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Reconstruction of human genome evolution in yeast: an educational primer for use with "systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes".

ABSTRACT: The evolution of eukaryotic organisms starting with the last eukaryotic common ancestor was accompanied by lineage-specific expansion of gene families. A paper by Garge et al. provides an excellent opportunity to have students explore how expansion of gene families via gene duplication results in protein specialization, in this case in the context of eukaryotic cytoskeletal organization . The authors tested hypotheses about conserved protein function by systematic "humanization" of the yeast cytoskeletal components while employing a wide variety of methodological approaches. We outline several exercises to promote students' ability to explore the genomic databases, perform bioinformatic analyses, design experiments for functional analysis of human genes in yeast and critically interpret results to address both specific and general questions.

SUBMITTER: Brzacova Z

PROVIDER: S-EPMC8633097 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Reconstruction of human genome evolution in yeast: an educational primer for use with "systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes".

Brzáčová Zuzana Z Peťková Mária M Veljačiková Katarína K Zajičková Terézia T Tomáška Ľubomír Ľ

Genetics 20211001 2

The evolution of eukaryotic organisms starting with the last eukaryotic common ancestor was accompanied by lineage-specific expansion of gene families. A paper by Garge et al. provides an excellent opportunity to have students explore how expansion of gene families via gene duplication results in protein specialization, in this case in the context of eukaryotic cytoskeletal organization . The authors tested hypotheses about conserved protein function by systematic "humanization" of the yeast cyt ...[more]

PMID: 34849890

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Project description:Despite over a billion years of evolutionary divergence, several thousand human genes possess clearly identifiable orthologs in yeast, and many have undergone lineage-specific duplications in one or both lineages. These duplicated genes may have been free to diverge in function since their expansion, and it is unclear how or at what rate ancestral functions are retained or partitioned among co-orthologs between species and within gene families. Thus, in order to investigate how ancestral functions are retained or lost post-duplication, we systematically replaced hundreds of essential yeast genes with their human orthologs from gene families that have undergone lineage-specific duplications, including those with single duplications (1 yeast gene to 2 human genes, 1:2) or higher-order expansions (1:>2) in the human lineage. We observe a variable pattern of replaceability across different ortholog classes, with an obvious trend toward differential replaceability inside gene families, and rarely observe replaceability by all members of a family. We quantify the ability of various properties of the orthologs to predict replaceability, showing that in the case of 1:2 orthologs, replaceability is predicted largely by the divergence and tissue-specific expression of the human co-orthologs, i.e., the human proteins that are less diverged from their yeast counterpart and more ubiquitously expressed across human tissues more often replace their single yeast ortholog. These trends were consistent with in silico simulations demonstrating that when only one ortholog can replace its corresponding yeast equivalent, it tends to be the least diverged of the pair. Replaceability of yeast genes having more than 2 human co-orthologs was marked by retention of orthologous interactions in functional or protein networks as well as by more ancestral subcellular localization. Overall, we performed >400 human gene replaceability assays, revealing 50 new human-yeast complementation pairs, thus opening up avenues to further functionally characterize these human genes in a simplified organismal context.

Dataset Information

Reconstruction of human genome evolution in yeast: an educational primer for use with "systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes".

Publications

Reconstruction of human genome evolution in yeast: an educational primer for use with "systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes".

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