Logo of procbhomepageaboutsubmitalertseditorial board
Proc Biol Sci. 2002 May 7; 269(1494): 953–960.
PMCID: PMC1690979

Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model.


The evolution of cis-regulatory elements (or enhancers) appears to proceed at dramatically different rates in different taxa. Vertebrate enhancers are often very highly conserved in their sequences, and relative positions, across distantly related taxa. In contrast, functionally equivalent enhancers in closely related Drosophila species can differ greatly in their sequences and spatial organization. We present a population-genetic model to explain this difference. The model examines the dynamics of fixation of pairs of individually deleterious, but compensating, mutations. As expected, small populations are predicted to have a high rate of evolution, and the rate decreases with increasing population size. In contrast to previous models, however, this model predicts that the rate of evolution by pairs of compensatory mutations increases dramatically for population sizes above several thousand individuals, to the point of greatly exceeding the neutral rate. Application of this model predicts that species with moderate population sizes will have relatively conserved enhancers, whereas species with larger populations will be expected to evolve their enhancers at much higher rates. We propose that the different degree of conservation seen in vertebrate and Drosophila enhancers may be explained solely by differences in their population sizes and generation times.

Full Text

The Full Text of this article is available as a PDF (295K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aparicio S, Morrison A, Gould A, Gilthorpe J, Chaudhuri C, Rigby P, Krumlauf R, Brenner S. Detecting conserved regulatory elements with the model genome of the Japanese puffer fish, Fugu rubripes. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1684–1688. [PMC free article] [PubMed]
  • Birky CW, Jr, Walsh JB. Effects of linkage on rates of molecular evolution. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6414–6418. [PMC free article] [PubMed]
  • Charlesworth B. The effect of background selection against deleterious mutations on weakly selected, linked variants. Genet Res. 1994 Jun;63(3):213–227. [PubMed]
  • Christiansen FB, Otto SP, Bergman A, Feldman MW. Waiting with and without recombination: the time to production of a double mutant. Theor Popul Biol. 1998 Jun;53(3):199–215. [PubMed]
  • Gillespie JH. The role of population size in molecular evolution. Theor Popul Biol. 1999 Apr;55(2):145–156. [PubMed]
  • Gillespie JH. The neutral theory in an infinite population. Gene. 2000 Dec 30;261(1):11–18. [PubMed]
  • Gumucio DL, Shelton DA, Bailey WJ, Slightom JL, Goodman M. Phylogenetic footprinting reveals unexpected complexity in trans factor binding upstream from the epsilon-globin gene. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6018–6022. [PMC free article] [PubMed]
  • Hancock JM, Shaw PJ, Bonneton F, Dover GA. High sequence turnover in the regulatory regions of the developmental gene hunchback in insects. Mol Biol Evol. 1999 Feb;16(2):253–265. [PubMed]
  • Hansen TF, Carter AJ, Chiu CH. Gene conversion may aid adaptive peak shifts. J Theor Biol. 2000 Dec 21;207(4):495–511. [PubMed]
  • Hardison R, Slightom JL, Gumucio DL, Goodman M, Stojanovic N, Miller W. Locus control regions of mammalian beta-globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights. Gene. 1997 Dec 31;205(1-2):73–94. [PubMed]
  • Innan H, Stephan W. Selection intensity against deleterious mutations in RNA secondary structures and rate of compensatory nucleotide substitutions. Genetics. 2001 Sep;159(1):389–399. [PMC free article] [PubMed]
  • KIMURA M. On the probability of fixation of mutant genes in a population. Genetics. 1962 Jun;47:713–719. [PMC free article] [PubMed]
  • Kimura M, Ohta T. The Average Number of Generations until Fixation of a Mutant Gene in a Finite Population. Genetics. 1969 Mar;61(3):763–771. [PMC free article] [PubMed]
  • Kondrashov AS. Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over? J Theor Biol. 1995 Aug 21;175(4):583–594. [PubMed]
  • Li WH, Nei M. Total number of individuals affected by a single deleterious mutation in a finite population. Am J Hum Genet. 1972 Nov;24(6 Pt 1):667–679. [PMC free article] [PubMed]
  • Liu T, Wu J, He F. Evolution of cis-acting elements in 5' flanking regions of vertebrate actin genes. J Mol Evol. 2000 Jan;50(1):22–30. [PubMed]
  • Ludwig MZ, Patel NH, Kreitman M. Functional analysis of eve stripe 2 enhancer evolution in Drosophila: rules governing conservation and change. Development. 1998 Mar;125(5):949–958. [PubMed]
  • Ludwig MZ, Bergman C, Patel NH, Kreitman M. Evidence for stabilizing selection in a eukaryotic enhancer element. Nature. 2000 Feb 3;403(6769):564–567. [PubMed]
  • Margarit E, Guillén A, Rebordosa C, Vidal-Taboada J, Sánchez M, Ballesta F, Oliva R. Identification of conserved potentially regulatory sequences of the SRY gene from 10 different species of mammals. Biochem Biophys Res Commun. 1998 Apr 17;245(2):370–377. [PubMed]
  • Ohta T, Tachida H. Theoretical study of near neutrality. I. Heterozygosity and rate of mutant substitution. Genetics. 1990 Sep;126(1):219–229. [PMC free article] [PubMed]
  • Parsch J, Tanda S, Stephan W. Site-directed mutations reveal long-range compensatory interactions in the Adh gene of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):928–933. [PMC free article] [PubMed]
  • Plaza S, Saule S, Dozier C. High conservation of cis-regulatory elements between quail and human for the Pax-6 gene. Dev Genes Evol. 1999 Mar;209(3):165–173. [PubMed]
  • Ross JL, Fong PP, Cavener DR. Correlated evolution of the cis-acting regulatory elements and developmental expression of the Drosophila Gld gene in seven species from the subgroup melanogaster. Dev Genet. 1994;15(1):38–50. [PubMed]
  • Stephan W. The rate of compensatory evolution. Genetics. 1996 Sep;144(1):419–426. [PMC free article] [PubMed]
  • Stern DL. Evolutionary developmental biology and the problem of variation. Evolution. 2000 Aug;54(4):1079–1091. [PubMed]
  • Stone JR, Wray GA. Rapid evolution of cis-regulatory sequences via local point mutations. Mol Biol Evol. 2001 Sep;18(9):1764–1770. [PubMed]
  • Sumiyama K, Kim CB, Ruddle FH. An efficient cis-element discovery method using multiple sequence comparisons based on evolutionary relationships. Genomics. 2001 Jan 15;71(2):260–262. [PubMed]
  • Tagle DA, Koop BF, Goodman M, Slightom JL, Hess DL, Jones RT. Embryonic epsilon and gamma globin genes of a prosimian primate (Galago crassicaudatus). Nucleotide and amino acid sequences, developmental regulation and phylogenetic footprints. J Mol Biol. 1988 Sep 20;203(2):439–455. [PubMed]
  • Takahashi H, Mitani Y, Satoh G, Satoh N. Evolutionary alterations of the minimal promoter for notochord-specific Brachyury expression in ascidian embryos. Development. 1999 Sep;126(17):3725–3734. [PubMed]
  • Tamarina NA, Ludwig MZ, Richmond RC. Divergent and conserved features in the spatial expression of the Drosophila pseudoobscura esterase-5B gene and the esterase-6 gene of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7735–7741. [PMC free article] [PubMed]

Articles from Proceedings of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...