Abstract
Many gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied. Here, we focused on structural cytoskeletal genes involved in critical cellular processes, including chromosome segregation, macromolecular transport, and cell shape maintenance. To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼81% of human cytoskeletal genes across seven gene families for their ability to complement a growth defect induced by inactivation or deletion of the corresponding yeast ortholog. In five of seven families-all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene. Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects. By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but failing to fully complement the cytoskeletal roles of their yeast orthologs, thus leading to abnormal cell morphologies. Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs. The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts.
Highlights
Gene duplication is regarded as one of the key drivers of evolution, contributing to the generation and accumulation of new genetic material within species[1,2]
We focused on orthologs constituting major structural elements of the eukaryotic cytoskeleton, including actin, myosin, septin, and tubulin gene families identifying 106 testable human-yeast ortholog pairs
Since human cytoskeletal gene families have undergone multiple duplication events, we systematically swapped each human gene within a family in place of its corresponding yeast ortholog to assay if present day human genes could still complement the lethal loss of their yeast ortholog(s)
Summary
Gene duplication is regarded as one of the key drivers of evolution, contributing to the generation and accumulation of new genetic material within species[1,2]. Only recently have efforts been made to test such functional equivalence more systematically, with several recent large-scale studies harnessing “the awesome power of yeast genetics” to systematically replace yeast genes by their human, plant, or even bacterial counterparts and assay for functional compatibility[5,6,7,8,9,10]. Humans and yeast last shared a common ancestor nearly a billion years ago, these studies have demonstrated that substantial fractions (12-47%) of tested essential yeast genes could be replaced by their human equivalents[5,6,7,8,9,11]. The ability of many human genes to functionally replace their yeast orthologs demonstrates the high degree of functional conservation in eukaryotic systems over billion year evolutionary timescales[9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
