The 81st Annual Meeting of the American Association of Physical Anthropologists (2012)

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


1Developmental Biology, Stanford University School of Medicine, 2Howard Hughes Medical Institute, Stanford University School of Medicine

Friday 5:00-5:15, Galleria South Add to calendar

Modern humans display marked variations in many biological traits, although their genotypic basis remains largely unknown. Much of this variation is thought to be due to regulatory mutations occurring in non-coding genomic regions. The Growth and Differentiation Factor 5 (GDF5) gene encodes a bone morphogenetic protein that controls both epiphyseal chondrocyte maturation and synovial joint formation. Recent studies have shown that high frequency genetic variants in GDF5 are significantly associated with both stature and osteoarthritis susceptibility in human populations. Although these associations are 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 (BAC) clones shows that key GDF5 regulatory sequences are located over a large physical interval both 5’ and 3’ prime of the gene. Multiple small enhancers map within these regions, each controlling expression in separate skeletal structures, including growth plates or individual synovial joints in the limb. 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.

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