CAREER: Leveraging natural diversity to uncover the genetic basis of host-microbiome interactions

About This Grant

The human gut microbiome is made up of trillions of microbes that influence digestion, immunity, and overall health. Scientists have found that people vary widely in the communities of microbes they host, but the reasons for this variation remain unclear. While studies suggest that genetics plays a role, it is not yet understood how specific genetic differences shape the microbiome. This project uses the Mexican tetra, a small fish with surface-dwelling and cave-dwelling forms, to explore how genes influence gut microbes. These fish have evolved in drastically different environments and display unique metabolic traits and microbiome profiles, even when raised under identical lab conditions. Their natural diversity makes them an ideal model for identifying the genes that shape gut microbes and for testing how those microbes affect traits like fat storage and blood sugar levels. In addition to advancing scientific knowledge, the project promotes STEM education and public engagement. A new course module for graduate students will provide training in modern genetic techniques. Undergraduate students will gain paid, hands-on laboratory research experience through a structured mentorship program. To support early science learning, the team will partner with the UNR Museum of Natural History to create an interactive lab activity for visiting elementary school groups using live fish. The museum will also host a public exhibit featuring the Mexican tetra to highlight how animals adapt to extreme environments. Through research, teaching, and outreach, this project will help train future scientists and increase public understanding of genetics, evolution, and the microbiome. Vertebrate gastrointestinal (GI) microbiomes are critical to host metabolism, physiology, and fitness, yet the genetic basis for host-driven variation in microbiota composition remains poorly understood. This research program will reveal genetic pathways that shape vertebrate GI microbiota composition and underlie natural diversity in host-microbiota interactions using the Mexican tetra, Astyanax mexicanus, as a model system. The project includes three integrated objectives. First, metagenomic sequencing and transcriptomic analysis will be used to compare GI microbiota composition, microbial function, and host gene expression across gut regions and life stages in multiple surface fish and cavefish ecotypes. Second, quantitative trait loci (QTL) mapping in surface/cave F2 hybrids will identify host genetic loci associated with microbiota composition and host traits. Third, CRISPR/Cas9 genome editing will be used to functionally test the effects of specific candidate variants by performing allele-swapping experiments between ecotypes. In parallel, microbial manipulation experiments that include microbiota transplants and metabolite supplementation will determine the extent to which microbial communities drive host phenotypic differences, such as fat accumulation and starvation resistance. This approach uniquely combines natural evolutionary replicates, high-resolution genetic mapping, and functional testing of both host genes and microbial contributors to investigate host-microbiota interactions. The results will reveal the molecular and physiological mechanisms linking host genetics and microbiota composition and will clarify the bidirectional relationship between microbiomes and vertebrate metabolic traits. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.