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Large-Scale Turnover of Functional Transcription Factor Binding Sites in Drosophila

DOI: 10.1371/journal.pcbi.0020130

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The gain and loss of functional transcription factor binding sites has been proposed as a major source of evolutionary change in cis-regulatory DNA and gene expression. We have developed an evolutionary model to study binding-site turnover that uses multiple sequence alignments to assess the evolutionary constraint on individual binding sites, and to map gain and loss events along a phylogenetic tree. We apply this model to study the evolutionary dynamics of binding sites of the Drosophila melanogaster transcription factor Zeste, using genome-wide in vivo (ChIP–chip) binding data to identify functional Zeste binding sites, and the genome sequences of D. melanogaster, D. simulans, D. erecta, and D. yakuba to study their evolution. We estimate that more than 5% of functional Zeste binding sites in D. melanogaster were gained along the D. melanogaster lineage or lost along one of the other lineages. We find that Zeste-bound regions have a reduced rate of binding-site loss and an increased rate of binding-site gain relative to flanking sequences. Finally, we show that binding-site gains and losses are asymmetrically distributed with respect to D. melanogaster, consistent with lineage-specific acquisition and loss of Zeste-responsive regulatory elements.


[1]  Wilson AC, Maxson LR, Sarich VM (1974) Two types of molecular evolution. Evidence from studies of interspecific hybridization. Proc Natl Acad Sci U S A 71: 2843–2847.
[2]  Tautz D (2000) Evolution of transcriptional regulation. Curr Opin Genet Dev 10: 575–579.
[3]  Levine M, Tjian R (2003) Transcription regulation and animal diversity. Nature 424: 147–151.
[4]  Wray GA (2003) Transcriptional regulation and the evolution of development. Int J Dev Biol 47: 675–684.
[5]  Gompel N, Prud'homme B, Wittkopp PJ, Kassner VA, Carroll SB (2005) Chance caught on the wing: Cis-regulatory evolution and the origin of pigment patterns in Drosophila. Nature 433: 481–487.
[6]  Rockman MV, Hahn MW, Soranzo N, Zimprich F, Goldstein DB, et al. (2005) Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol 3(12): e387..
[7]  Tanaka M, Hale LA, Amores A, Yan YL, Cresko WA, et al. (2005) Developmental genetic basis for the evolution of pelvic fin loss in the pufferfish Takifugu rubripes. Dev Biol 281: 227–239.
[8]  Shapiro MD, Marks ME, Peichel CL, Blackman BK, Nereng KS, et al. (2004) Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 428: 717–723.
[9]  Small S, Levine M (1991) The initiation of pair-rule stripes in the Drosophila blastoderm. Curr Opin Genet Dev 1: 255–260.
[10]  Zinzen RP, Senger K, Levine M, Papatsenko D (2006) Computational models for neurogenic gene expression in the Drosophila embryo. Curr Biol 16: 1358–1365.
[11]  Hunt C, Morimoto RI (1985) Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci U S A 82: 6455–6459.
[12]  Duret L, Bucher P (1997) Searching for regulatory elements in human noncoding sequences. Curr Opin Struct Biol 7: 399–406.
[13]  Wasserman WW, Palumbo M, Thompson W, Fickett JW, Lawrence CE (2000) Human–mouse genome comparisons to locate regulatory sites. Nat Genet 26: 225–228.
[14]  McGuire AM, Hughes JD, Church GM (2000) Conservation of DNA regulatory motifs and discovery of new motifs in microbial genomes. Genome Res 10: 744–757.
[15]  McCue L, Thompson W, Carmack C, Ryan MP, Liu JS, et al. (2001) Phylogenetic footprinting of transcription factor binding sites in proteobacterial genomes. Nucleic Acids Res 29: 774–782.
[16]  Levy S, Hannenhalli S, Workman C (2001) Enrichment of regulatory signals in conserved non-coding genomic sequence. Bioinformatics 17: 871–877.
[17]  Dermitzakis ET, Clark AG (2002) Evolution of transcription factor binding sites in mammalian gene regulatory regions: Conservation and turnover. Mol Biol Evol 19: 1114–1121.
[18]  Moses AM, Chiang DY, Kellis M, Lander ES, Eisen MB (2003) Position specific variation in the rate of evolution in transcription factor binding sites. BMC Evol Biol 3: 19.
[19]  Prud'homme B, Gompel N, Rokas A, Kassner VA, Williams TM, et al. (2006) Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene. Nature 440: 1050–1053.
[20]  Ludwig MZ, Palsson A, Alekseeva E, Bergman CM, Nathan J, et al. (2005) Functional evolution of a cis-regulatory module. PLoS Biol 3(4): e93..
[21]  Piano F, Parisi MJ, Karess R, Kambysellis MP (1999) Evidence for redundancy but not trans factor-cis element coevolution in the regulation of Drosophila Yp genes. Genetics 152: 605–616.
[22]  Ludwig MZ, Patel NH, Kreitman M (1998) Functional analysis of eve stripe 2 enhancer evolution in Drosophila: Rules governing conservation and change. Development 125: 949–958.
[23]  Ludwig MZ, Bergman C, Patel NH, Kreitman M (2000) Evidence for stabilizing selection in a eukaryotic enhancer element. Nature 403: 564–567.
[24]  Ren B, Robert F, Wyrick JJ, Aparicio O, Jennings EG, et al. (2000) Genome-wide location and function of DNA binding proteins. Science 290: 2306–2309.
[25]  Iyer VR, Horak CE, Scafe CS, Botstein D, Snyder M, et al. (2001) Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409: 533–538.
[26]  Tamura K, Subramanian S, Kumar S (2004) Temporal patterns of fruit fly (Drosophila) evolution revealed by mutation clocks. Mol Biol Evol 21: 36–44.
[27]  Lachaise D, Cariou M, David J, Lemeunier F, Tsacas L, et al. (1988) Historical biogeography of the species subgroup. Evolutionary Biology 22: 159–225.
[28]  Russo CA, Takezaki N, Nei M (1995) Molecular phylogeny and divergence times of drosophilid species. Mol Biol Evol 12: 391–404.
[29]  Brudno M, Do CB, Cooper GM, Kim MF, Davydov E, et al. (2003) LAGAN and Multi-LAGAN: Efficient tools for large-scale multiple alignment of genomic DNA. Genome Res 13: 721–731.
[30]  Halpern AL, Bruno WJ (1998) Evolutionary distances for protein-coding sequences: Modeling site-specific residue frequencies. Mol Biol Evol 15: 910–917.
[31]  Hasegawa M, Kishino H, Yano T (1985) Dating of the human–ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22: 160–174.
[32]  Felsenstein J (1981) Evolutionary trees from DNA sequences: A maximum likelihood approach. J Mol Evol 17: 368–376.
[33]  Mustonen V, Lassig M (2005) Evolutionary population genetics of promoters: Predicting binding sites and functional phylogenies. Proc Natl Acad Sci U S A 102: 15936–15941.
[34]  Mahmoudi T, Zuijderduijn LM, Mohd-Sarip A, Verrijzer CP (2003) GAGA facilitates binding of Pleiohomeotic to a chromatinized Polycomb response element. Nucleic Acids Res 31: 4147–4156.
[35]  Biggin MD, Tjian R (1988) Transcription factors that activate the Ultrabithorax promoter in developmentally staged extracts. Cell 53: 699–711.
[36]  Biggin MD, Bickel S, Benson M, Pirrotta V, Tjian R (1988) Zeste encodes a sequence-specific transcription factor that activates the Ultrabithorax promoter in vitro. Cell 53: 713–722.
[37]  Benson M, Pirrotta V (1988) The Drosophila zeste protein binds cooperatively to sites in many gene regulatory regions: Implications for transvection and gene regulation. EMBO J 7: 3907–3915.
[38]  Bergman CM, Carlson JW, Celniker SE (2005) Drosophila DNase I footprint database: A systematic genome annotation of transcription factor binding sites in the fruitfly, . Bioinformatics 21: 1747–1749.
[39]  Moses AM, Chiang DY, Pollard DA, Iyer VN, Eisen MB (2004) MONKEY: Identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model. Genome Biol 5: R98.
[40]  Dermitzakis ET, Bergman CM, Clark AG (2003) Tracing the evolutionary history of Drosophila regulatory regions with models that identify transcription factor binding sites. Mol Biol Evol 20: 703–714.
[41]  Stone JR, Wray GA (2001) Rapid evolution of cis-regulatory sequences via local point mutations. Mol Biol Evol 18: 1764–1770.
[42]  MacArthur S, Brookfield JF (2004) Expected rates and modes of evolution of enhancer sequences. Mol Biol Evol 21: 1064–1073.
[43]  Costas J, Casares F, Vieira J (2003) Turnover of binding sites for transcription factors involved in early Drosophila development. Gene 310: 215–220.
[44]  Khaitovich P, Weiss G, Lachmann M, Hellmann I, Enard W, et al. (2004) A neutral model of transcriptome evolution. PLoS Biol 2(5): e132..
[45]  Fay JC, McCullough HL, Sniegowski PD, Eisen MB (2004) Population genetic variation in gene expression is associated with phenotypic variation in . Genome Biol 5: R26.
[46]  Gilad Y, Oshlack A, Rifkin SA (2006) Natural selection on gene expression. Trends Genet 22: 256–261.
[47]  Andolfatto P (2005) Adaptive evolution of non-coding DNA in Drosophila. Nature 437: 1149–1152.
[48]  Hahn MW, Rockman MV, Soranzo N, Goldstein DB, Wray GA (2004) Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans. Genetics 167: 867–877.
[49]  Rockman MV, Hahn MW, Soranzo N, Goldstein DB, Wray GA (2003) Positive selection on a human-specific transcription factor binding site regulating IL4 expression. Curr Biol 13: 2118–2123.
[50]  Rockman MV, Hahn MW, Soranzo N, Loisel DA, Goldstein DB, et al. (2004) Positive selection on MMP3 regulation has shaped heart disease risk. Curr Biol 14: 1531–1539.
[51]  Stormo GD (2000) DNA binding sites: Representation and discovery. Bioinformatics 16: 16–23.
[52]  Toth J, Biggin MD (2000) The specificity of protein–DNA crosslinking by formaldehyde: In vitro and in drosophila embryos. Nucleic Acids Res 28: e4.
[53]  Walter J, Dever CA, Biggin MD (1994) Two homeo domain proteins bind with similar specificity to a wide range of DNA sites in Drosophila embryos. Genes Dev 8: 1678–1692.
[54]  Bohlander SK, Espinosa R III, Le Beau MM, Rowley JD, Diaz MO (1992) A method for the rapid sequence-independent amplification of microdissected chromosomal material. Genomics 13: 1322–1324.
[55]  Yang Z (1997) PAML: A program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13: 555–556.
[56]  Staden R (1984) Computer methods to locate signals in nucleic acid sequences. Nucleic Acids Res 12: 505–519.
[57]  Stormo GD, Schneider TD, Gold L, Ehrenfeucht A (1982) Use of the “Perceptron” algorithm to distinguish translational initiation sites in . Nucleic Acids Res 10: 2997–3011.
[58]  Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, et al. (1997) Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res 25: 3389–3402.
[59]  Pollard DA, Iyer VN, Moses AM, Eisen MB (2006) Whole genome phylogeny of the species subgroup: Widespread discordance with species tree and evidence for incomplete lineage sorting. PLoS Genet 2(10). In press.
[60]  Durbin R, Eddy S, Krogh A, Mitchison G (1998) Biological sequence analysis: Probabililstic models of proteins and nucleic acids. Cambridge (United Kingdom): Cambridge University Press.
[61]  Pollard DA, Moses AM, Iyer VN, Eisen MB (2006) Detecting the limits of regulatory element conservation and divergence estimation using pairwise and multiple alignments. BMC Bioinformatics 7: 376.
[62]  Comeron JM, Kreitman M (2000) The correlation between intron length and recombination in Drosophila. Dynamic equilibrium between mutational and selective forces. Genetics 156: 1175–1190.
[63]  Schneider TD, Stephens RM (1990) Sequence logos: A new way to display consensus sequences. Nucleic Acids Res 18: 6097–6100.
[64]  Staden R (1989) Methods for calculating the probabilities of finding patterns in sequences. Comput Appl Biosci 5: 89–96.


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