Pleiotropy accelerates tooth phenotypic and genomic evolution - An in silico study under the lens of development

Pleiotropy, which can occur when a gene affects multiple traits, is a central property of living organisms, influencing their response to mutations and their evolutionary trajectories. Despite many studies and discussions, it remains very difficult to reconcile molecular, developmental and quantitative evolutionary genetics viewpoints on pleiotropy and appreciate how much it puts constraints on genetic evolution, phenotypic evolution and adaptation. Here, we revisit this question by simulating evolution in silico. Our model captures multiple levels of integration observed in complex organisms: from genes to development to phenotype to fitness, additionally allowing to remove pleiotropy to directly test its effect. We focus on the pleiotropic interactions between two organs, specifically teeth. Fitness is determined from the functional interaction between these two teeth, which are produced by an in silico model of tooth morphogenesis. The developmental parameters are produced by a genome consisting of pleiotropic genes which may be influenced by one tooth-specific transcriptional regulator per tooth. Our simulations with and without pleiotropy confirm several acknowledged consequences of pleiotropy. It reduced genetic and phenotypic exploration, and facilitated the rapid accumulation of adaptive mutations in the modular cis-regulatory regions of pleiotropic genes, which are specific to each tooth. Unexpectedly, pleiotropy promoted fitness improvements, morphological complexity, and the accumulation of genetic divergence. Mutations in pleiotropic genes contributed significantly to adaptation, and removing pleiotropy did not increase the proportion of adaptive mutations. Thus pleiotropy does not act as a conservative force, but a channeling force promoting genetic divergence. Significance StatementThe notion of "Gene pleiotropy", just as the notion of "gene", crosses different fields of biology, but appreciations vary on how frequent it is and how much it favors conservation or divergence at the molecular, developmental or phenotypic scale. One reason is the discrepancies of viewpoints between these three scales, another the difficulty to manipulate pleiotropy experimentally. Here, we performed in silico evolution experiments with a computational toy model focusing on the pleiotropy between two organs while bridging the molecular, developmental and phenotypic scales. Moreover, we compared evolutionary scenarios where the two organs shared or not pleiotropic genes. Our results reconcile observations and show that sharing pleiotropic genes accelerates genetic divergence, even though non-pleiotropic genes diverge faster than pleiotropic genes.