Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk
Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk
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DOI：
10.1016/j.cell.2020.02.057
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发表时间：
2020-04-16
期刊：
影响因子：
64.5
通讯作者：
Capellini, Terence D.
中科院分区：
文献类型：
--
作者：
Richard, Daniel;Liu, Zun;Capellini, Terence D.
在人类进化过程中，膝关节通过改变软骨细胞发育程序来适应两足动物的生物力学要求。这种适应过程可能对健康造成有害后果。今天，有2.5亿人患有骨关节炎，其风险变异在软骨细胞基因附近的非编码序列中富集，这些位点可能在膝关节进化过程中得到优化。我们通过对关节软骨细胞的表观遗传学分析来探索这种关系，揭示了膝关节调节元件的古老选择和最近的限制和漂移，这些因素也重叠了骨关节炎变异，这些变异通过倾向于修改受限制的功能序列来促进疾病的遗传性。我们提出了一个模型，即遗传违反调控约束，在膝关节发育期间容忍，导致成人病理。为了支持这一观点，我们在数十亿人的风险位点（GDF5-UQCC1）中发现了一种因果增强子变体（rs6060369），显示了它如何影响小鼠膝盖形状和骨关节炎。总的来说，我们的方法将人类解剖学的进化新方面与其发病机制联系起来。
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.