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Gene family level comparative analysis of gene expression in mammals validates the ortholog conjecture.

ABSTRACT: The ortholog conjecture (OC), which is central to functional annotation of genomes, posits that orthologous genes are functionally more similar than paralogous genes at the same level of sequence divergence. However, a recent study challenged the OC by reporting a greater functional similarity, in terms of Gene Ontology (GO) annotations and expression profiles, among within-species paralogs compared with orthologs. These findings were taken to indicate that functional similarity of homologous genes is primarily determined by the cellular context of the genes, rather than evolutionary history. However, several subsequent studies suggest that GO annotations and microarray data could artificially inflate functional similarity between paralogs from the same organism. We sought to test the OC using approaches distinct from those used in previous studies. Analysis of a large RNAseq data set from multiple human and mouse tissues shows that expression similarity (correlations coefficients, rank's, or Z-scores) between orthologs is substantially greater than that for between-species paralogs with the same sequence divergence, in agreement with the OC and the results of recent detailed analyses. These findings are further corroborated by a fine-grain analysis in which expression profiles of orthologs and paralogs were compared separately for individual gene families. Expression profiles of within-species paralogs are more strongly correlated than profiles of orthologs but it is shown that this is caused by high background noise, that is, correlation between profiles of unrelated genes in the same organism. Z-scores and rank scores show a nonmonotonic dependence of expression profile similarity on sequence divergence. This complexity of gene expression evolution after duplication might be at least partially caused by selection for protein dosage rebalancing following gene duplication.

SUBMITTER: Rogozin IB

PROVIDER: S-EPMC4007545 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Gene family level comparative analysis of gene expression in mammals validates the ortholog conjecture.

Rogozin Igor B IB Managadze David D Shabalina Svetlana A SA Koonin Eugene V EV

Genome biology and evolution 20140401 4

The ortholog conjecture (OC), which is central to functional annotation of genomes, posits that orthologous genes are functionally more similar than paralogous genes at the same level of sequence divergence. However, a recent study challenged the OC by reporting a greater functional similarity, in terms of Gene Ontology (GO) annotations and expression profiles, among within-species paralogs compared with orthologs. These findings were taken to indicate that functional similarity of homologous ge ...[more]

PMID: 24610837

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Project description:The ortholog conjecture posits that orthologous genes are functionally more similar than paralogous genes. This conjecture is a cornerstone of phylogenomics and is used daily by both computational and experimental biologists in predicting, interpreting, and understanding gene functions. A recent study, however, challenged the ortholog conjecture on the basis of experimentally derived Gene Ontology (GO) annotations and microarray gene expression data in human and mouse. It instead proposed that the functional similarity of homologous genes is primarily determined by the cellular context in which the genes act, explaining why a greater functional similarity of (within-species) paralogs than (between-species) orthologs was observed. Here we show that GO-based functional similarity between human and mouse orthologs, relative to that between paralogs, has been increasing in the last five years. Further, compared with paralogs, orthologs are less likely to be included in the same study, causing an underestimation in their functional similarity. A close examination of functional studies of homologs with identical protein sequences reveals experimental biases, annotation errors, and homology-based functional inferences that are labeled in GO as experimental. These problems and the temporary nature of the GO-based finding make the current GO inappropriate for testing the ortholog conjecture. RNA sequencing (RNA-Seq) is known to be superior to microarray for comparing the expressions of different genes or in different species. Our analysis of a large RNA-Seq dataset of multiple tissues from eight mammals and the chicken shows that the expression similarity between orthologs is significantly higher than that between within-species paralogs, supporting the ortholog conjecture and refuting the cellular context hypothesis for gene expression. We conclude that the ortholog conjecture remains largely valid to the extent that it has been tested, but further scrutiny using more and better functional data is needed.

Project description:Marsupials or metatherians are a group of mammals that are distinct in giving birth to young at early stages of development and in having a prolonged investment in lactation. The group consists of nearly 350 extant species, including kangaroos, koala, possums, and their relatives. Marsupials are an old lineage thought to have diverged from early therian mammals some 160 million years ago in the Jurassic, and have a remarkable evolutionary and biogeographical history, with extant species restricted to the Americas, mostly South America, and to Australasia. Although the group has been the subject of decades of phylogenetic research, the marsupial tree of life remains controversial, with most studies focusing on only a fraction of the species diversity within the infraclass. Here we present the first Methaterian species-level phylogeny to include 80% of the extant marsupial species and five nuclear and five mitochondrial markers obtained from Genbank and a recently published retroposon matrix. Our primary goal is to provide a summary phylogeny that will serve as a tool for comparative research. We evaluate the extent to which the phylogeny recovers current phylogenetic knowledge based on the recovery of "benchmark clades" from prior studies-unambiguously supported key clades and undisputed traditional taxonomic groups. The Bayesian phylogenetic analyses recovered nearly all benchmark clades but failed to find support for the suborder Phalagiformes. The most significant difference with previous published topologies is the support for Australidelphia as a group containing Microbiotheriidae, nested within American marsupials. However, a likelihood ratio test shows that alternative topologies with monophyletic Australidelphia and Ameridelphia are not significantly different than the preferred tree. Although further data are needed to solidify understanding of Methateria phylogeny, the new phylogenetic hypothesis provided here offers a well resolved and detailed tool for comparative analyses, covering the majority of the known species richness of the group.

Dataset Information

Gene family level comparative analysis of gene expression in mammals validates the ortholog conjecture.

Publications

Gene family level comparative analysis of gene expression in mammals validates the ortholog conjecture.

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