Microproteins, Mobile Genetic elements and Strain-level resolution in the microbiome – a path to precision medicine

Ami Bhatt⁰
(0) Stanford University

Abstract
From climate change to agriculture, and human health to the oceanic food chain, microbes are at the base of every major system in the earth and life sciences. Far from being passive passengers, these organisms strongly interact with the environment – be it the ocean floor or the human body. Yet, for all of this interaction, the dynamics between human hosts and bacteria (microbiome) has only been explored in earnest for the last twenty or so years, and even then, most studies have collapsed spectacular strain heterogeneity (indeed, millions of different strains) into monolithic “species”. Positing that “strains matter”, as do the genes that specific organisms encode – our lab has developed and applied molecular and computational methods that help us link microbes to specific biological phenomena. Recently, our laboratory discovered >4,500 new small protein families encoded in microbial genomes. These genes had laid ‘hidden in plain sight’ due to the computational and experimental challenges in identifying them. We have validated that many of these predicted genes are transcribed and translated, and have enabled their rapid annotation using a deep learning approach. Moving forward, we hope to wield the precise microbiome measurement tools we have developed to systematically dissect the role of genomic plasticity in microbial adaptation (including antibiotic resistance), leverage mobile genetic elements to revolutionize genome engineering and gene therapy, and decode microbial microprotein communication to enable a breakthrough in microbe-inspired drug discovery. In so doing, we hope to revolutionize how we investigate microbiomes.