Abstract
The ortholog conjecture implies that functional similarity between orthologous genes is higher than between paralogs. It has been supported using levels of expression and Gene Ontology term analysis, although the evidence was rather weak and there were also conflicting reports. In this study on 12 species we provide strong evidence of high conservation in tissue-specificity between orthologs, in contrast to low conservation between within-species paralogs. This allows us to shed a new light on the evolution of gene expression patterns. While there have been several studies of the correlation of expression between species, little is known about the evolution of tissue-specificity itself. Ortholog tissue-specificity is strongly conserved between all tetrapod species, with the lowest Pearson correlation between mouse and frog at r = 0.66. Tissue-specificity correlation decreases strongly with divergence time. Paralogs in human show much lower conservation, even for recent Primate-specific paralogs. When both paralogs from ancient whole genome duplication tissue-specific paralogs are tissue-specific, it is often to different tissues, while other tissue-specific paralogs are mostly specific to the same tissue. The same patterns are observed using human or mouse as focal species, and are robust to choices of datasets and of thresholds. Our results support the following model of evolution: in the absence of duplication, tissue-specificity evolves slowly, and tissue-specific genes do not change their main tissue of expression; after small-scale duplication the less expressed paralog loses the ancestral specificity, leading to an immediate difference between paralogs; over time, both paralogs become more broadly expressed, but remain poorly correlated. Finally, there is a small number of paralog pairs which stay tissue-specific with the same main tissue of expression, for at least 300 million years.
Highlights
The ortholog conjecture is widely used to transfer annotation among genes, for example in newly sequenced genomes
The debate was truly launched by Nehrt et al [5] who reported in a large scale study, based on expression levels similarity and Gene Ontology (GO) analysis in human and mouse, that paralogs are better predictors of function than orthologs
Using a very similar GO analysis but correcting biases in the data, from 13 bacterial and eukaryotic species, Altenhoff et al [8] found more functional similarity between orthologs than between paralogs based on GO annotation analysis, but the differences were very slight
Summary
The ortholog conjecture is widely used to transfer annotation among genes, for example in newly sequenced genomes. The most widely accepted model is that orthologs diverge slower, and that the generation of paralogs through duplication leads to strong divergence and even change of function. It is expected that in general homologs diverge functionally with time The test of these hypotheses poses fundamental questions of molecular evolution, about the rate of functional evolution and the role of duplications, and is essential to the use of homologs in genome annotations. The debate was truly launched by Nehrt et al [5] who reported in a large scale study, based on expression levels similarity and Gene Ontology (GO) analysis in human and mouse, that paralogs are better predictors of function than orthologs. Using a very similar GO analysis but correcting biases in the data, from 13 bacterial and eukaryotic species, Altenhoff et al [8] found more functional similarity between orthologs than between paralogs based on GO annotation analysis, but the differences were very slight
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