Recent evolution of the developing human intestine affects metabolic and barrier functions.
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| Title: | Recent evolution of the developing human intestine affects metabolic and barrier functions. |
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| Authors: | Yu, Qianhui, Kilik, Umut, Secchia, Stefano, Adam, Lukas, Tsai, Yu-Hwai, Fauci, Christiana, Janssens, Jasper, Childs, Charlie J., Walton, Katherine D., López-Sandoval, Rubén, Wu, Angeline, Almató Bellavista, Marina, Huang, Sha, Steiner, Calen A., Throm, Yannick, Boyle, Michael James, He, Zhisong, Beumer, Joep, Treutlein, Barbara, Lowe, Craig B. |
| Source: | Science. 8/21/2025, Vol. 389 Issue 6762, p1-13. 13p. |
| Subjects: | Metabolic regulation, Lactase, Immunity, Gene expression, Epithelial cells |
| Abstract: | 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. Editor's summary: Organs such as the skin, lungs, and intestine must interact directly with chemicals and other organisms from the outside world. Given that exposures change with environments, these organs must adapt to new conditions while also remaining flexible to environmental change. Yu et al. used comparative genomics and cell atlas data from the human intestine to identify locations under recent selection in humans, finding genes involved in immunity and metabolism. They also generated human and chimpanzee intestinal organoids that recapitulated gene expression in these species and helped to identify cell types of interest with human-specific changes. These results illuminate the evolution of the human intestine and provide a model for this difficult to study tissue. —Corinne Simonti INTRODUCTION: The innovation of cooking and the transition from hunter-gatherer to agricultural societies created a distinctly human gut environment compared with that of our great ape relatives. The modern human intestine exhibits distinct morphological, metabolic, and immunological adaptations, including an increase in the allometric relationship between the small and large intestines. Intestinal epithelial cells directly interface with the luminal environment, facilitating nutrient absorption while forming a barrier against microbiota. Prenatal gene regulatory mechanisms orchestrate intestinal development and function; however, the species-specific molecular adaptations of epithelial cells remain poorly understood. RATIONALE: Cross-species comparisons of genomic sequences, gene expression, and chromatin accessibility can link evolutionary changes to cellular function at the molecular level. Pluripotent stem cell–derived intestinal organoids model intestinal development, which enables the study of otherwise inaccessible developing chimpanzee tissues and functional assays in physiologically relevant contexts. We integrated single-cell sequencing data from developing human and mouse intestinal tissues with data from great ape intestinal organoids and used comparative genomics to characterize the evolutionary dynamics of intestinal cell types and their molecular machinery. We then performed functional assays in human organoids to examine how human-specific selection on gene regulatory regions affects gene expression. RESULTS: Assessment of nonsynonymous-to-synonymous substitution ratios of expressed genes and deepest ancestry analysis of accessible regulatory regions revealed that enterocytes of the developing human intestinal epithelium are rapidly evolving. We identified genes with human-specific expression profiles and associated open chromatin regions with differential accessibility between humans and chimpanzees in epithelial cells. These findings, combined with evolutionary rate analysis, indicate recent evolutionary changes in the human intestinal epithelium, particularly in barrier function and metabolism. We cataloged and ranked epithelial regulatory regions by composite evolutionary selection signatures and then conducted functional assays on top candidates in human small intestinal organoids. We validated a cis-regulatory region in the MCM6 gene as a functional enhancer for the LCT gene, suggesting how a positively selected polymorphism associated with lactose tolerance in adulthood disrupts a repressor-binding site. We functionally highlight several other recent gene regulatory changes in regions associated with PDX1, RBP2, and IGFPB2. Notably, IGFBP2 has two enhancers overlapping human accelerated regions and exhibiting higher chromatin accessibility in developing human intestinal epithelial cells compared with chimpanzee counterparts. In silico mutagenesis predictions and variant-resolved enhancer assays confirmed elevated enhancer activity of selected loci compared with the ancestral sequence. CRISPR-Cas9 deletion of each enhancer reduced IGFBP2 gene expression in small intestinal organoids. CONCLUSION: Our work highlights the interface between humans and our external environment during developmental stages, when metabolic and barrier functions are being established. We characterized recent evolutionary dynamics in the developing human intestine, identified human-specific molecular features, and functionally evaluated regulatory regions in a complex human model system. The human selection signatures and the elevated chromatin accessibility of two functionally validated enhancers of IGFBP2 in humans suggest that recent evolutionary modifications within the insulin and insulin-like signaling pathways affect human small intestine development. This research advances our understanding of human intestinal gene regulatory mechanisms in an evolutionary context and reveals the functional effects of human-specific selection that may contribute to modern disease risks. Recent evolution affects the developing human intestine epithelium.: Comparative genomic analysis of expressed genes and accessible regulatory regions in developing human intestinal epithelium revealed recent evolutionary changes affecting metabolism and barrier function. Human and chimpanzee pluripotent stem cell (PSC)–derived organoids, combined with primary developing human and mouse intestinal tissues, identified regulatory regions selected in human controlling cell type–dependent gene expression. Enhancer assays and loss-of-function experiments in organoids provided functional validation. WT, wild-type; KO, knockout. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | 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. Editor's summary: Organs such as the skin, lungs, and intestine must interact directly with chemicals and other organisms from the outside world. Given that exposures change with environments, these organs must adapt to new conditions while also remaining flexible to environmental change. Yu et al. used comparative genomics and cell atlas data from the human intestine to identify locations under recent selection in humans, finding genes involved in immunity and metabolism. They also generated human and chimpanzee intestinal organoids that recapitulated gene expression in these species and helped to identify cell types of interest with human-specific changes. These results illuminate the evolution of the human intestine and provide a model for this difficult to study tissue. —Corinne Simonti INTRODUCTION: The innovation of cooking and the transition from hunter-gatherer to agricultural societies created a distinctly human gut environment compared with that of our great ape relatives. The modern human intestine exhibits distinct morphological, metabolic, and immunological adaptations, including an increase in the allometric relationship between the small and large intestines. Intestinal epithelial cells directly interface with the luminal environment, facilitating nutrient absorption while forming a barrier against microbiota. Prenatal gene regulatory mechanisms orchestrate intestinal development and function; however, the species-specific molecular adaptations of epithelial cells remain poorly understood. RATIONALE: Cross-species comparisons of genomic sequences, gene expression, and chromatin accessibility can link evolutionary changes to cellular function at the molecular level. Pluripotent stem cell–derived intestinal organoids model intestinal development, which enables the study of otherwise inaccessible developing chimpanzee tissues and functional assays in physiologically relevant contexts. We integrated single-cell sequencing data from developing human and mouse intestinal tissues with data from great ape intestinal organoids and used comparative genomics to characterize the evolutionary dynamics of intestinal cell types and their molecular machinery. We then performed functional assays in human organoids to examine how human-specific selection on gene regulatory regions affects gene expression. RESULTS: Assessment of nonsynonymous-to-synonymous substitution ratios of expressed genes and deepest ancestry analysis of accessible regulatory regions revealed that enterocytes of the developing human intestinal epithelium are rapidly evolving. We identified genes with human-specific expression profiles and associated open chromatin regions with differential accessibility between humans and chimpanzees in epithelial cells. These findings, combined with evolutionary rate analysis, indicate recent evolutionary changes in the human intestinal epithelium, particularly in barrier function and metabolism. We cataloged and ranked epithelial regulatory regions by composite evolutionary selection signatures and then conducted functional assays on top candidates in human small intestinal organoids. We validated a cis-regulatory region in the MCM6 gene as a functional enhancer for the LCT gene, suggesting how a positively selected polymorphism associated with lactose tolerance in adulthood disrupts a repressor-binding site. We functionally highlight several other recent gene regulatory changes in regions associated with PDX1, RBP2, and IGFPB2. Notably, IGFBP2 has two enhancers overlapping human accelerated regions and exhibiting higher chromatin accessibility in developing human intestinal epithelial cells compared with chimpanzee counterparts. In silico mutagenesis predictions and variant-resolved enhancer assays confirmed elevated enhancer activity of selected loci compared with the ancestral sequence. CRISPR-Cas9 deletion of each enhancer reduced IGFBP2 gene expression in small intestinal organoids. CONCLUSION: Our work highlights the interface between humans and our external environment during developmental stages, when metabolic and barrier functions are being established. We characterized recent evolutionary dynamics in the developing human intestine, identified human-specific molecular features, and functionally evaluated regulatory regions in a complex human model system. The human selection signatures and the elevated chromatin accessibility of two functionally validated enhancers of IGFBP2 in humans suggest that recent evolutionary modifications within the insulin and insulin-like signaling pathways affect human small intestine development. This research advances our understanding of human intestinal gene regulatory mechanisms in an evolutionary context and reveals the functional effects of human-specific selection that may contribute to modern disease risks. Recent evolution affects the developing human intestine epithelium.: Comparative genomic analysis of expressed genes and accessible regulatory regions in developing human intestinal epithelium revealed recent evolutionary changes affecting metabolism and barrier function. Human and chimpanzee pluripotent stem cell (PSC)–derived organoids, combined with primary developing human and mouse intestinal tissues, identified regulatory regions selected in human controlling cell type–dependent gene expression. Enhancer assays and loss-of-function experiments in organoids provided functional validation. WT, wild-type; KO, knockout. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adr8628 |
