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Genetics. Apr 1999; 151(4): 1531–1545.
PMCID: PMC1460548

Preservation of duplicate genes by complementary, degenerative mutations.

Abstract

The origin of organismal complexity is generally thought to be tightly coupled to the evolution of new gene functions arising subsequent to gene duplication. Under the classical model for the evolution of duplicate genes, one member of the duplicated pair usually degenerates within a few million years by accumulating deleterious mutations, while the other duplicate retains the original function. This model further predicts that on rare occasions, one duplicate may acquire a new adaptive function, resulting in the preservation of both members of the pair, one with the new function and the other retaining the old. However, empirical data suggest that a much greater proportion of gene duplicates is preserved than predicted by the classical model. Here we present a new conceptual framework for understanding the evolution of duplicate genes that may help explain this conundrum. Focusing on the regulatory complexity of eukaryotic genes, we show how complementary degenerative mutations in different regulatory elements of duplicated genes can facilitate the preservation of both duplicates, thereby increasing long-term opportunities for the evolution of new gene functions. The duplication-degeneration-complementation (DDC) model predicts that (1) degenerative mutations in regulatory elements can increase rather than reduce the probability of duplicate gene preservation and (2) the usual mechanism of duplicate gene preservation is the partitioning of ancestral functions rather than the evolution of new functions. We present several examples (including analysis of a new engrailed gene in zebrafish) that appear to be consistent with the DDC model, and we suggest several analytical and experimental approaches for determining whether the complementary loss of gene subfunctions or the acquisition of novel functions are likely to be the primary mechanisms for the preservation of gene duplicates. For a newly duplicated paralog, survival depends on the outcome of the race between entropic decay and chance acquisition of an advantageous regulatory mutation.Sidow 1996(p. 717) On one hand, it may fix an advantageous allele giving it a slightly different, and selectable, function from its original copy. This initial fixation provides substantial protection against future fixation of null mutations, allowing additional mutations to accumulate that refine functional differentiation. Alternatively, a duplicate locus can instead first fix a null allele, becoming a pseudogene.Walsh 1995 (p. 426) Duplicated genes persist only if mutations create new and essential protein functions, an event that is predicted to occur rarely.Nadeau and Sankoff 1997 (p. 1259) Thus overall, with complex metazoans, the major mechanism for retention of ancient gene duplicates would appear to have been the acquisition of novel expression sites for developmental genes, with its accompanying opportunity for new gene roles underlying the progressive extension of development itself.Cooke et al. 1997 (p. 362)

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Nadeau JH, Sankoff D. Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution. Genetics. 1997 Nov;147(3):1259–1266. [PMC free article] [PubMed]
  • Ahn S, Tanksley SD. Comparative linkage maps of the rice and maize genomes. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7980–7984. [PMC free article] [PubMed]
  • Amores A, Force A, Yan YL, Joly L, Amemiya C, Fritz A, Ho RK, Langeland J, Prince V, Wang YL, et al. Zebrafish hox clusters and vertebrate genome evolution. Science. 1998 Nov 27;282(5394):1711–1714. [PubMed]
  • Arnone MI, Davidson EH. The hardwiring of development: organization and function of genomic regulatory systems. Development. 1997 May;124(10):1851–1864. [PubMed]
  • Bailey GS, Poulter RT, Stockwell PA. Gene duplication in tetraploid fish: model for gene silencing at unlinked duplicated loci. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5575–5579. [PMC free article] [PubMed]
  • Bender W, Akam M, Karch F, Beachy PA, Peifer M, Spierer P, Lewis EB, Hogness DS. Molecular Genetics of the Bithorax Complex in Drosophila melanogaster. Science. 1983 Jul 1;221(4605):23–29. [PubMed]
  • Bisbee CA, Baker MA, Wilson AC, Haji-Azimi I, Fischberg M. Albumin phylogeny for clawed frogs (Xenopus). Science. 1977 Feb 25;195(4280):785–787. [PubMed]
  • Bradley D, Carpenter R, Sommer H, Hartley N, Coen E. Complementary floral homeotic phenotypes result from opposite orientations of a transposon at the plena locus of Antirrhinum. Cell. 1993 Jan 15;72(1):85–95. [PubMed]
  • Carr JL, Shashikant CS, Bailey WJ, Ruddle FH. Molecular evolution of Hox gene regulation: cloning and transgenic analysis of the lamprey HoxQ8 gene. J Exp Zool. 1998 Jan 1;280(1):73–85. [PubMed]
  • Chen J, Ruley HE. An enhancer element in the EphA2 (Eck) gene sufficient for rhombomere-specific expression is activated by HOXA1 and HOXB1 homeobox proteins. J Biol Chem. 1998 Sep 18;273(38):24670–24675. [PubMed]
  • Clark AG. Invasion and maintenance of a gene duplication. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2950–2954. [PMC free article] [PubMed]
  • Coen ES, Meyerowitz EM. The war of the whorls: genetic interactions controlling flower development. Nature. 1991 Sep 5;353(6339):31–37. [PubMed]
  • Cooke J, Nowak MA, Boerlijst M, Maynard-Smith J. Evolutionary origins and maintenance of redundant gene expression during metazoan development. Trends Genet. 1997 Sep;13(9):360–364. [PubMed]
  • Duboule D, Dollé P. The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. EMBO J. 1989 May;8(5):1497–1505. [PMC free article] [PubMed]
  • Dupé V, Davenne M, Brocard J, Dollé P, Mark M, Dierich A, Chambon P, Rijli FM. In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). Development. 1997 Jan;124(2):399–410. [PubMed]
  • Ekker M, Wegner J, Akimenko MA, Westerfield M. Coordinate embryonic expression of three zebrafish engrailed genes. Development. 1992 Dec;116(4):1001–1010. [PubMed]
  • Ekker SC, Ungar AR, Greenstein P, von Kessler DP, Porter JA, Moon RT, Beachy PA. Patterning activities of vertebrate hedgehog proteins in the developing eye and brain. Curr Biol. 1995 Aug 1;5(8):944–955. [PubMed]
  • Kirchhamer CV, Yuh CH, Davidson EH. Modular cis-regulatory organization of developmentally expressed genes: two genes transcribed territorially in the sea urchin embryo, and additional examples. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9322–9328. [PMC free article] [PubMed]
  • Ellies DL, Stock DW, Hatch G, Giroux G, Weiss KM, Ekker M. Relationship between the genomic organization and the overlapping embryonic expression patterns of the zebrafish dlx genes. Genomics. 1997 Nov 1;45(3):580–590. [PubMed]
  • Krumlauf R. Hox genes in vertebrate development. Cell. 1994 Jul 29;78(2):191–201. [PubMed]
  • Langston AW, Thompson JR, Gudas LJ. Retinoic acid-responsive enhancers located 3' of the Hox A and Hox B homeobox gene clusters. Functional analysis. J Biol Chem. 1997 Jan 24;272(4):2167–2175. [PubMed]
  • Ferris SD, Whitt GS. Loss of duplicate gene expression after polyploidisation. Nature. 1977 Jan 20;265(5591):258–260. [PubMed]
  • Ferris SD, Whitt GS. Evolution of the differential regulation of duplicate genes after polyploidization. J Mol Evol. 1979 Apr 12;12(4):267–317. [PubMed]
  • Lee KH, Xu Q, Breitbart RE. A new tinman-related gene, nkx2.7, anticipates the expression of nkx2.5 and nkx2.3 in zebrafish heart and pharyngeal endoderm. Dev Biol. 1996 Dec 15;180(2):722–731. [PubMed]
  • Gardner CA, Barald KF. Expression patterns of engrailed-like proteins in the chick embryo. Dev Dyn. 1992 Apr;193(4):370–388. [PubMed]
  • Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978 Dec 7;276(5688):565–570. [PubMed]
  • Gaut BS, Doebley JF. DNA sequence evidence for the segmental allotetraploid origin of maize. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6809–6814. [PMC free article] [PubMed]
  • Gavalas A, Studer M, Lumsden A, Rijli FM, Krumlauf R, Chambon P. Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development. 1998 Mar;125(6):1123–1136. [PubMed]
  • 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. [PubMed]
  • Liu S, McLeod E, Jack J. Four distinct regulatory regions of the cut locus and their effect on cell type specification in Drosophila. Genetics. 1991 Jan;127(1):151–159. [PMC free article] [PubMed]
  • Goodman MM, Stuber CW, Newton K, Weissinger HH. Linkage relationships of 19 enzyme Loci in maize. Genetics. 1980 Nov;96(3):697–710. [PMC free article] [PubMed]
  • Logan C, Willard HF, Rommens JM, Joyner AL. Chromosomal localization of the human homeo box-containing genes, EN1 and EN2. Genomics. 1989 Feb;4(2):206–209. [PubMed]
  • Graf JD, Kobel HR. Genetics of Xenopus laevis. Methods Cell Biol. 1991;36:19–34. [PubMed]
  • Lundin LG. Evolution of the vertebrate genome as reflected in paralogous chromosomal regions in man and the house mouse. Genomics. 1993 Apr;16(1):1–19. [PubMed]
  • Grenier JK, Garber TL, Warren R, Whitington PM, Carroll S. Evolution of the entire arthropod Hox gene set predated the origin and radiation of the onychophoran/arthropod clade. Curr Biol. 1997 Aug 1;7(8):547–553. [PubMed]
  • Maconochie MK, Nonchev S, Studer M, Chan SK, Pöpperl H, Sham MH, Mann RS, Krumlauf R. Cross-regulation in the mouse HoxB complex: the expression of Hoxb2 in rhombomere 4 is regulated by Hoxb1. Genes Dev. 1997 Jul 15;11(14):1885–1895. [PubMed]
  • Helentjaris T, Weber D, Wright S. Identification of the genomic locations of duplicate nucleotide sequences in maize by analysis of restriction fragment length polymorphisms. Genetics. 1988 Feb;118(2):353–363. [PMC free article] [PubMed]
  • Mena M, Ambrose BA, Meeley RB, Briggs SP, Yanofsky MF, Schmidt RJ. Diversification of C-function activity in maize flower development. Science. 1996 Nov 29;274(5292):1537–1540. [PubMed]
  • Holland LZ, Kene M, Williams NA, Holland ND. Sequence and embryonic expression of the amphioxus engrailed gene (AmphiEn): the metameric pattern of transcription resembles that of its segment-polarity homolog in Drosophila. Development. 1997 May;124(9):1723–1732. [PubMed]
  • Morizot DC, Slaugenhaupt SA, Kallman KD, Chakravarti A. Genetic linkage map of fishes of the genus Xiphophorus (Teleostei: Poeciliidae). Genetics. 1991 Feb;127(2):399–410. [PMC free article] [PubMed]
  • Nadeau JH, Sankoff D. Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution. Genetics. 1997 Nov;147(3):1259–1266. [PMC free article] [PubMed]
  • Holland PW, Garcia-Fernàndez J. Hox genes and chordate evolution. Dev Biol. 1996 Feb 1;173(2):382–395. [PubMed]
  • Holland PW, Garcia-Fernàndez J, Williams NA, Sidow A. Gene duplications and the origins of vertebrate development. Dev Suppl. 1994:125–133. [PubMed]
  • Nowak MA, Boerlijst MC, Cooke J, Smith JM. Evolution of genetic redundancy. Nature. 1997 Jul 10;388(6638):167–171. [PubMed]
  • Hughes AL. The evolution of functionally novel proteins after gene duplication. Proc Biol Sci. 1994 May 23;256(1346):119–124. [PubMed]
  • Ozçelik T, Porteus MH, Rubenstein JL, Francke U. DLX2 (TES1), a homeobox gene of the Distal-less family, assigned to conserved regions on human and mouse chromosomes 2. Genomics. 1992 Aug;13(4):1157–1161. [PubMed]
  • Jack J, DeLotto Y. Structure and regulation of a complex locus: the cut gene of Drosophila. Genetics. 1995 Apr;139(4):1689–1700. [PMC free article] [PubMed]
  • Palopoli MF, Patel NH. Evolution of the interaction between Hox genes and a downstream target. Curr Biol. 1998 May 7;8(10):587–590. [PubMed]
  • Jack JW. Molecular organization of the cut locus of Drosophila melanogaster. Cell. 1985 Oct;42(3):869–876. [PubMed]
  • Pébusque MJ, Coulier F, Birnbaum D, Pontarotti P. Ancient large-scale genome duplications: phylogenetic and linkage analyses shed light on chordate genome evolution. Mol Biol Evol. 1998 Sep;15(9):1145–1159. [PubMed]
  • Pendleton JW, Nagai BK, Murtha MT, Ruddle FH. Expansion of the Hox gene family and the evolution of chordates. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6300–6304. [PMC free article] [PubMed]
  • Joyner AL, Martin GR. En-1 and En-2, two mouse genes with sequence homology to the Drosophila engrailed gene: expression during embryogenesis. Genes Dev. 1987 Mar;1(1):29–38. [PubMed]
  • Piatigorsky J, Wistow G. The recruitment of crystallins: new functions precede gene duplication. Science. 1991 May 24;252(5009):1078–1079. [PubMed]
  • Kappen C, Ruddle FH. Evolution of a regulatory gene family: HOM/HOX genes. Curr Opin Genet Dev. 1993 Dec;3(6):931–938. [PubMed]
  • Pickett FB, Meeks-Wagner DR. Seeing double: appreciating genetic redundancy. Plant Cell. 1995 Sep;7(9):1347–1356. [PMC free article] [PubMed]
  • Kidwell MG, Lisch D. Transposable elements as sources of variation in animals and plants. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7704–7711. [PMC free article] [PubMed]
  • Pöpperl H, Bienz M, Studer M, Chan SK, Aparicio S, Brenner S, Mann RS, Krumlauf R. Segmental expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx. Cell. 1995 Jun 30;81(7):1031–1042. [PubMed]
  • Thompson JR, Chen SW, Ho L, Langston AW, Gudas LJ. An evolutionary conserved element is essential for somite and adjacent mesenchymal expression of the Hoxa1 gene. Dev Dyn. 1998 Jan;211(1):97–108. [PubMed]
  • Postlethwait JH, Yan YL, Gates MA, Horne S, Amores A, Brownlie A, Donovan A, Egan ES, Force A, Gong Z, et al. Vertebrate genome evolution and the zebrafish gene map. Nat Genet. 1998 Apr;18(4):345–349. [PubMed]
  • Walsh JB. How often do duplicated genes evolve new functions? Genetics. 1995 Jan;139(1):421–428. [PMC free article] [PubMed]
  • Watterson GA. On the time for gene silencing at duplicate Loci. Genetics. 1983 Nov;105(3):745–766. [PMC free article] [PubMed]
  • Saitou N, Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987 Jul;4(4):406–425. [PubMed]
  • Seoighe C, Wolfe KH. Extent of genomic rearrangement after genome duplication in yeast. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4447–4452. [PMC free article] [PubMed]
  • Wessler SR, Bureau TE, White SE. LTR-retrotransposons and MITEs: important players in the evolution of plant genomes. Curr Opin Genet Dev. 1995 Dec;5(6):814–821. [PubMed]
  • Shubin N, Tabin C, Carroll S. Fossils, genes and the evolution of animal limbs. Nature. 1997 Aug 14;388(6643):639–648. [PubMed]
  • Sidow A. Gen(om)e duplications in the evolution of early vertebrates. Curr Opin Genet Dev. 1996 Dec;6(6):715–722. [PubMed]
  • White S, Doebley J. Of genes and genomes and the origin of maize. Trends Genet. 1998 Aug;14(8):327–332. [PubMed]
  • Slusarski DC, Motzny CK, Holmgren R. Mutations that alter the timing and pattern of cubitus interruptus gene expression in Drosophila melanogaster. Genetics. 1995 Jan;139(1):229–240. [PMC free article] [PubMed]
  • White SE, Habera LF, Wessler SR. Retrotransposons in the flanking regions of normal plant genes: a role for copia-like elements in the evolution of gene structure and expression. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11792–11796. [PMC free article] [PubMed]
  • Stock DW, Ellies DL, Zhao Z, Ekker M, Ruddle FH, Weiss KM. The evolution of the vertebrate Dlx gene family. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10858–10863. [PMC free article] [PubMed]
  • Whitkus R, Doebley J, Lee M. Comparative genome mapping of Sorghum and maize. Genetics. 1992 Dec;132(4):1119–1130. [PMC free article] [PubMed]
  • Studer M, Pöpperl H, Marshall H, Kuroiwa A, Krumlauf R. Role of a conserved retinoic acid response element in rhombomere restriction of Hoxb-1. Science. 1994 Sep 16;265(5179):1728–1732. [PubMed]
  • Wolfe KH, Shields DC. Molecular evidence for an ancient duplication of the entire yeast genome. Nature. 1997 Jun 12;387(6634):708–713. [PubMed]
  • Studer M, Lumsden A, Ariza-McNaughton L, Bradley A, Krumlauf R. Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature. 1996 Dec 19;384(6610):630–634. [PubMed]
  • Zardoya R, Abouheif E, Meyer A. Evolutionary analyses of hedgehog and Hoxd-10 genes in fish species closely related to the zebrafish. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13036–13041. [PMC free article] [PubMed]
  • Studer M, Gavalas A, Marshall H, Ariza-McNaughton L, Rijli FM, Chambon P, Krumlauf R. Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development. 1998 Mar;125(6):1025–1036. [PubMed]
  • Zhang J, Nei M. Evolution of Antennapedia-class homeobox genes. Genetics. 1996 Jan;142(1):295–303. [PMC free article] [PubMed]
  • Takahata N, Maruyama T. Polymorphism and loss of duplicate gene expression: a theoretical study with application of tetraploid fish. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4521–4525. [PMC free article] [PubMed]
  • Zhou YH, Li WH. Gene conversion and natural selection in the evolution of X-linked color vision genes in higher primates. Mol Biol Evol. 1996 Jul;13(6):780–783. [PubMed]
  • Thisse C, Thisse B, Schilling TF, Postlethwait JH. Structure of the zebrafish snail1 gene and its expression in wild-type, spadetail and no tail mutant embryos. Development. 1993 Dec;119(4):1203–1215. [PubMed]

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