The genetic, symbiotic, and evolutionary bases of the human gut mycobiome

Project Summary Holobionts assemble their microbial communities from a biosphere teeming with bacteria, viruses, and fungi, yet host-associated studies of microbial communities are largely dominated by bacteria-centric foci that overlook the kingdom-level diversity of bionts in hosts. Gut fungi in animal hosts interact with members of the gut bacteriome, respond to diets, and contribute to gut homeostasis, but can be difficult to study due to the relatively low biomass in the gut. Hence, the host genetic, evolutionary, and bacterial community factors that influence mycobiome form, function, and diversity are often overlooked but potentially indispensable for understanding the missing or less studied components of the holobiont. Such effects in humans have not, thus far, been investigated. While several gut bacteria are heritable, associate with human genetic variants, and codiverge with hominids, the potential genetic and evolutionary bases of the gut mycobiome remain enigmatic. Thus, the central hypothesis of this proposal is that genetic variants, gut bacterial genes and taxa, and/or hominid evolution shape the diversity and composition of human gut fungi. I will test this hypothesis with three specific aims. First, I will determine human genetic heritability of the gut mycobiome by sequencing the gut mycobiome of monozygotic and dizygotic twin participants in the TwinsUK cohort. Heritable gut bacteria and fungi will be compared for correlations in monozygotic compared to dizygotic twins that may suggest co-heritability (Aim 1). In Aim 2, I will investigate the number and types of mycobiome-associated human genetic variants in a genome-wide association analysis (GWAS) of the human gut mycobiome, and I will evaluate the number and types of bacterial taxa and functional genetic categories that underpin gut fungi variation using a microbiome-wide association test (MWAS). In Aim 3, I will evaluate if evolutionary history of humans and their closest hominid relatives influences the structure of the gut mycobiome via tests of topological congruency, co-diversification, and machine learning. Together, these analyses will break new ground on resolving experimental, quantitative, and conceptual themes of human gut fungi that may parallel those for human gut bacteria. The devised training plan to support my career development includes the assembly of a multi-institutional Postdoctoral Mentoring Committee, mentoring opportunities and training in higher education pedagogy, and scientific education outreach activities. The proposed research is carried out under the guidance of Dr. Seth Bordenstein and Dr. Emily Davenport at The Pennsylvania State University.