The Pleiotropy Hypothesis of Molecular Evolution

Under the nearly-neutral model of protein evolution, the evolutionary rate is virtually determined by the selection intensity ( S ), which can be decomposed into S =- K × B ₀ , where K is the gene pleiotropy defined by the number of fitness-related traits (molecular phenotypes) and B ₀ is the baseline of the selection intensity. Hence, the variation of S (sequence conservation) among genes may have two resources: one is the variation of gene pleiotropy among genes ( K -mode), and the other is the variation of baseline intensity among genes ( B -mode). While K can be effectively estimated (denoted by K _e ) based on the phylogenetic analysis of protein sequences, the correlation between K _e and empirical pleiotropy measures remains uninvestigated. In this paper, we show positive correlations of effective gene pleiotropy with protein-protein interactions, expression broadness, enzyme connections, and involved biological processes. We thus propose the pleiotropy hypothesis ( K -mode), suggesting that the rate variation among proteins is mainly due to the variation of gene pleiotropy, revealing a sophisticated display of multiple gene functionality.