Genetic redundancy

Genetic redundancy is a term typically used to describe situations where a given biochemical function is redundantly encoded by two or more genes. In these cases, mutations (or defects) in one of these genes will have a smaller effect on the fitness of the organism than expected from the genes’ function. Characteristic examples of genetic redundancy include (Enns, Kanaoka et al. 2005) and (Pearce, Senis et al. 2004). Many more examples are thoroughly discussed in (Kafri, Levy & Pilpel. 2006).

The main source of genetic redundancy is the process of gene duplication which generates multiplicity in gene copy number. A second and less frequent source of genetic redundancy are convergent evolutionary processes leading to genes that are close in function but unrelated in sequence (Galperin, Walker & Koonin 1998). Genetic redundancy has classically aroused much debate in the context of evolutionary biology (Nowak et al., 1997; Kafri, Springer & Pilpel . 2009).

From an evolutionary standpoint, genes with overlapping functions implies minimal, if any, selective pressures acting on these genes. One therefore expects that the genes participating in such buffering of mutations will be subject to severe mutational drift diverging their functions and/or expression patterns with considerably high rates. Indeed it has been shown that the functional divergence of paralogous pairs in both yeast and human is an extremely rapid process. Taking these notions into account, the very existence of genetic buffering, and the functional redundancies required for it, presents a paradox in light of the evolutionary concepts. On one hand, for genetic buffering to take place there is a necessity for redundancies of gene function, on the other hand such redundancies are clearly unstable in face of natural selection and are therefore unlikely to be found in evolved genomes.

To understand genetic redundancy and biological robustness we must not think in linear terms of single causality where A causes B causes C causes D causes E. Rather it must be appreciated that biological systems operate as in a scale-free network. In a scale-free network the distribution of node linkage follows a power law, in that it contains many nodes with a low number of links, few nodes with many links and very few nodes with a high number of links. A scale-free network is very much like the internet: the major part of the websites makes only a few links, less make an intermediate number of links, whereas a minor part makes the majority of links. Usually hundreds of routers routinely malfunction on the Internet at any moment, but the network rarely suffers major disruptions. As many as 80 percent of randomly selected Internet routers can fail and the remaining ones will still form a compact cluster in which there will still be a path between any two nodes [Barabasi et al., 2003]. Likewise, genes never operate alone but in redundant scale-free networks with an incredible level of buffering capacity.

An interactive network of cooperating proteins that substitute for or by-pass each other’s functions provide the robustness of biological system. It is hard to imagine how selection acts on individual nodes of a scale-free, redundant genetic system. From an evolutionary standpoint, genes with overlapping functions implies minimal, if any, selective pressures acting on these genes. One therefore expects that the genes participating in such buffering of mutations will be subject to severe mutational drift diverging their functions and/or expression patterns with considerably high rates. Although the functional divergence of paralogous gene pairs can be extremely fast, redundant genes do commonly not mutate faster than essential genes (Winzeler EA et al. 1999; Wagner A, 2000; Kitami T, 2002].

References

Pearce, A. C., Y. A. Senis, et al. (2004). "Vav1 and vav3 have critical but redundant roles in mediating platelet activation by collagen." J Biol Chem 279(52): 53955-62.
Enns, L. C., M. M. Kanaoka, et al. (2005). "Two callose synthases, GSL1 and GSL5, play an essential and redundant role in plant and pollen development and in fertility." Plant Mol Biol 58(3): 333-49.
Kafri, R., M. Levy, et al. (2006). "The regulatory utilization of genetic redundancy through responsive backup circuits." Proc Natl Acad Sci U S A 103(31): 11653-8.
Galperin, M. Y., Walker, D. R. & Koonin, E. V. (1998) Genome Res 8, 779-90.
Kafri R, Springer M, Pilpel Y. Genetic redundancy: new tricks for old genes. Cell. 2009 Feb 6;136(3):389-92.
Barabasi A, Bonabeau LE. Scale-free Networks, Sci Am 2003, volume 288, pages 60-69
Kitami T, Nadeau JH. Biochemical networking contributes more to genetic buffering in human and mouse metabolic pathways than does gene duplication. Nat Genet 2002, volume 32, pages 191-194.
Wagner A. Robustness against mutations in genetic networks of yeast. Nat Genet 2000; 24:355-361.
Winzeler EA et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 1999, volume 285, pages 901-906.