The Ortholog Conjecture Revisited: the Value of Orthologs and Paralogs in Function Prediction

Abstract

The computational prediction of gene function is a key step in making full use of newly sequenced genomes. Function is generally predicted by transferring annotations from homologous genes or proteins for which experimental evidence exists. The "ortholog conjecture" proposes that orthologous genes should be preferred when making such predictions, as they evolve functions more slowly than paralogous genes. Previous research has provided little support for the ortholog conjecture, though the incomplete nature of the data cast doubt on the conclusions. Here we use experimental annotations from over 40,000 proteins, drawn from over 80,000 publications, to revisit the ortholog conjecture in two pairs of species: (i) Homo sapiens and Mus musculus and (ii) Saccharomyces cerevisiae and Schizosaccharomyces pombe. By making a distinction between questions about the evolution of function versus questions about the prediction of function, we find strong evidence against the ortholog conjecture in the context of function prediction, though questions about the evolution of function remain difficult to address. In both pairs of species, we quantify the amount of data that must be ignored if paralogs are discarded, as well as the resulting loss in prediction accuracy. Taken as a whole, our results support the view that the types of homologs used for function transfer are largely irrelevant to the task of function prediction. Aiming to maximize the amount of data used for this task, regardless of whether it comes from orthologs or paralogs, is most likely to lead to higher prediction accuracy.

Special care is needed in applying phylogenetic comparative methods to gene trees with speciation and duplication nodes

“…Time calibration of ancient duplication events is one of the major issues we uncovered. (Nehrt et al 2011;Dunn et al 2018;Stamboulian et al 2020). Our results provide additional support for the ortholog conjecture using tissue specificity data in a phylogenetic framework after controlling for biases.…”

“…The "ortholog conjecture", a standard model of phylogenomics, has become a topic of debate in recent years (Koonin 2005;Studer and Robinson-Rechavi 2009;Nehrt et al 2011;Altenhoff et al 2012;Chen and Zhang 2012;Gabaldón and Koonin 2013;Rogozin et al 2014;Kryuchkova-Mostacci and Robinson-Rechavi 2016;Dunn et al 2018;Stamboulian et al 2020). The ortholog conjecture is routinely used by both experimental and computational biologists in predicting or understanding gene function.…”

New Approaches for Inferring Phylogenies in the Presence of Paralogs

“…This sentiment is echoed repeatedly in the literature [6,7], based on the belief that, since orthologous genes are related by speciation events alone, their relationships should more accurately reflect the species phylogeny. Similar claims are made about the privileged use of orthologs in protein-function prediction [8][9][10].…”

Contingency, Repeatability and Predictability in the Evolution of a Prokaryotic Pangenome

“…Furthermore, we assume that these functions remain constant over time, despite evolutionary changes in the gene sequences. This is of course, unlikely to be completely accurate (Koonin, 2005, Stamboulian et al, 2020. Our dataset almost certainly contains genes that are placed into the same family but have different functions and confer different fitness effects.…”