Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system, and show that great ape #organoids provide insight into human biology. 🙏Thanks 🙏 to all authors! Especially co-first authors: @CY_Qianhui_YU @KlkUmut @stefanosecchia 11/11

We identify and functionally evaluate 2 human accelerated regions (HARs) at the IGFBP2 locus. Provocatively, these data indicate that the IGF pathway contributed to evolutionary change in the developing human intestine, potentially augmenting small intestine length. 10/11

Organoid KO/Reporter assays confirm a bona fide Lactase expression enhancer within an MCM6 intron. Deep learning predicts that a selected SNP associated with lactase persistence removes a transcriptional repressor binding site, a potential mechanism for hypolactasia. 9/11

We used a composite annotation to identify intestinal gene regulatory regions that have strong signatures of function and evolutionary change in humans. Willow plots aesthetically showcase the diverse gene ontologies affected by regulatory changes. 8/10

We identified conservation and divergence between human and chimpanzee intestinal epithelial gene regulation associated with metabolic and barrier functions. 7/10

Truly incredible chimpanzee intestinal tissues can be generated from chimpanzee pluripotent stem cells, providing a very exciting inroad into comparative species analysis! Builds on extraordinary work from @JimWellsLab @TheSpenceLab #organoids #evodevo 6/10

Pluripotent stem cells can generate intestinal organoid tissues that have remarkable similarity to primary tissue counterparts. We performed a multiplexed reporter assay to assess putative enhancers for activity in intestinal organoids. 5/10

We explored the evolution of cell types and gene regulation by comparing tissue and #organoids from humans, chimps, and mice. Many genes and reg. regions active in enterocytes and associated with barrier function and metabolism have signatures of recent change. 4/10

At birth, the human GI tract becomes exposed to the outside world. Prior to birth, gene regulatory networks must orchestrate intestinal development to prepare for dynamic diet and microbiota exposures, which change over lifespan. 3/10

Recent genetic change affects gut function, including variants involved in Crohn’s disease (CD), inflammatory bowel disease (IBD), and hypolactasia. An evolutionary perspective on the developing intestine has human health relevance and can shed light on modern GI disorders. 2/10