About six million years ago, our ancestors developed the bipedal gait. The upright posture allowed them to adapt to new environments more easily and left their hands free to use tools, for example - an important step in human evolution. But what are the genetic bases that shape our skeleton and enable us to walk upright? Researchers have now answered this question using over 30,000 whole-body X-ray images and genome data with the help of machine learning. The results also provide information about connections between our skeletal shape and diseases such as osteoarthritis and back pain.
Our skeleton is uniquely adapted to walk upright: unlike all other primates, our arms are shorter than our legs and the spine is vertically aligned over a relatively narrow pelvis. These adaptations have developed over millions of years of human evolution and are considered one of the most important steps on the way to modern humans. At the same time, however, they are also associated with skeletal disease risks, including back pain, knee problems and osteoarthritis. While changes in human anatomy are well documented in fossils, it has been unclear which genes underlie our unique skeletal shape.
Selection pressure for skeletal changes
A team led by Eucharist Kun from the University of Texas in Austin has now investigated this question. To do this, the team used full-body X-rays from over 30,000 people recorded in the UK Biobank, a large biomedical database in the UK. Kun and his team evaluated these images with the help of machine learning and combined the results with the genome data of the respective people. In this way, the researchers found 145 locations in the genome that are associated with specific features of the skeletal shape, including the width of the shoulders and hips, the length ratio of the arms and legs, and the distances between numerous other points on the body.
It turned out that the places in the genome that are associated with skeletal features are mainly in so-called "accelerated" regions, which have developed very rapidly in humans compared to humans and other vertebrates. Such sites were also found in regulatory regions of genes, which are transcribed to varying degrees in humans and human beings during development. "What we see here is the first genomic evidence that there was selection pressure on genetic variants that affect skeletal proportions and enabled the transition from knucklewalking to bipedism," says Kun's colleague Vagheesh Narasimhan.
Body proportions determine the risk of disease
The team also found that some genetic variants associated with the typical human skeletal shape increase the risk of certain musculoskeletal disorders. For example, people with a higher hip width-to-height ratio are more likely to develop osteoarthritis and hip pain. People whose thighs are particularly long for their height are at higher risk of knee problems, and people whose legs are relatively short for their height are more likely to suffer from back pain. "These diseases are caused by biomechanical loads on the joints over the course of life," says Kun. "Skeletal proportions affect everything from walking to sitting, and it makes sense that they are risk factors for these disorders."
From the perspective of the researchers, the study can both be helpful for evolutionary research and open up new perspectives for better understanding and treating diseases of the musculoskeletal system. "Our work provides a guide linking specific genes to skeletal length in different parts of the body, allowing developmental biologists to study them systematically," says co-author Tarjinder Singh of Columbia University.
Source: Eucharist Kun (University of Texas at Austin) et al., Science, doi: 10.1126/science.adf8009