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Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes
Riddhiman K Garge1, Jon M Laurent1,2, Aashiq H Kachroo3
1Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Texas 78712.
Genetics
|June 12, 2020
Summary
Human gene duplications have led to diverse cytoskeletal functions. Researchers "humanized" yeast genes to find that few duplicated human cytoskeletal genes fully replace yeast orthologs, revealing functional divergence.
Area of Science:
- Cell Biology
- Genetics
- Evolutionary Biology
Background:
- Gene duplication is a major driver of evolutionary innovation, particularly in the human lineage.
- The functional consequences of gene duplication, especially for cytoskeletal genes, remain incompletely understood.
- Cytoskeletal proteins are crucial for fundamental cellular processes like division, transport, and shape maintenance.
Purpose of the Study:
- To investigate the functional redundancy and divergence of duplicated human cytoskeletal genes.
- To assess the ability of human cytoskeletal genes to complement essential functions in yeast.
- To establish yeast models for studying human gene function in a simplified eukaryotic context.
Main Methods:
- Systematic "humanization" of seven yeast cytoskeletal gene families (actin, myosin, tubulin, septin) by replacing yeast genes with their human orthologs.
- Testing approximately 81% of human cytoskeletal genes for their ability to rescue growth defects upon yeast gene deletion.
- Phenotypic analysis of humanized yeast strains, including cell morphology, meiosis, and mating, compared to deletion phenotypes of interaction partners.
Main Results:
- At least one human gene successfully complemented the growth defect in five out of seven gene families studied.
- Despite rescuing growth, human genes showed differential abilities in restoring cell morphology, meiosis, and mating.
- Instances were identified where human actin and septin genes performed essential functions but failed to fully complement yeast cytoskeletal roles, leading to abnormal cell morphologies.
Conclusions:
- Duplicated human cytoskeletal genes have functionally diverged, with only a subset capable of replacing essential yeast ortholog functions.
- Humanized yeast strains serve as valuable platforms for characterizing the roles of human genes in simplified eukaryotic systems.
- The study highlights the complex evolutionary trajectory of gene families and the nuanced functional specialization following duplication events.
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