Recent evolution of the developing human intestine affects metabolic and barrier functions

• 成果类型: Article
• 署名作者: Yu, Qianhui; Kilik, Umut; Secchia, Stefano; Adam, Lukas; Tsai, Yu-Hwai; Fauci, Christiana; Janssens, Jasper; Childs, Charlie J.; Walton, Katherine D.; Lopez-Sandoval, Ruben; Wu, Angeline; Almato Bellavista, Marina; Huang, Sha; Steiner, Calen A.; Throm, Yannick; Boyle, Michael James; He, Zhisong; Beumer, Joep; Treutlein, Barbara; Lowe, Craig B.; Spence, Jason R.; Camp, J. Gray
• 署名单位: Roche Holding; University of Basel; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Michigan System; University of Michigan; Duke University; University of Colorado System; University of Colorado Anschutz Medical Campus; Yale University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9305
• DOI: 10.1126/science.adr8628
• 发表日期: 2025-08-21
• 关键词: coverage neanderthal genome; transcription-factor; lactase persistence; in-vitro; growth-factors; cell; organoids; vertebrate; expression; sequence

摘要

Diet, microbiota, and other exposures make the intestinal epithelium a nexus for evolutionary change; however, little is known about genomic changes associated with adaptation to a distinctly human environment. In this work, we interrogate the evolution of cell types in the developing human intestine by comparing tissue and organoids from humans, chimpanzees, and mice. We find that recent changes in primates are associated with immune barrier function and lipid and xenobiotic metabolism and that human-specific genetic features affect these functions. Enhancer assays, genetic deletion, and in silico mutagenesis resolve evolutionarily important enhancers of lactase (LCT) and insulin-like growth factor binding protein 2 (IGFBP2). Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system and show that great ape organoids provide insight into human biology.