Redundancy, antiredundancy, and the robustness of genomes

Abstract

Genetic mutations that lead to undetectable or minimal changes in phenotypes are said to reveal redundant functions. Redundancy is common among phenotypes of higher organisms that experience low mutation rates and small population sizes. Redundancy is less common among organisms with high mutation rates and large populations, or among the rapidly dividing cells of multicellular organisms. In these cases, one even observes the opposite tendency: a hypersensitivity to mutation, which we refer to as antiredundancy. In this paper we analyze the evolutionary dynamics of redundancy and antiredundancy. Assuming a cost of redundancy, we find that large populations will evolve antiredundant mechanisms for removing mutants and thereby bolster the robustness of wild-type genomes; whereas small populations will evolve redundancy to ensure that all individuals have a high chance of survival. We propose that antiredundancy is as important for developmental robustness as redundancy, and is an essential mechanism for ensuring tissue-level stability in complex multicellular organisms. We suggest that antiredundancy deserves greater attention in relation to cancer, mitochondrial disease, and virus infection.genomic stability ͉ mutation selection ͉ canalization ͉ fitness landscape ͉ quasispecies

The cost of replication fidelity in human immunodeficiency virus type 1

“…HIV-1 in particular and RNA viruses in general are characterized by enormous burst sizes, small genomes with frequently overlapping reading frames, fluctuating population sizes, lack of redundancy and short generation times (Holland et al 1982;Perelson et al 1996). They thus represent an extreme form of r -selected populations, in which fast replication is strongly favoured (Pianka 1970;Krakauer & Plotkin 2002). For this reason, the interplay between the cost of fidelity and mutational load might produce different outcomes in RNA viruses and more complex organisms.…”

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

“…Here, IRF-3 was substituting IRF-1, underlining the importance of genetic redundancy mechanisms in the cellular response. 39,45 In fact, genetic redundancy may account for heterogeneity within a population of tumor cells, 35,46 allowing the appearance of a particular phenotype or the expression of alternative trans-regulatory genes under defined selective constraints. Referring to IRFknockout studies in mouse cells, there is substantial evidence that different IRFs substitute each other in a redundant manner to ensure a robust host defense against viral infections.…”

“…Considering cancer as a dynamic and emergent biological system 33 whose heterogeneity facilitates cell survival even under hazardous conditions, 34 we asked whether a long term established cervical carcinoma cell line like HeLa possesses inherent redundancy mechanism(s) 35,36 where an antiviral response, normally associated with a benign phenotype, can be reselected. Because these cells were usually not detectable due to the presence of nonresponsive cells, superimposing this population, 6 we used the IFN-b sensitive EMCV as an indicator to monitor survival of cells, rescued on the basis of their antiviral state.…”

Levels of selection in positive-strand virus dynamics

“…Traits valuable at the within-cell level do not perform as well as traits required at the level of the population of cells. Such a large reduction in viability might only be sustainable because of the large number of virus particles generated, reflecting the relationship between genomic stability and population size (Krakauer & Plotkin, 2002).…”