Molecular mechanisms of paralogous compensation and the robustness of cellular networks

Abstract

Robustness is the ability of a system to maintain its function despite environmental or genetic perturbation. Genetic robustness is a key emerging property of living systems and is achieved notably by the presence of partially redundant parts that result from gene duplication. Functional overlap between paralogs allows them to compensate for each other's loss, as commonly revealed by aggravating genetic interactions. However, the molecular mechanisms linking the genotype (loss of function of a gene) to the phenotype (genetic buffering by a paralog) are still poorly understood and the molecular aspects of this compensation are rarely addressed in studies of gene duplicates. Here, we review molecular mechanisms of functional compensation between paralogous genes, many of which from studies that were not meant to study this phenomenon. We propose a standardized terminology and, depending on whether or not the molecular behavior of the intact gene is modified in response to the deletion of its paralog, we classify mechanisms of compensation into passive and active events. We further describe three non-exclusive mechanisms of active paralogous compensation for which there is evidence in the literature: changes in abundance, in localization, and in protein interactions. This review will serve as a framework for the genetic and molecular analysis of paralogous compensation, one of the universal features of genetic systems.

CRMP1 and CRMP2 have synergistic but distinct roles in dendritic development

“…Indeed, the expression level of CRMP1 was increased in crmp2 −/− when compared to the WT cortex, suggesting paralogous compensation for CRMP2 deficiency (Diss et al . ). We also found that there was no defect in axon formation of layer V pyramidal neurons of crmp2 −/− mice (Fig.…”

TNL‐mediated immunity in Arabidopsis requires complex regulation of the redundant ADR1 gene family

“…On the other, when the background autoimmunity is too strong, it is more difficult to detect a marginal decrease in plant size due to increased immunity caused by the loss of ADR1-L1. Gene expression may be upregulated to compensate for the loss of their functionally redundant paralogs (Diss et al, 2014). The Arabidopsis R-SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) genes VAMP721 and VAMP722 are transcriptionally upregulated in the respective mutant to compensate for the loss of the other (Kwon et al, 2008).…”

Absence of the Drosophila jump muscle actin Act79B is compensated by up‐regulation of Act88F

“…Previous studies in other systems have demonstrated that actin isoforms have the capacity to up-regulate their transcription in an attempt to compensate for a functional perturbation or deregulation of the system (Kumar et al, 1997; Nowak et al, 2009; Diss et al, 2014). While some of these studies have found that this overexpression is not compensatory and does nothing to rescue the function of the muscle (Fyrberg et al, 1998; Crawford et al, 2002), here we show a system in which low levels of ectopic expression of a distinct actin isoform can rescue sarcomere structure to provide functional compensation.…”

“…The mechanism by which Act88F expression expands into the jump muscle is yet to be determined, and reflects a broader phenomenon of active paralogous compensation, where the expression pattern of one paralog alters in the absence of expression of the other paralog (Diss et al, 2014). Of interest, the rules for how Drosophila actin genes alter their expression in response to changing levels of actins in neighboring muscles is distinct for each actin, because while we show here that a change in Act88F expression can compensate for the loss of Act79B, the converse is not true: Act88F nulls fail to accumulate any myofibrillar actin in their flight muscles, and are flightless (Hiromi and Hotta, 1985; Drummond et al, 1991).…”