PgmNr Y3128: Uncovering rules governing gene replacement between humans and yeast.

Authors:
Jon M. Laurent 1 ; Aashiq H. Kachroo 1 ; Christopher M. Yellman 1 ; Austin G. Meyer 1,2 ; Claus O. Wilke 1,2,3 ; Edward M. Marcotte 1,2,4


Institutes
1) Center for Systems and Synthetic Biology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX; 2) Center for Computational Biology and Bioinformatics, University of Texas at Austin, Austin, TX; 3) Department of Integrative Biology, University of Texas at Austin, Austin, TX; 4) Department of Molecular Biosciences, University of Texas at Austin, Austin, TX.


Keyword: Evolution/Comparative Genomics

Abstract:

    Owing to its ease of manipulation and rapid growth, the baker’s yeast Saccharomyces cerevisiae is a popular model organism for studying many aspects of eukaryotic biology. Due to the functional conservation still present between much of the human and yeast proteome, yeast has served an important role in the study of human biology and disease. Inspired by these studies, our lab has been systematically testing which essential yeast proteins are replaceable by their human counterparts, screening for functionality by the human genes’ ability to rescue growth in the absence of the yeast proteins. We have found that replacement of genes with 1:1 orthology is governed largely by gene modules, such that pathways or complexes are similarly replaceable or not (Kachroo et al. (2015) Science, 348:921-925).

    We have now begun to expand our replacement set to include all other essential yeast-human orthologs, covering all ortholog classes (e.g., many:1, 1:many, many:many). We have now tested over 700 pairs of orthologs between the two species. We have observed a variable pattern of replaceability across different ortholog classes, with an obvious bias towards differential replaceability inside gene families, rather than all members of a family being similarly able to replace. In order to determine which properties of co-orthologs can potentially explain this differential replaceability, we have assembled a set of quantitative features of the genes and gene families, including calculated properties of the genes’ sequences (e.g., gene and protein lengths, sequence similarities, codon usage) and other properties such as protein interactions, mRNA and protein abundances, and transcription and translation rates. We then quantify how well each feature can predict replaceability, while differentiating between co-orthologs. Further, given our comprehensive results of individual replacements and the rules governing them (e.g. modularity, expression levels), we have now begun to integrate multiple members of human pathways or complexes into the yeast genome, with the goal of building entirely ‘humanized’ processes.

    These data demonstrate that a substantial portion of conserved yeast and human genes perform much the same roles in both organisms even after >1 billion years of evolution, and provide a direct test of the ortholog-function conjecture across gene familes. Many of the genes that can be replaced have important roles in human disease, including cancer. 'Humanized’ strains will simplify drug discovery against human proteins, enable studies of the consequences of human genetic polymorphisms, and empower functional studies of entire human cellular processes in a simplified organism.