Uncovering rules governing functional complementation between species

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Jon Laurent, Aashiq H Kachroo, Christopher M Yellman, Edward M Marcotte

Center for Systems and Synthetic Biology, United States

The remarkable degree of evolutionary conservation of most essential genes means that homologous genes often share the same functions, even between very distantly related organisms. Beyond retaining the same functions within their respective organisms, many essential genes can also be exchanged between organisms; that is, they both retain the core functionality of the common ancestor gene and can perform that function in the context of multiple extant organisms. This property has been exploited to clone human genes by complementing yeast mutants, in spite of yeast and humans diverging more than 1 billion years ago. While isolated examples are known, it is unknown if these are the exception to the rule, or if this is a general property of even the most distant homologs. Thus, we ask to what extent human genes functionally replace their yeast counterparts by systematically testing all essential yeast genes with single (1:1) human orthologs. We find many essential yeast genes can be replaced by their human equivalents with little to no detectable growth defects. Additionally, we aim to uncover rules governing the ability to complement by testing features of both human and yeast genes for their ability to predict replaceability. These data suggest that the core functions of many essential yeast genes are well retained and not subject to excessive neutral drift in those functions present in the last common ancestor of yeast and humans, even after greater than 1 billion years of divergent evolution.