The role of population size, pleiotropy and fitness effects of mutations in the evolution of overlapping gene functions (original) (raw)

Abstract

Sheltered from deleterious mutations, genes with overlapping or partially redundant functions may be important sources of novel gene functions. While most partially redundant genes originated in gene duplications, it is much less clear why genes with overlapping functions have been retained, in some cases for hundreds of millions of years. A case in point is the many partially redundant genes in vertebrates, the result of ancient gene duplications in primitive chordates. Their persistence and ubiquity become surprising when it is considered that duplicate and original genes often diversify very rapidly, especially if the action of natural selection is involved. Are overlapping gene functions perhaps maintained because of their protective role against otherwise deleterious mutations? There are two principal objections against this hypothesis, which are the main subject of this article. First, because overlapping gene functions are maintained in populations by a slow process of "second order" selection, population sizes need to be very high for this process to be effective. It is shown that even in small populations, pleiotropic mutations that affect more than one of a gene's functions simultaneously can slow the mutational decay of functional overlap after a gene duplication by orders of magnitude. Furthermore, brief and transient increases in population size may be sufficient to maintain functional overlap. The second objection regards the fact that most naturally occurring mutations may have much weaker fitness effects than the rather drastic "knock-out" mutations that lead to detection of partially redundant functions. Given weak fitness effects of most mutations, is selection for the buffering effect of functional overlap strong enough to compensate for the diversifying force exerted by mutations? It is shown that the extent of functional overlap maintained in a population is not only independent of the mutation rate, but also independent of the average fitness effects of mutation. These results are discussed with respect to experimental evidence on redundant genes in organismal development.

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Selected References

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  1. Avise J. C., Ball R. M., Arnold J. Current versus historical population sizes in vertebrate species with high gene flow: a comparison based on mitochondrial DNA lineages and inbreeding theory for neutral mutations. Mol Biol Evol. 1988 Jul;5(4):331–344. doi: 10.1093/oxfordjournals.molbev.a040504. [DOI] [PubMed] [Google Scholar]
  2. Bailey W. J., Kim J., Wagner G. P., Ruddle F. H. Phylogenetic reconstruction of vertebrate Hox cluster duplications. Mol Biol Evol. 1997 Aug;14(8):843–853. doi: 10.1093/oxfordjournals.molbev.a025825. [DOI] [PubMed] [Google Scholar]
  3. Basson M. E., Thorsness M., Rine J. Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5563–5567. doi: 10.1073/pnas.83.15.5563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bengtsson B. O. Deleterious mutations and the origin of the meiotic ploidy cycle. Genetics. 1992 Jul;131(3):741–744. doi: 10.1093/genetics/131.3.741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bitgood M. J., McMahon A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol. 1995 Nov;172(1):126–138. doi: 10.1006/dbio.1995.0010. [DOI] [PubMed] [Google Scholar]
  6. Cadigan K. M., Grossniklaus U., Gehring W. J. Functional redundancy: the respective roles of the two sloppy paired genes in Drosophila segmentation. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6324–6328. doi: 10.1073/pnas.91.14.6324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cirera S., Aguadé M. Molecular evolution of a duplication: the sex-peptide (Acp70A) gene region of Drosophila subobscura and Drosophila madeirensis. Mol Biol Evol. 1998 Aug;15(8):988–996. doi: 10.1093/oxfordjournals.molbev.a026014. [DOI] [PubMed] [Google Scholar]
  8. Clark A. G. Invasion and maintenance of a gene duplication. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2950–2954. doi: 10.1073/pnas.91.8.2950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cooke J., Nowak M. A., Boerlijst M., Maynard-Smith J. Evolutionary origins and maintenance of redundant gene expression during metazoan development. Trends Genet. 1997 Sep;13(9):360–364. doi: 10.1016/s0168-9525(97)01233-x. [DOI] [PubMed] [Google Scholar]
  10. Datta S., Stark K., Kankel D. R. Enhancer detector analysis of the extent of genomic involvement in nervous system development in Drosophila melanogaster. J Neurobiol. 1993 Jun;24(6):824–841. doi: 10.1002/neu.480240609. [DOI] [PubMed] [Google Scholar]
  11. Doolittle R. F. Convergent evolution: the need to be explicit. Trends Biochem Sci. 1994 Jan;19(1):15–18. doi: 10.1016/0968-0004(94)90167-8. [DOI] [PubMed] [Google Scholar]
  12. Ferris S. D., Whitt G. S. Evolution of the differential regulation of duplicate genes after polyploidization. J Mol Evol. 1979 Apr 12;12(4):267–317. doi: 10.1007/BF01732026. [DOI] [PubMed] [Google Scholar]
  13. Ferris S. D., Whitt G. S. Loss of duplicate gene expression after polyploidisation. Nature. 1977 Jan 20;265(5591):258–260. doi: 10.1038/265258a0. [DOI] [PubMed] [Google Scholar]
  14. Force A., Lynch M., Pickett F. B., Amores A., Yan Y. L., Postlethwait J. Preservation of duplicate genes by complementary, degenerative mutations. Genetics. 1999 Apr;151(4):1531–1545. doi: 10.1093/genetics/151.4.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. González-Gaitán M., Rothe M., Wimmer E. A., Taubert H., Jäckle H. Redundant functions of the genes knirps and knirps-related for the establishment of anterior Drosophila head structures. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8567–8571. doi: 10.1073/pnas.91.18.8567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goodson H. V., Spudich J. A. Identification and molecular characterization of a yeast myosin I. Cell Motil Cytoskeleton. 1995;30(1):73–84. doi: 10.1002/cm.970300109. [DOI] [PubMed] [Google Scholar]
  17. Hanks M., Wurst W., Anson-Cartwright L., Auerbach A. B., Joyner A. L. Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2. Science. 1995 Aug 4;269(5224):679–682. doi: 10.1126/science.7624797. [DOI] [PubMed] [Google Scholar]
  18. Higashijima S., Michiue T., Emori Y., Saigo K. Subtype determination of Drosophila embryonic external sensory organs by redundant homeo box genes BarH1 and BarH2. Genes Dev. 1992 Jun;6(6):1005–1018. doi: 10.1101/gad.6.6.1005. [DOI] [PubMed] [Google Scholar]
  19. Hoffmann F. M. Drosophila abl and genetic redundancy in signal transduction. Trends Genet. 1991 Nov-Dec;7(11-12):351–355. doi: 10.1016/0168-9525(91)90254-f. [DOI] [PubMed] [Google Scholar]
  20. Joyner A. L., Herrup K., Auerbach B. A., Davis C. A., Rossant J. Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science. 1991 Mar 8;251(4998):1239–1243. doi: 10.1126/science.1672471. [DOI] [PubMed] [Google Scholar]
  21. Kimura M., King J. L. Fixation of a deleterious allele at one of two "duplicate" loci by mutation pressure and random drift. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2858–2861. doi: 10.1073/pnas.76.6.2858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kondrashov A. S., Crow J. F. Haploidy or diploidy: which is better? Nature. 1991 May 23;351(6324):314–315. doi: 10.1038/351314a0. [DOI] [PubMed] [Google Scholar]
  23. Li X., Noll M. Evolution of distinct developmental functions of three Drosophila genes by acquisition of different cis-regulatory regions. Nature. 1994 Jan 6;367(6458):83–87. doi: 10.1038/367083a0. [DOI] [PubMed] [Google Scholar]
  24. Lundgren K., Walworth N., Booher R., Dembski M., Kirschner M., Beach D. mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2. Cell. 1991 Mar 22;64(6):1111–1122. doi: 10.1016/0092-8674(91)90266-2. [DOI] [PubMed] [Google Scholar]
  25. Maconochie M., Nonchev S., Morrison A., Krumlauf R. Paralogous Hox genes: function and regulation. Annu Rev Genet. 1996;30:529–556. doi: 10.1146/annurev.genet.30.1.529. [DOI] [PubMed] [Google Scholar]
  26. Marshall C. R., Raff E. C., Raff R. A. Dollo's law and the death and resurrection of genes. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12283–12287. doi: 10.1073/pnas.91.25.12283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nadeau J. H., Sankoff D. Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution. Genetics. 1997 Nov;147(3):1259–1266. doi: 10.1093/genetics/147.3.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ohta T. Simulating evolution by gene duplication. Genetics. 1987 Jan;115(1):207–213. doi: 10.1093/genetics/115.1.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Otto S. P., Goldstein D. B. Recombination and the evolution of diploidy. Genetics. 1992 Jul;131(3):745–751. doi: 10.1093/genetics/131.3.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Padgett R. W., Wozney J. M., Gelbart W. M. Human BMP sequences can confer normal dorsal-ventral patterning in the Drosophila embryo. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2905–2909. doi: 10.1073/pnas.90.7.2905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Perrot V., Richerd S., Valéro M. Transition from haploidy to diploidy. Nature. 1991 May 23;351(6324):315–317. doi: 10.1038/351315a0. [DOI] [PubMed] [Google Scholar]
  32. Schena M. Genome analysis with gene expression microarrays. Bioessays. 1996 May;18(5):427–431. doi: 10.1002/bies.950180513. [DOI] [PubMed] [Google Scholar]
  33. Ting C. T., Tsaur S. C., Wu M. L., Wu C. I. A rapidly evolving homeobox at the site of a hybrid sterility gene. Science. 1998 Nov 20;282(5393):1501–1504. doi: 10.1126/science.282.5393.1501. [DOI] [PubMed] [Google Scholar]
  34. Venuti J. M., Goldberg L., Chakraborty T., Olson E. N., Klein W. H. A myogenic factor from sea urchin embryos capable of programming muscle differentiation in mammalian cells. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6219–6223. doi: 10.1073/pnas.88.14.6219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Watterson G. A. On the time for gene silencing at duplicate Loci. Genetics. 1983 Nov;105(3):745–766. doi: 10.1093/genetics/105.3.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Weintraub H. The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell. 1993 Dec 31;75(7):1241–1244. doi: 10.1016/0092-8674(93)90610-3. [DOI] [PubMed] [Google Scholar]
  37. Zhang J., Rosenberg H. F., Nei M. Positive Darwinian selection after gene duplication in primate ribonuclease genes. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3708–3713. doi: 10.1073/pnas.95.7.3708. [DOI] [PMC free article] [PubMed] [Google Scholar]