The genetic changes that make us human have stayed hidden
Compared with other great apes, humans possess a suite of remarkable traits: large brains and advanced cognition, complex speech and a skeleton built for upright, two-legged walking. Understanding how these features arose is not merely a question of natural history: it is central to understanding, and ultimately treating, diseases that are disproportionately common in humans. But while these traits are well described at the level of the body, the specific DNA changes that helped produce them have remained largely unknown. Pinpointing which genetic differences matter, and how they act, has long been one of the central challenges in studying human evolution.
The human genome contains roughly three billion DNA “letters” and differs from the chimpanzee genome by only about 1 to 4%, depending on how those differences are counted. The protein-coding regions are almost identical between the two species. This has led scientists to conclude that much of what drives human evolution lies outside these regions, in non-coding regulatory sequences that determine when, where and how strongly genes are turned on. The challenge has been technical: for any given sequence, it has been extremely difficult to determine whether a human-specific change actually alters gene activity or is simply a harmless bystander.
Mapping the switches behind human skeletal evolution
In this study, the researchers set out to overcome this bottleneck by focusing on the human skeleton. They combined two complementary experimental approaches to identify, on a genome-wide scale, the regulatory changes that shaped skeletal evolution.
First, the team compared the genomes of more than 15,000 people with those of 139 great apes, including chimpanzees, bonobos, gorillas and orangutans, and identified roughly 5.7 million changes that arose only along the human lineage. About 561,000 of these changes fell within candidate promoter and enhancer regions. The researchers then synthesized both the human and ancestral forms of each sequence and tested them in cultured cartilage cells using MPRA, a method that measures the activity of hundreds of thousands of regulatory sequences at once. This screen narrowed the field to about 15,000 human-specific variants that measurably altered gene activity.
The team next tested the effects of these regulatory changes in a shared cellular environment. They fused human and gorilla induced pluripotent stem (iPS) cells to create interspecies hybrid cells, then directed them to develop into progenitor cells capable of forming bone and cartilage. Because the human and gorilla chromosomes occupied the same cells, the researchers could compare their activity directly, without the confounding effects that can arise when the two species are studied in separate cultures. Applying the same strategy to previously generated human-chimpanzee hybrid cells, they identified genes that are regulated differently in humans and other great apes.
The strongest signal emerged in pathways related to glycosaminoglycans (GAGs). GAGs are major components of the extracellular matrix, a scaffold that surrounds and supports cells, and help maintain the structure, elasticity and water content of cartilage. In the human-gorilla hybrid cells, many GAG-related genes were less active on the human chromosomes than on the gorilla chromosomes, consistent with the effects of human-specific regulatory changes.
The same pattern was seen in joint tissue. When the researchers measured GAG content in elbow and knee samples from humans and other great apes, levels varied little among the other great apes but were only about one-quarter to one-third as high in humans. Taken together, the results suggest that evolutionary changes in enhancers controlling GAG-related genes lowered GAG levels in human cartilage. This shift may have contributed to distinctive features of our skeleton while also helping to explain why conditions such as osteoarthritis are far more common in humans than in our ape relatives.
Looking ahead
The implications extend beyond the skeleton. By combining MPRA with interspecies hybrid cells, the study allows researchers to move beyond genome sequence comparisons and test directly how human-specific variants affect gene activity in cells. The same approach could be used to investigate the regulatory basis of other traits that distinguish humans, including features of the brain and skin, and to examine how evolutionary changes contribute to diseases that disproportionately affect humans.
“By constructing the first functional atlas of human-specific cis-regulatory variants, our study uncovers how regulation drove the unique evolution of the human skeleton, bridging a long-standing gap in evolutionary biology,” commented first author Yizhi Yan, “Moving forward, applying our integrative approach will help further decode the genetic blueprint of human uniqueness and unlock new perspectives on human-specific diseases.”
Glossary
Genome: The complete set of DNA in an organism.
Regulatory DNA: DNA sequences that control when, where and how strongly genes are switched on, rather than providing instructions for making proteins.
Promoters and enhancers: Types of regulatory DNA. Promoters sit near the genes they control, while enhancers can act from farther away to increase or modify gene activity.
Massively parallel reporter assay (MPRA): A laboratory method that tests thousands of DNA sequences at the same time to determine how strongly each one affects gene activity.
Induced pluripotent stem (iPS) cells: Adult cells that have been reprogrammed into a stem-cell-like state, allowing them to develop into many different cell types.
Interspecies hybrid cells: Cells created by fusing cells from two different species. Because both sets of chromosomes share the same cellular environment, researchers can compare their activity directly.
Glycosaminoglycans (GAGs): Long sugar molecules that help cartilage retain water, maintain its structure and withstand pressure.
Cis-regulatory variant: A DNA change that affects the activity of a nearby gene without altering the protein encoded by that gene.
Nature
Experimental study
Cells
The Gene Regulatory Evolution of the Human Skeleton
23-Sep-2026