以色列魏茨曼科学研究所David Gokhman研究团队的一项最新研究的研究开发出了人类骨骼的基因调控进化。该项研究成果发表在2026年9月23日出版的《自然》上。

骨骼改变是人类演化的核心，使得双足行走、大颅腔和分娩等适应性得以实现。尽管其重要性，导致人类独特形态的遗传变化大多仍不清楚。在此，研究人员系统绘制了塑造人类骨骼演化的基因调控变化。利用软骨细胞中的大规模平行报告基因检测，他们对启动子和增强子中的561,410个人源替换进行了检测，鉴定出15,077个具有人类特异性调控活性的位点。随后，他们生成了人-猿杂交细胞，并将其分化为骨软骨祖细胞。将杂交细胞与MPRA测量相结合，产生了人类特异性顺式调控表达变化及其驱动序列变异的全基因组图谱。这些图谱揭示了细胞外基质的广泛重塑，包括糖胺聚糖生物合成的显著抑制，导致人类关节GAG含量比非人猿类减少约三至四倍。研究人员发现，这种人类特异性转变具有选择特征，可能是人类对退行性骨骼疾病异常易感的关键因素。总之，研究结果揭示了人类骨骼细胞外基质的协调演化重塑，并为剖析人类骨骼生物学的遗传基础建立了一个全面框架。

附：英文原文

Title: The gene-regulatory evolution of the human skeleton

Author: Yan, Yizhi, Mishol, Nadav, Lange, Katharina, Zhang, Zicong, Bodek, Gal, Kigel, Aya, Priel, Noam, Egyes, Nachshon, Ronen, Omer, Nini, Itamar, Rotenstreich, Liat, Philosoph, Amit, Martinez, Sira, Beltramone, Silvia, Tsujikawa, Rika, Rozenblatt, Adi, Wange, Lucas Esteban, Torralvo, Mara, Hirsh, Guy, Elboim, Yael, Viukov, Sergey, Korenfeld, Idan, Damal Kandadai, Mythili, Cluzeau, Ocane, Nissim-Rafinia, Malka, Meshorer, Eran, Hanna, Jacob H., Vereecke, Evie, Marom, Assaf, Kuhlwilm, Martin, Bourque, Guillaume, Marques-Bonet, Tomas, Fishilevich, Simon, Inoue, Fumitaka, Gokhman, David

Issue&Volume: 2026-09-23

Abstract: Skeletal modifications were central to human evolution, enabling adaptations for bipedalism, large cranial vaults and childbirth1. Despite their importance, the genetic changes that gave rise to the unique human form remain mostly unknown2. Here we systematically map the gene-regulatory changes that shaped human skeletal evolution. Using massively parallel reporter assays (MPRAs) in chondrocytes, we assayed 561,410 human-derived substitutions in promoters and enhancers, identifying 15,077 loci with human-specific regulatory activity. We then generated human–ape hybrid cells and differentiated them into osteochondral progenitors. Integrating the hybrid cells with MPRA measurements produced genome-wide atlases of human-specific changes in cis-regulatory expression, and the sequence variants that drive them. These atlases reveal an extensive rewiring of the extracellular matrix (ECM), including a marked suppression of glycosaminoglycan (GAG) biosynthesis, leading to an approximately three-to-fourfold reduction in joint GAG content in humans compared with non-human apes. We find that this human-specific shift bears signatures of selection, and is likely to be a key contributor to the exceptional susceptibility of humans to degenerative skeletal diseases3,4,5. Together, our results reveal a coordinated evolutionary remodelling of the human skeletal ECM, and establish a comprehensive framework for dissecting the genetic basis of human skeletal biology.

DOI: 10.1038/s41586-026-11053-x

Source: https://www.nature.com/articles/s41586-026-11053-x