said King, a human genetics expert. BRCA 1 Breast cancer gene. “We were actually saying that people from populations that you all have never visited are just as important to understanding health and disease as people whose DNA we’ll have in the first place. [human genome] continuity”

However, the initial project faced criticism from a number of groups, including activists, indigenous groups, biologists, and anthropologists, and never received permanent funding from the National Human Genome Research Institute, ultimately moving forward as a community-organized effort. “It was frustrating for project organizers to get support in the field of human population genetics but not see that support translate into funding. In the early years of genomics, it was an unexpected realization of how much funding the science received,” says Rosenberg. “The ultimate scientific impact of the project was disproportionate to how much funding it received.”

The conversation also brought out broader lessons about how research takes shape in a field. For Ramachandran, HGDP highlights the role of systems and institutions in determining what becomes—and what does not—mainstream. “It’s important to understand the structures that support research and how these structures influence which ideas are adopted,” she says.

At its core, the HGDP was tackling questions that went far beyond data collection: how to model the world’s genetic diversity and by whom? What responsibilities do researchers have to the communities they study? How should population genetics be linked to biomedicine? And what happens when scientific projects are challenged beyond traditional academic norms?

“This project is an example of some of the most respected people in the field of human population genetics trying to address these difficult questions,” says Rosenberg. “And for today’s researchers facing similar challenges, those early efforts can serve as an important historical precedent.”

Ramachandran says many of the questions raised by the HGDP are now re-emerging in the context of large biobanks. Debates over sampling, representation, and interpretation resonate from the early days of the project. While sequencing ever-larger numbers of people can reveal vast genetic variation, she adds, understanding how that variation arose — and how history shaped it — still requires evolutionary thinking, and large datasets come with their limitations.

“Initially, Luca was talking about sampling a 5,000 population. There’s no coordinated project nearly that broad,” says Rosenberg. “However, the emphasis on worldwide genetic variation in the original vision of the HGDP paved the way for various human variation projects that were subsequently implemented by others.”

Greeley, a leading scholar of law and the biosciences, noted the project’s role in leading the field toward better management of its inherent difficulties. Twenty-five years later, the scientific and organizational challenges that shaped the HGDP are highly relevant to researchers today. By documenting these reflections, Rosenberg and Ramachandran hope to provide a resource for those facing the same challenges today.