The Complexity of Genetic Redundancy

Abstract

Genetic redundancy is often associated with the duplication of an open reading frame within a genome or a multiplicity of regulatory elements sharing a target. Genetic redundancy is inferred when the modification or deletion of a portion of functional genetic material results in minimal changes to a trait or organismal phenotype – robustness – and when this genetic information is surplus to a reference, non‐robust, genome. Robustness has been attributed to buffering mechanisms promoted by duplicates and to compensatory pathways that can be independent of duplication. Most redundant duplicates are rapidly lost from genomes by mutation and drift. The preservation of redundancy requires some form of epistasis or pleiotropy, typically evolving through subfunctionalization of gene products. The term redundancy is too coarse to capture the full range of phenomena that it is used to describe and new concepts are required for dealing with multi‐locus and context‐dependent robustness.

Key Concepts:

  • Redundancy arises through mechanisms that compensate for the loss of functional genetic information.

  • Redundancy can be achieved through a duplication of a structural or regulatory gene.

  • Redundancy arises neutrally through partial or whole‐genome duplication and can persist without selection for short periods of time.

  • The long‐term preservation of redundancy requires specific genetic mechanisms, epistastis or pleiotropy, and on‐going selection pressures.

  • Redundancy is most common in species found in small populations with large genomes for whom neutral processes, dominated by drift, play a significant role.

  • Genetic or structural similarity among perturbed (knockout or knockdown) duplicates, to imply functional interchangeability, is empirically the strongest predictor of genetic redundancy.

  • Alternative, functionally equivalent pathways, that do not share genetic duplicates, can provide mechanisms of redundancy.

  • Redundancy is context‐dependent and often involves numerous factors to include epigenetic modification, environmental compensation, not just genetic loci.

  • Recent studies showing a very high incidence of loss‐function variants in human genomes provide strong support for the prevalence of mechanisms of redundancy.

  • New concepts are required to capture the robustness of genomes that go beyond mechanisms of redundancy. These new concepts will need to deal effectively with the contribution of numerous loci and factors – collective robustness.

Keywords: robustness; canalisation; genome architecture; evodevo; regulatory network; evolution; subfunctionalization

Figure 1.

Convergent activation and nonspecific negative feedback can lead to functional redundancy in a gene regulatory network. Proteins A and B are transcription factors produced at an equal rate and capable of activating the expression of gene C. Gene A activates C at a rate ka and gene B activates C at a rate kb. Gene C can be thought to work according to three different negative feedback mechanisms: (1) encode a protein capable of inhibiting the production of A and B, (2) encode a protein inhibiting the activation of C by A and B or (3) increase the decay of A and B mRNA. In all three cases the inhibitory influence of C is given by the rate constant kc. All three proteins are degraded at an equal rate d. We are interested in the steady state concentration of C following the knockout of A in comparison with the steady state concentration of C in the wildtype (in which A and B are both present). The ratio of mutant to wild‐type concentration of C assuming feedback mechanisms (1) and (2) is given by If we assume that ka=kb, then the reduction in steady state concentration of C is about 30%. The steady state ratio assuming feedback mechanism (3) depends on the rate of protein decay d. When the decay rate is very small (d→0), then the ratio is equal to 1. In other words, the circuit is completely redundant with respect to the loss of A. When the decay rate is very fast (d→∝) then for ka=kb, the ratio of mutant to wildtype is 0.5. For realistic rates of decay, the ratio remains approximately equal to 1. This toy model shows that for a range of negative feedback mechanisms, this network structure produces a degree of functional redundancy greater than the additive contribution of individual genes.

close

References

Averof M and Akam M (1995) Hox genes and the diversification of insect and crustacean body plans. Nature 376(6539): 420–423.

Bozorgmehr J and Esfandiar H (2012) The effect of functional compensation among duplicate genes can constrain their evolutionary divergence. Journal of Genetics 91(1): 1–8.

Chen Y and Gridley T (2013) The SNAI1 and SNAI2 proteins occupy their own and each other's promoter during chondrogenesis. Biochemical and Biophysical Research Communications 435(3): 356–360.

Cooke J, Nowak MA, Boerlijst M and Maynard‐Smith J (1997) Evolutionary origins and maintenance of redundant gene expression during metazoan development. Trends in Genetics 13(9): 360–364.

Delattre M and Félix M‐A (2009) The evolutionary context of robust and redundant cell biological mechanisms. BioEssays 31(5): 537–545.

Des Marais DL and Rausher MD (2008) Escape from adaptive conflict after duplication in an anthocyanin pathway gene. Nature 454: 762–765.

Elena SF, Wilke CO, Ofria C and Lenski RE (2007) Effects of population size and mutation rate on the evolution of mutational robustness. Evolution; International Journal of Organic Evolution 61(3): 666–674.

Enderton HB (2001) A Mathematical Introduction to Logic. Amsterdam: Academic Press. Elsevier.

Erzberger A, Hampp G, Granada AE, Albrecht U and Herzel H (2013) Genetic redundancy strengthens the circadian clock leading to a narrow entrainment range. Journal of the Royal Society, Interface/the Royal Society 10(84): 20130221.

Fernández A, Tzeng Y‐H and Hsu S‐B (2011) Subfunctionalization reduces the fitness cost of gene duplication in humans by buffering dosage imbalances. BMC Genomics 12(1): 604. doi:10.1186/1471‐2164‐12‐604.

Fontana W and Schuster P (1998) Continuity in evolution: on the nature of transitions. Science 280(5368): 1451–1455.

Force A, Lynch M, Pickett FB et al. (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151: 1531–1545.

Gibson G and Wagner G (2000) Canalization in evolutionary genetics: a stabilizing theory? BioEssays 22(4): 372–380.

Gu Z, Steinmetz LM, Gu X et al. (2003) Role of duplicate genes in genetic robustness against null mutations. Nature 418: 387–391.

Heard E (2005) Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. Current Opinion in Genetics & Development 15(5): 482–489.

Huynen MA, Stadler PF and Fontana W (1996) Smoothness within ruggedness: the role of neutrality in adaptation. Proceedings of the National Academy of Sciences of the USA 93(1): 397–401.

Ihmels J, Collins SR, Schuldiner M, Krogan NJ and Weissman JS (2007) Backup without redundancy: genetic interactions reveal the cost of duplicate gene loss. Molecular System Biology 3: 86–97.

Kimura M (1983) The Neutral Theory of Molecular Evolution. Cambridge: Cambridge University Press.

Krakauer DC and Nowak MA (1999) Evolutionary preservation of redundant duplicated genes. Seminars in Cell and Developmental Biology 10(5): 555–559.

Krakauer DC and Plotkin JB (2002) Redundancy, antiredundancy, and the robustness of genomes. Proceedings of the National Academy of Sciences of the USA 99(3): 1405–1409.

Lewontin RC (1974–1975) The problem of genetic diversity. Harvey Lectures 70: Series 1–Series 20.

Li J, Yuan Z and Zhang Z (2010) The cellular robustness by genetic redundancy in budding yeast. PLoS Genetics, Public Library of Science 6(11): e1001187. doi:10.1371/journal.pgen.1001187.

Lu X and Li Y (1999) Related articles, nucleotide, protein Drosophila Src42A is a negative regulator of RTK signaling. Developmental Biology 208(1): 233–243.

Lynch M and Connery JS (2000) The evolutionary fate and consequences of duplicate genes. Science 290: 1151–1155.

MacArthur DG and Tyler‐Smith C (2010) Loss‐of‐function variants in the genomes of healthy humans. Human Molecular Genetics 19(R2): R125–R130.

MacArthur DG, Balasubramanian S, Frankish A et al. (2012) A systematic survey of loss‐of‐function variants in human protein‐coding genes. Science (New York, NY) 335(6070): 823–828.

Maleszka R, Mason PH and Barron AB (2014) Epigenomics and the concept of degeneracy in biological systems. Briefings in Functional Genomics 13(3): 191–202.

Mendonça AG, Alves RJ and Pereira‐Leal JB (2011) Loss of genetic redundancy in reductive genome evolution. PLoS Computational Biology 7(2): e1001082. doi:10.1371/journal.pcbi.1001082.

Noda‐García L and Barona‐Gómez F (2013) Enzyme evolution beyond gene duplication: A model for incorporating horizontal gene transfer. Mobile Genetic Elements 3(5): e26439. doi:10.4161/mge.26439.

North KN, Yang N, Wattanasirichaigoon D et al. (1999) A common nonsense mutation results in alpha‐actinin‐3 deficiency in the general population. Nature Genetics 21(4): 353–354.

Nowak MA, Boerlijst MC, Cooke J and Smith JM (1997) Evolution of genetic redundancy. Nature 388(6638): 167–171.

Ortega S, Malumbres M and Barbacid M (2002) Cyclin D‐dependent kinases, INK4 inhibitors and cancer. Biochimica et Biophysica Acta 1602(1): 73–87.

Palanichamy JK and Rao DS (2014) miRNA dysregulation in cancer: towards a mechanistic understanding. Frontiers in Genetics 5: 54. doi:10.3389/fgene.2014.00054.

Rutherford SL and Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396(6709): 336–342.

Sekhon RS and Chopra S (2009) Progressive loss of DNA methylation releases epigenetic gene silencing from a tandemly repeated maize Myb gene. Genetics 181: 81–91.

Simon‐Loriere E and Holmes EC (2013) Gene duplication is infrequent in the recent evolutionary history of RNA viruses. Molecular Biology and Evolution 30(6): 1263–1269.

Tautz D (1992) Redundancies, development and the flow of information. BioEssays 14(4): 263–266.

Tautz D (2000) A genetic uncertainty problem. Trends in Genetics 16(11): 475–477.

Thomas JH (1993) Thinking about genetic redundancy. Trends in Genetics 9(11): 395–399.

de Visser JGM, Hermisson J, Wagner GP et al. (2003) Perspective: evolution and detection of genetic robustness. Evolution 57: 1959–1972.

Waddington CH (1942) Canalization of development and the inheritance of acquired characters. Nature 150: 563–565.

Wagner A (2000a) The role of population size, pleiotropy and fitness effects of mutations in the evolution of overlapping gene functions. Genetics 154(3): 1389–1401.

Wagner A (2000b) Robustness against mutations in genetic networks of yeast. Nature Genetics 24(4): 355–361.

Wang Y, Wang X, Tang H et al. (2011) Modes of gene duplication contribute differently to genetic novelty and redundancy, but show parallels across divergent angiosperms. PLoS One 6(12): e28150.

Further Reading

Ihmels J, Collins SR, Schuldiner M, Krogan NJ and Weissman JS (2007) Backup without redundancy: genetic interactions reveal the cost of duplicated genes. Molecular System Biology 3: 1–11.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Krakauer, David C(Dec 2014) The Complexity of Genetic Redundancy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006116.pub3]