A team of researchers has created the first functional map of gene-control changes that are unique to humans, focusing on the development of the human skeleton. Their study, published in the journal Nature, was led by researchers from Kyoto University and the Weizmann Institute of Science. The team discovered that a family of molecules known as glycosaminoglycans (GAGs)—which help cushion and maintain cartilage—has become less prominent in human evolution. This finding could help explain why humans have distinct skeletal features and are more prone to conditions like osteoarthritis compared to other great apes. To uncover these changes, the researchers combined two advanced techniques: massively parallel reporter assays (MPRAs), which allow scientists to test the activity of many genetic sequences at once, and the use of human-ape hybrid cells. By comparing the genomes of over 15,000 people with those of 139 great apes, they identified about 5.7 million genetic changes that occurred only in the human lineage. Of these, around 561,000 changes were located in regions of the genome that control gene activity, such as promoters and enhancers. Using MPRA, the researchers tested these genetic sequences in cartilage cells grown in the lab, narrowing down the list to about 15,000 human-specific variants that significantly altered gene activity. They then created hybrid cells by fusing human and gorilla induced pluripotent stem (iPS) cells—cells that can be coaxed to become various types of tissue. These hybrid cells were directed to develop into progenitor cells capable of forming bone and cartilage. In these hybrid cells, many genes related to GAGs were less active on the human chromosomes compared to the gorilla chromosomes, indicating the influence of human-specific regulatory changes. The study also found that GAG levels in human joint tissues, such as the elbow and knee, were only about one-quarter to one-third of those found in other great apes. This reduction in GAGs may have contributed to the unique structure of the human skeleton and could explain the higher prevalence of joint-related diseases in humans. The research not only sheds light on skeletal evolution but also provides a new method for studying how genetic regulation has shaped other human traits and diseases that disproportionately affect humans. First author Yizhi Yan emphasized that the study bridges a major gap in evolutionary biology by showing how regulatory changes have driven the unique development of the human skeleton.