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.

Purpose of review This review aims to evaluate current research findings relevant to weight stigmatization, to acknowledge the deleterious impact it has on the health of the paediatric population and to provide insight to optimize future guidelines for the treatment of individuals with overweight and obesity. Recent findings Obesity prevalence continues to rise in the USA with estimates in children from ages 2–19 years of 18.5%, an all-time high. With the increase in obesity, there has been a concomitant increase in weight stigma, which affects both youth and general population across varied levels of socioeconomic status and body sizes. Summary Weight stigma is a contributing phenomenon to the current obesity epidemic, as individuals with stigmatized experiences (weight-based teasing, bullying, victimization) have increased risks for acquiring adverse health outcomes that encompass the physical, behavioural and psychological. Weight stigma can also lead affected individuals to internalize such experiences which decrease their overall quality of life. Sources of stigma may come from peers, family, educators, media, as well as healthcare professionals, as highlighted in this review. Efforts to establish prevention and treatment strategies for weight stigma may generate further traction to help improve global obesity rates. Video abstract http://links.lww.com/COE/A15