@article {1521630,
	title = {Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk},
	journal = {Cell},
	volume = {181},
	number = {2},
	year = {2020},
	month = {2020 Apr 16},
	pages = {362-381.e28},
	abstract = {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.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2020.02.057},
	author = {Richard, Daniel and Liu, Zun and Cao, Jiaxue and Kiapour, Ata M and Willen, Jessica and Yarlagadda, Siddharth and Jagoda, Evelyn and Kolachalama, Vijaya B and Sieker, Jakob T and Chang, Gary H and Muthuirulan, Pushpanathan and Young, Mariel and Masson, Anand and Konrad, Johannes and Hosseinzadeh, Shayan and Maridas, David E and Rosen, Vicki and Krawetz, Roman and Roach, Neil and Capellini, Terence D}
}
