When evolution hurts: height, arthritis risk, and the regulatory architecture of GDF5 function

The Growth and Differentiation Factor 5 ( GDF5 ) gene controls both epiphyseal chondrocyte maturation and synovial joint formation. Recent studies have shown that high frequency genetic variants in GDF5 are significantly associated with stature and osteoarthritis risk in human populations. Although these associations have been highly replicated, the causal base pairs controlling height and arthritis risk are still unknown. Here we use studies in transgenic and knockout mice to identify the regulatory regions controlling normal GDF5 expression and function. Scanning studies with large Bacterial Artificial Chromosome clones shows that key GDF5 regulatory sequences are located over a large physical interval both 5 and 3 prime of the gene. Multiple enhancers map within these regions, each controlling expression in separate skeletal structures, including limb growth plates or individual synovial joints. Several of these enhancers map in the genetic interval that is strongly associated with both height and arthritis risk in humans. Molecular signatures suggest that a variant regulatory block at the GDF5 locus has been the target of strong natural selection during recent human evolution, particularly in out‐of‐Africa populations. Past selection at the locus has driven some human regulatory variants to very high frequency, with important consequences for the overall risk of arthritis in modern populations. Grant Funding Source : national institute of health