Tissue-Specificity of Gene Expression Diverges Slowly between Orthologs, and Rapidly between Paralogs

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.Author Summary: From specific examples, it has been assumed by comparative biologists that the same gene in different species has the same function, whereas duplication of a gene inside one species to create several copies allows them to acquire different functions. Yet this model was little tested until recently, and then has proven harder than expected to confirm. One of the problems is defining "function" in a way which can be easily studied. We introduce a new way of considering function: how specific is the activity ("expression") of a gene? Genes which are specific to certain tissues have functions related to these tissues, whereas genes which are broadly active over many or all tissues have more general functions for the organism. We find that this "tissue-specificity" evolves very slowly in the absence of duplication, while immediately after duplication the new gene copy differs. This shows that indeed duplication leads to a strong increase in the evolution of new functions.