Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk.

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5 - UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis. • Human/mouse long bone chondrocyte ATAC-seq reveals site-specific regulatory elements • Ancient positive and purifying selection shape human knee regulation and morphology • Modern human drift and pleiotropy violate regulatory constraint conferring OA risk • Validation at GDF5 reveals a single regulatory variant impacting both shape and OA Epigenetic profiling of chondrocytes reveals selection and constraint on knee regulatory elements including those overlapping osteoarthritis risk variants, including a functionally verified common enhancer variant sufficient to affect knee shape in mouse. [ABSTRACT FROM AUTHOR]