Regulatory constraint and selection during human knee evolution drive modern osteoarthritis risk

The evolution of human bipedalism exposed the knee to unique biomechanical challenges, requiring changes in knee anatomy giving rise to the modern-day configuration. In order to better understand the relationship between derived knee morphology and the genetic factors associated with osteoarthritis risk, we performed epigenetic profiling of murine forelimb/hindlimb growth plates to identify regulatory elements shaping formation of specific knee structures, identifying signals of ancient positive selection upon which more recent genetic drift overlaps risk-associated loci. Our functional analyses of an osteoarthritis-risk variant within a reproducibly-associated locus establishes a novel model for studying this degenerative disease. Examination of open chromatin regions in multiple different growth plates (proximal vs distal femur, tibia, humerus, radius) at E15.5

人类两足行走的演化过程使膝关节面临独特的生物力学挑战，促使膝关节解剖结构发生适应性改变，最终形成了现代人类的膝关节构型。为深入解析衍生型膝关节形态与骨关节炎（osteoarthritis）风险相关遗传因子之间的关联，我们对小鼠（murine）前肢/后肢生长板开展了表观遗传谱分析（epigenetic profiling），以识别调控特定膝关节结构发育的调控元件；在此过程中，我们鉴定出了古老正向选择的信号，而近期发生的遗传漂变与该信号上的风险相关位点存在重叠。我们针对一个可重复验证关联位点内的骨关节炎风险变异体开展的功能分析，为这类退行性疾病的研究构建了全新模型。本研究对胚胎发育第15.5天（E15.5）的多种不同生长板（股骨近端与远端、胫骨、肱骨、桡骨）的开放染色质区域进行了检测。