Of yeast and men : insights into evolution and human health from 1 billion years of divergence




Garge, Riddhiman Kannan

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Life on the planet is incredibly diverse and it is often easy to compare and contrast the many features that distinguish any two pairs of species from each other. Despite this diversity, all organisms on Earth share a common origin. This shared ancestry establishes conservation at the core of biology. The concept of conservation (or what’s equivalent) across species organizes biology and stems from the natural selection of favorable traits in organisms. Evolutionary conservation extends even to the genetic and molecular level with genes, proteins, and the networks they constitute also sharing common ancestry. This property enables biologists to study conserved genes (orthologs) in simpler model organisms and relate them to their corresponding human equivalents. Despite this, it is largely unclear the extents to which orthologs between species are functionally compatible. The dissertation aims to directly address this question via cross-species gene swaps. By systematically humanizing yeast genes, this dissertation provides insights into how orthologous genes between species functionally diverge and evolve over vast timescales. In chapter one, I present conservation as a powerful organizing principle in biology and the roles orthologous biological systems play in connecting genotype and phenotype. In chapters two and three, I describe efforts to apply humanized yeast as a platform to study functional divergence in orthologs constituting expanded gene families and examine the trends that underlie them. In chapter four, I describe the synthesis of observations from multiple research threads including humanized yeast, model organisms, evolutionary conservation of biological systems, and global signatures of pesticide resistance to uncover a novel class of antifungals all capable of functioning as vascular disrupting agents. Finally, in chapter five, I discuss the future of cross-species gene swaps, humanized yeast, and their utility to human health and disease



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