The genetic architecture of the human skeletal form

Combining data from full-body x-ray images and associated genomic data from more than 30,000 UK Biobank participants, researchers have helped illuminate the genetic basis of human skeletal proportions. The findings not only provide new insights into the evolution of the human skeletal form and its role in musculoskeletal disease, but they also demonstrate the utility of using population-scale imaging data from biobanks to understand both disease-related and normal physical variation among humans.

Of all primates, humans are the only ones to have evolved to be normally bipedal, an adaptation that may have facilitated the use of tools and accelerated cognitive development.

Specific anatomical properties of the human skeleton, such as shorter arms relative to legs, a narrow body and pelvis, and the vertical orientation of the vertebral column, stabilize our upright posture and enable our unique ability to walk on two legs. These broad changes to skeletal proportions (SPs) evolved gradually over several million years. However, while the morphological changes of the skeletal form across human evolution are well studied, their genetic basis remains unknown.

To study the genetic basis of human SPs and how it’s linked to evolution and musculoskeletal disease, Eucharist Kun and colleagues applied deep-learning models and methods in computer vision to derive human skeletal measurements from full-body X-ray images from 31,221 individuals in the UK Biobank.

Using associated genetic data for the participants, the researchers identified 145 independent genetic loci associated with SPs. The authors discovered that although limb proportions exhibit strong genetic sharing, they are uncorrelated with body width proportions, a finding that provides insight into the constraints placed on the evolution of the skeletal form.

The researchers analysis also revealed specific associations between osteoarthritis and hip and knee SPs, illustrating the biomechanical role the proportions of these joints may play in shaping specific risk factors for various musculoskeletal disorders.

What’s more, in contrast to other traits, the findings show that SP loci are linked to regions of the genome that were accelerated in human evolution and in regions that were differently regulated between great apes and humans.