Pleiotropy is a fundamental concept in genetics, referring to the phenomenon where a single gene can affect multiple phenotypic traits. Recent studies have shown that many genes exhibit pleiotropy, meaning that a single gene can cause changes in various biochemical and physiological characteristics, thereby having a broad impact on biological processes. However, pleiotropy can cause evolutionary constraints. When a gene mutates and simultaneously affects multiple traits, this mutation is usually beneficial for only one specific trait while being detrimental to others. Since evolution largely depends on the overall changes in related traits, changes in a single beneficial trait are often difficult to detect and retain, thus pleiotropy actually limits the evolutionary adaptation of organisms. This raises a puzzling question: if pleiotropy can hinder evolution, how did such widespread genetic pleiotropy originate and evolve?

Recently, the collaborative team of Professor Chen Xiaoshu from Sun Yat-sen University's School of Medicine and Professor He Xionglei from the School of Life Sciences published a research paper titled "Most pleiotropic effects of gene knockouts are evolutionarily transient in yeasts" in Molecular Biology and Evolution, conducting a comprehensive study on the knockout effects of transcription factors to reveal the evolutionary characteristics of pleiotropy.

The researchers conducted parallel gene knockout experiments on 100 transcription factors in two strains of Saccharomyces cerevisiae, systematically quantifying the pleiotropic effects of these knockouts on gene expression levels. Results from both strains confirmed the widespread presence of pleiotropic effects, where the knockout of a single gene typically affects the expression levels of multiple genes. Notably, the pleiotropic effects caused by knockouts varied rapidly between strains with different genetic backgrounds, with about 85% being non-conserved. Further analysis indicated that conserved effects are often directly related to the function of the knocked-out transcription factor, while non-conserved effects seem to be more transient responses. Additionally, the researchers measured 184 yeast cell morphological traits of these knockout strains and observed patterns consistent with gene expression.

Since gene knockouts can be considered a form of mutation, the researchers speculated that the reason for this instability could be traced back to the adaptive process of mutations. Whenever a new mutation arises, it may disrupt the homeostasis within the cell in an unknown way, leading to various responses. In this process, natural selection tends to retain adaptive responses while gradually eliminating those that are maladaptive or slightly harmful.

Therefore, the low conservation of pleiotropy may be the result of the rapid loss and acquisition of pleiotropic functions in different genetic backgrounds after divergence. To test this hypothesis, the researchers further studied the pleiotropic effects of genetic variation in a population of about 1000 hybrid offspring from the two strains. They observed that newly evolved expression quantitative trait loci (eQTL) affect the expression of more genes than ancient eQTL. This suggests that natural selection is gradually eliminating maladaptive or slightly harmful pleiotropic responses.

Based on these findings, the researchers proposed a new model for the evolution of pleiotropy: most mutations originate from a highly pleiotropic natural state, and evolution gradually prunes harmful pleiotropic effects, retaining only adaptive and conserved effects, making most pleiotropic effects evolutionarily transient. This model indicates a two-way interaction between pleiotropy and evolution, thus potentially alleviating the constraints of pleiotropy on evolution to some extent. Furthermore, the study's results that pleiotropic effects of knockouts are evolutionarily transient suggest that most knockout effects need to be re-evaluated for their biological significance, and their conservation should be considered a priority when understanding phenotypic effects.

Professor Chen Xiaoshu and Professor He Xionglei from Sun Yat-sen University are the co-corresponding authors of the article, and Associate Professor Liu Li is the sole first author of the article.

Original Article Link: //doi.org/10.1093/molbev/msae189