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Accurate quantification of functional analogy among close homologs.

ABSTRACT: Correctly evaluating functional similarities among homologous proteins is necessary for accurate transfer of experimental knowledge from one organism to another, and is of particular importance for the development of animal models of human disease. While the fact that sequence similarity implies functional similarity is a fundamental paradigm of molecular biology, sequence comparison does not directly assess the extent to which two proteins participate in the same biological processes, and has limited utility for analyzing families with several parologous members. Nevertheless, we show that it is possible to provide a cross-organism functional similarity measure in an unbiased way through the exclusive use of high-throughput gene-expression data. Our methodology is based on probabilistic cross-species mapping of functionally analogous proteins based on Bayesian integrative analysis of gene expression compendia. We demonstrate that even among closely related genes, our method is able to predict functionally analogous homolog pairs better than relying on sequence comparison alone. We also demonstrate that the landscape of functional similarity is often complex and that definitive "functional orthologs" do not always exist. Even in these cases, our method and the online interface we provide are designed to allow detailed exploration of sources of inferred functional similarity that can be evaluated by the user.

SUBMITTER: Chikina MD

PROVIDER: S-EPMC3033368 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Accurate quantification of functional analogy among close homologs.

Chikina Maria D MD Troyanskaya Olga G OG

PLoS computational biology 20110203 2

Correctly evaluating functional similarities among homologous proteins is necessary for accurate transfer of experimental knowledge from one organism to another, and is of particular importance for the development of animal models of human disease. While the fact that sequence similarity implies functional similarity is a fundamental paradigm of molecular biology, sequence comparison does not directly assess the extent to which two proteins participate in the same biological processes, and has l ...[more]

PMID: 21304936

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Project description:VIP1 is a bZIP protein in Arabidopsis thaliana. VIP1 accumulates in the nucleus under hypo-osmotic conditions and interacts with the promoters of hypo-osmolarity-responsive genes, CYP707A1 and CYP707A3 (CYP707A1/3), but neither overexpression of VIP1 nor truncation of its DNA-binding region affects the expression of CYP707A3 in vivo, raising the possibility that VIP and other proteins are functionally redundant. Here we show further analyses on VIP1 and its close homologs, namely, Arabidopsis group I bZIP proteins. The patterns of the signals of the GFP-fused group I bZIP proteins were similar in onion and Arabidopsis cells, suggesting that they have similar subcellular localization. In a yeast one-hybrid assay, the group I bZIP proteins caused reporter gene activation in the yeast reporter strain. VIP1 and other group I bZIP proteins showed positive results in a yeast two-hybrid assay and a bimolecular fluorescence complementation assay, suggesting that they physically interact. These results support the idea that they have somewhat similar functions. By gel shift assays, VIP1-binding sequences in the CYP707A1/3 promoters were confirmed to be AGCTGT/G. Their presence in the promoters of the genes that respond to hypo-osmotic conditions was evaluated using previously published microarray data. Interestingly, a significantly higher proportion of the promoters of the genes that were up-regulated by rehydration treatment and/or submergence treatment (treatment by a hypotonic solution) and a significantly lower proportion of the promoters of the genes that were down-regulated by such treatment shared AGCTGT/G. To further assess the physiological role of VIP1, constitutively nuclear-localized variants of VIP1 were generated. When overexpressed in Arabidopsis, some of them as well as VIP1 caused growth retardation under a mannitol-stressed condition, where VIP1 is localized mainly in the cytoplasm. This raises the possibility that the expression of VIP1 itself rather than its nuclear localization is responsible for regulating the mannitol responses.

Dataset Information

Accurate quantification of functional analogy among close homologs.

Publications

Accurate quantification of functional analogy among close homologs.

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