2020年3月26日，美国哈佛大学Terence D. Capellini研究小组在《细胞》杂志在线发表了他们的最新成果。他们发现，进化选择和人类膝关节软骨细胞调节的约束参与影响骨关节炎的风险。
据研究人员介绍，在人类进化过程中，膝盖通过改变软骨细胞发育程序适应了两足动物的生物力学要求。这种适应性过程可能不会对健康造成有害影响。如今，骨关节炎发生在2.5亿人中，其危险变异富集在软骨细胞基因附近的非编码序列，这些基因座可能在膝关节进化过程中得到了优化。
研究人员通过表观遗传分析关节软骨细胞来探索了这种关系，并揭示出历史选择以及膝关节调节元件的近期约束和漂移，这也与骨关节炎变异重叠，这些变异通过倾向于修饰受约束的功能序列而有助于疾病遗传。研究人员提出了一个模型，即膝关节发育过程中的遗传改变导致成人病理。
因此，研究人员发现了数十亿存在危险位点（GDF5- UQCC1）人群中的致病增强子变体（rs6060369），并揭示了它如何影响小鼠的膝盖形状和骨关节炎。总体而言，这一方法将人体解剖学的进化新方面与其发病机理联系起来。
附：英文原文
Title: Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk
Author: Daniel Richard, Zun Liu, Jiaxue Cao, Ata M. Kiapour, Jessica Willen, Siddharth Yarlagadda, Evelyn Jagoda, Vijaya B. Kolachalama, Jakob T. Sieker, Gary H. Chang, Pushpanathan Muthuirulan, Mariel Young, Anand Masson, Johannes Konrad, Shayan Hosseinzadeh, David E. Maridas, Vicki Rosen, Roman Krawetz, Neil Roach, Terence D. Capellini
Issue&Volume: 2020-03-26
Abstract: During human evolution, the knee adapted to the biomechanical demands of bipedalismby altering chondrocyte developmental programs. This adaptive process was likely notwithout deleterious consequences to health. Today, osteoarthritis occurs in 250 millionpeople, with risk variants enriched in non-coding sequences near chondrocyte genes,loci that likely became optimized during knee evolution. We explore this relationshipby epigenetically profiling joint chondrocytes, revealing ancient selection and recentconstraint and drift on knee regulatory elements, which also overlap osteoarthritisvariants that contribute to disease heritability by tending to modify constrainedfunctional sequence. We propose a model whereby genetic violations to regulatory constraint,tolerated during knee development, lead to adult pathology. In support, we discovera 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 methodslink an evolutionarily novel aspect of human anatomy to its pathogenesis.
DOI: 10.1016/j.cell.2020.02.057
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30234-8