Hundreds of new primate genomes offer window into human health—and our past

Humans have long seen themselves mirrored in other primates, with apes’ social behavior and cognitive abilities shedding light on our own. Now, two international teams have stared deeper into the mirror. By sequencing the genomes of more than 200 nonhuman primates, from palm-size mouse lemurs to 200-kilogram gorillas, they have come up with clues to human health and disease, and to the origin of our species.

The genomes and their analyses, reported today in Science and Science Advances, represent a massive effort involving more than 100 researchers from about 20 countries who braved logistical challenges and bureaucratic gauntlets to collect blood samples from some 800 wild and captive primates. The resulting data show how knowing a primate's genetic diversity could improve the odds of saving highly endangered species.

But our own species could also benefit. One team used the genomes to train a machine learning tool that could assess whether human genetic variants are likely to cause disease. And both explored the complexity of primates’ evolution, shedding light on our own. "This massive sample will ultimately spark new and unexpected research directly relevant to human origins," says Luis Darcy Verde Arregoitia, a mammalogist at the Mexico Institute of Ecology who was not involved with either group.

The bigger of the two genome efforts was spearheaded not by a primatologist or evolutionary biologist, but a clinical geneticist at the DNA-sequencing company Illumina. For Kyle Farh, like many in medicine, the genomics revolution has been a source of frustration as well as hope. Human gene sequencing has turned up myriad variants of individual genes that might explain diseases or treatments. But human genetics alone often can't tell whether a variant is medically relevant.

Farh thought he could find more clarity by searching for analogous variants in other primate species. "We recognized that data from our own species was insufficient." After testing the idea with the primate genomes available several years ago, in 2019 he reached out to evolutionary geneticist Tomas Marques-Bonet from the Institute of Evolutionary Biology in Barcelona, Spain, and primate geneticist Jeffrey Rogers at Baylor College of Medicine with a proposal. If they could come up with blood samples from multiple members of many of the world's 500-plus primates, Illumina would help fund the DNA sequencing.

The ambition was staggering, say some scientists outside the project. "It takes an enormous amount of time, effort, and government permits to obtain genetic samples of wild primates," says Paul Garber, a biological anthropologist emeritus at the University of Illinois Urbana-Champaign. And it's even more difficult for species classified as threatened—which more than 60% of nonhuman primates are.

Undaunted, Marques-Bonet signed up researchers around the world. "It was an amazing opportunity to expand the scope of my research interests," recalls ecologist Jean Boubli, who grew up and worked in Brazil before setting up a U.K. lab at the University of Salford. He contributed samples for 77 South American species, most obtained during his 30 years of exploring and living in the Amazon, collaborating with local scientists, museums, and zoos.

Getting blood samples from anesthetized or restrained wild primates in zoos or captive breeding centers was often challenging, says another contributor, Govindhaswamy Umapathy. A conservation biologist at the Centre for Cellular and Molecular Biology, Umapathy travelled from state to state in India to lobby forest managers and local officials for access to gibbons, lorises, macaques, and lemurs.

Led by Marques-Bonet's postdoc Lukas Kuderna, now at Illumina, the consortium sequenced 703 individuals of 211 species using "short-read" technology in which DNA is first broken into small bits. The new data joined 106 already sequenced genomes from 29 additional primate species and a set of new genomes for 27 other primate species. Those genomes came from the second consortium, co-led by Dong-Dong Wu, a geneticist at the Chinese Academy of Sciences's Kunming Institute of Zoology, which used a technique that read longer stretches of DNA.

With their data and the other primate genomes, Wu and his colleagues honed the family tree for this group of mammals and identified unexpected genomic rearrangements—duplicated or inverted regions of chromosomes, for example—that distinguished primates living in different environments, such as tropical rainforest and semidesert. Further study may reveal whether the shuffling helped those species adapt to the various conditions.

The trove of primate genomes allowed Farh, Rogers, Marques-Bonet, and colleagues to go hunting for single nucleotide polymorphisms (SNPs), individual DNA base variations within or between species that may change the proteins encoded by genes or alter a gene's activity. They found 4.3 million that altered a protein's amino acid sequence. "The initial presentations took my breath away," recalls Amanda Melin, a biological anthropologist at the University of Calgary who provided samples of Costa Rican primates. "The scale of it was really staggering."

On the assumption that a human SNP with commonly observed counterparts in primates probably doesn't cause disease, Farh exonerated many human variants. His team also used the "benign" primate SNPs to train a neural network, called Primate AI-3D. With AlphaFold, a protein-structure prediction tool based on artificial intelligence (AI), as its scaffold, his program builds 3D models of each protein. Based on the benign SNPs, it identifies regions where changes to the protein's structure would not disrupt its function. Conversely, changes in other regions were more likely to cause problems.

He then applied the AI to predict the potential harm of human SNPs. And when he and colleagues matched those predictions with a database of human base changes that had been tentatively linked to diseases, they concluded 6% of the SNPs are likely innocent. "I was a bit skeptical" at first, says Kaitlin Samocha, a geneticist at Massachusetts General Hospital. But, "This resource is a great way to ‘rule out’ a variant as being damaging and does move the needle on our ability to interpret protein-altering variation."

The team also used the primate-trained AI to do the opposite: Identify harmful genes. They applied it to the health records and gene variant data of 454,712 people in the UK BioBank to find SNPs likely to play a role in 90 human health concerns. "It allows us to identify which genes are potential drug targets," Farh says.

Neil Risch, a geneticist at the University of California, San Francisco, says other researchers will need to vet the AI predictions. But he does think these primate genomes "are treasured samples."

Evolutionary biologists agree. Already the genomes have revealed an important role in evolution for hybridization, once thought to be rare. In one Science paper, Wu and his colleagues show that the critically endangered gray snub-nosed monkey, which is endemic to mountains in south-central China, arose after the golden snub-nosed monkey mated with the ancestors of two other species in that genus, Rhinopithecus. Moreover, one of the three groups of macaques arose through hybridization between the other two, about 3.5 million years ago, they report in Science Advances.

The other consortium, led by Rogers, also found signs of rampant hybridization in the DNA of 225 wild baboons from multiple species, which conservation biologist Julius Keyyu at the Tanzania Wildlife Research Institute helped obtain and analyze. "This work provides a potential analog to recent human evolution," notes Eleanor Scerri, an evolutionary archaeologist at the Max Planck Institute of Geo anthropology. Increasing evidence shows that intermingling once occurred among various hominids—Neanderthals, modern humans, Denisovans, and maybe others—tens of thousands of years ago.

The primates that are delivering these insights are themselves under threat from habitat destruction and other human activity. But a surprising finding from the studies could aid efforts to save them. Normally a population crash in a species also narrows its genetic diversity, thanks to inbreeding among the survivors. Yet all but 15 primate species sequenced by the team still had relatively high genetic diversity—higher than humans. That was true even in extremely endangered ones such as the northern sportive lemur (Lepilemur septentrionalis) of which only 40 are known to exist, all within 12 square kilometers of Madagascar.

This suggests the primates’ population crashes, some likely caused by human habitat destruction, were so recent that there hasn't been time for inbreeding to lower the species’ diversity. "The population declines are so rapid that genetics does not manage to catch up with it," says Katerina Guschanski, an evolutionary biologist at the University of Edinburgh and Uppsala University.

Umapathy and others say the finding is encouraging, because higher diversity should make species more resilient. As animal ecologist Fabiano Melo from Viçosa Federal University, who collaborates with Boubli, points out, "It means that we still have time to revert this situation."