Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes.

Autor:	Garge RK; Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Texas 78712., Laurent JM; Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Texas 78712.; Institute for Systems Genetics, Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York 10016., Kachroo AH; The Department of Biology, Centre for Applied Synthetic Biology, Concordia University, Montreal, H4B 1R6 Quebec, Canada marcotte@icmb.utexas.edu aashiq.kachroo@concordia.ca., Marcotte EM; Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Texas 78712 marcotte@icmb.utexas.edu aashiq.kachroo@concordia.ca.
Jazyk:	angličtina
Zdroj:	Genetics [Genetics] 2020 Aug; Vol. 215 (4), pp. 1153-1169. Date of Electronic Publication: 2020 Jun 10.
DOI:	10.1534/genetics.120.303378
Abstrakt:	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. (Copyright © 2020 Garge et al.)
Databáze:	MEDLINE
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