Evolution of Transcription Factors in Caenorhabditis


Transcription factors (TFs) are regulatory proteins controlling gene expression by binding specific motifs associated with their target genes and playing essential roles during development and physiological response to stimuli. The evolution of transcriptional regulation is an important source of phenotypic diversity. The genome of the nematode Caenorhabditis elegans encodes a similar proportion of TFs as the human genome, although TF families show different patterns of expansion in human and in worm. The TF repertoire of C. elegans is well diversified with over 50 TF families. Alternative splicing and gene duplication contribute to the functional diversity of TFs and the rapid evolution of TF protein sequence suggests that TF evolution plays important roles in developmental evolution. Many of the principles that guided the diversification of the worm TFs are likely to be applicable to the evolution of TFs in other organisms.

Key Concepts:

  • The genome of C. elegans encodes 988 TFs belonging to 50 distinct families based on the type of DNA‐binding domain.

  • The worm and human genomes encode a similar proportion of TFs, and in both species a third of the TFs show tissue‐specific gene expression.

  • Alternative splicing increases the number of TF transcripts by 22%.

  • Gene duplication contributes significantly to the functional diversification of TFs, and several examples illustrate the different evolutionary trajectories taken by TF duplicates.

  • Tissue‐specific expression, alternative splicing, gene duplication and the combinatorial regulatory activity of TFs reduce the pleiotropic constraints operating on TF sequence evolution.

  • TF factor sequence evolution plays an unappreciated role in developmental evolution.

  • TFs can harbour high level of amino acid variation both between species and within populations.

Keywords: transcription factors; Caenorhabditis; gene duplication; alternative splicing; gene regulation; transcription networks

Figure 1.

The distribution of TF families in C. elegans based on the type of DNA‐binding domain. The bar graph shows the frequency of the major TF families, with the category ‘others’ grouping TFs belonging to families with less than five members. The y‐axis is truncated in order to bring frequencies to visible proportions. The distribution of subfamilies within the large (HD), (WH) and (ZF) families is also shown in the pie charts. Redrawn from Haerty et al. .

Figure 2.

The TF repertoire in Caenorhabditis species. The phylogenetic relationship among the Caenorhabditis species having a genome sequence is shown on the left panel (Jovelin and Phillips, ) with black boxes indicating the independent origin of a selfing mode of reproduction. The number of TFs identified in C. elegans (988) and in the two related species C. briggsae (995) and C. remanei (1093) is shown on the right panel (Haerty et al., ). C. elegans shares a set of 652 orthologous TFs with C. briggsae and C. remanei (in yellow) but also has 215 unique TFs with no apparent orthology to the TFs found in the other species (in red), and 121 TFs with orthologs in either species (in blue).

Figure 3.

Alternative splicing, gene duplication and the combinatorial mode of action of TFs increase the functional diversification of individual TFs while also reducing the pleiotropic effects of mutations. (a) The (bZIP) zip‐4 encodes three alternative transcripts that differ by 13% on average in their protein sequence. Lines represent introns. Variable exons are coloured and the common coding region to all three transcripts is shown in grey. (b) The three evolutionary fates facing gene duplicates. The GATA factor elt‐4, a duplicate of elt‐2, may be on its way to become a pseudogene (Fukushige et al., ). The duplicates egl‐38 and pax‐2 may have been retained in C. elegans because they have partitioned subfunctions present in their ancestor and preserved in their single co‐ortholog in C. briggsae (Wang et al., ). Functional divergence between the Hox paralogs mab‐5 and lin‐39 may have contributed to their retention in C. elegans. The organisation of the MAB‐5 protein is shown on top with the (HP), the (NA) and the three helixes (H) of the homeodomain shown in colour. Amino acid substitutions (black bars) in the NA/HI confer functional specificity to MAB‐5 in regulating ray formation whereas amino acid substitutions in other parts of the protein confer specificity to LIN‐39 in regulating vulva formation (Gutierrez et al., ). (c) The combinatorial action of TFs results in cell‐specific regulation of target genes. The LIM homeobox lim‐6 regulates the expression of unc‐25 in the RIS, AVL and DVD neurons but has no effect on unc‐25 expression in the RME neurons (Hobert et al., ). A possible mechanism is that lim‐6 regulates the expression of unc‐25 with a cofactor that is absent in the RME neurons. Alternatively, a repressor of lim‐6 could be specifically expressed in the RME neurons.

Figure 4.

TFs controlling chemosensory neuron differentiation evolve faster than the structural chemosensory genes expressed in the same neurons. Comparison of the average interspecies nucleotide divergence between 15 TFs (yellow) and 54 chemosensory genes expressed in 11 chemosensory neurons (green). Protein sequence evolution is measured by the rate of amino acid replacements (dN) and by controlling for the mutation rate (dN/dS). Amino acid replacements are further classified as radical (dR/dS) if the new amino acid has different charge and polarity or conservative (dC/dS) if it retains the same chemical properties. Four other chemical characteristics, charge, polarity, volume and polarity, charge and aromatic showed the same pattern of faster radical and conservative amino acid changes in TFs (Jovelin, ). Significance was obtained by a Wilcoxon two‐sample test. **P<0.01, ***P<0.001.

Figure 5.

TFs accumulate high levels of genetic variation both within populations and between species. (a) Comparison of interspecies divergence between 48 TFs controlling neuron differentiation and 37 non‐TF (structural) genes. (b) Comparison of the ratio of amino acid replacement to synonymous polymorphisms (A/S) between a subset of 31 neuronal TFs and 37 structural genes. (c) TFs controlling chemosensory neuron differentiation evolve faster than TFs required for the development of motorneurons and than those affecting multiple neuron types. (d) The level of amino acid polymorphisms is also higher for the TFs controlling chemosensory neuron differentiation than for the other neuronal TFs (Jovelin, ). Significance was obtained by a likelihood ratio test for interspecies divergence (a and c) and by a χ2 test for the within‐species diversity (b and d). *P<0.05, **P<0.01, ***P<0.001.



Aboobaker AA and Blaxter ML (2003) Hox gene loss during dynamic evolution of the nematode cluster. Current Biology 13: 37–40.

Alonso CR and Wilkins AS (2005) The molecular elements that underlie developmental evolution. Nature Reviews Genetics 6: 709–715.

Baker CR, Tuch BB and Johnson AD (2011) Extensive DNA‐binding specificity divergence of a conserved transcription regulator. Proceedings of the National Academy of Sciences of the USA 108: 7493–7498.

Burga A, Casanueva MO and Lehner B (2011) Predicting mutation outcome from early stochastic variation in genetic interaction partners. Nature 480: 250–253.

Carroll SB (2001) Chance and necessity: the evolution of morphological complexity and diversity. Nature 409: 1102–1109.

Carroll SB (2005) Evolution at two levels: on genes and form. PLoS Biology 3: e245.

Christensen R, de la Torre‐Ubieta L, Bonni A, and Colon‐Ramos DA (2011) A conserved PTEN/FOXO pathway regulates neuronal morphology during C. elegans development. Development 138: 5257–5267.

Coroian C, Broitman‐Maduro G and Maduro MF (2006) Med‐type GATA factors and the evolution of mesendoderm specification in nematodes. Developmental Biology 289: 444–455.

Cutter AD (2008) Divergence times in Caenorhabditis and Drosophila inferred from direct estimates of the neutral mutation rate. Molecular Biology and Evolution 25: 778–786.

Dekker T, Ibba I, Siju KP, Stensmyr MC and Hansson BS (2006) Olfactory shifts parallel superspecialism for toxic fruit in Drosophila melanogaster sibling, D. sechellia. Current Biology 16: 101–109.

Drummond DA, Bloom JD, Adami C et al. (2005) Why highly expressed proteins evolve slowly. Proceedings of the National Academy of Sciences of the USA 102: 14338–14343.

Duboule D (2007) The rise and fall of Hox gene clusters. Development 134: 2549–2560.

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

Fukushige T, Goszczynski B, Tian H and McGhee JD (2003) The evolutionary duplication and probable demise of an endodermal GATA factor in Caenorhabditis elegans. Genetics 165: 575–588.

Garcia‐Fernandez J (2005) The genesis and evolution of homeobox gene clusters. Nature Reviews Genetics 6: 881–892.

Gerstein MB, Lu ZJ, Van Nostrand EL et al. (2010) Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330: 1775–1787.

Ghaemmaghami S, Huh WK, Bower K et al. (2003) Global analysis of protein expression in yeast. Nature 425: 737–741.

Grove CA, De Masi F, Barrasa MI et al. (2009) A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 138: 314–327.

Gu Z, Steinmetz LM, Gu X et al. (2003) Role of duplicate genes in genetic robustness against null mutations. Nature 421: 63–66.

Guo Y, Lang S and Ellis RE (2009) Independent recruitment of F box genes to regulate hermaphrodite development during nematode evolution. Current Biology 19: 1853–1860.

Gutierrez A, Knoch L, Witte H and Sommer RJ (2003) Functional specificity of the nematode Hox gene mab‐5. Development 130: 983–993.

Haerty W, Artieri C, Khezri N, Singh RS and Gupta BP (2008) Comparative analysis of function and interaction of transcription factors in nematodes: extensive conservation of orthology coupled to rapid sequence evolution. BMC Genomics 9: 399.

Hahn MW (2009) Distinguishing among evolutionary models for the maintenance of gene duplicates. Journal of Heredity 100: 605–617.

He X and Zhang J (2005) Rapid subfunctionalization accompanied by prolonged and substantial neofunctionalization in duplicate gene evolution. Genetics 169: 1157–1164.

Hobert O (2008) Regulatory logic of neuronal diversity: terminal selector genes and selector motifs. Proceedings of the National Academy of Sciences of the USA 105: 20067–20071.

Hobert O, Tessmar K and Ruvkun G (1999) The Caenorhabditis elegans lim‐6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons. Development 126: 1547–1562.

Hope IA, Mounsey A, Bauer P and Aslam S (2003) The forkhead gene family of Caenorhabditis elegans. Gene 304: 43–55.

Hsiao TL and Vitkup D (2008) Role of duplicate genes in robustness against deleterious human mutations. PLoS Genetics 4: e1000014.

Hu M, Lok JB, Ranjit N et al. (2010) Structural and functional characterisation of the fork head transcription factor‐encoding gene, Hc‐daf‐16, from the parasitic nematode Haemonchus contortus (Strongylida). International Journal for Parasitology 40: 405–415.

Irimia M, Rukov JL, Penny D et al. (2008) Widespread evolutionary conservation of alternatively spliced exons in Caenorhabditis. Molecular Biology and Evolution 25: 375–382.

Jovelin R (2009) Rapid sequence evolution of transcription factors controlling neuron differentiation in Caenorhabditis. Molecular Biology and Evolution 26: 2373–2386.

Jovelin R and Cutter AD (2011) MicroRNA sequence variation potentially contributes to within‐species functional divergence in the nematode Caenorhabditis briggsae. Genetics 189: 967–976.

Jovelin R, Dunham JP, Sung FS and Phillips PC (2009) High nucleotide divergence in developmental regulatory genes contrasts with the structural elements of olfactory pathways in Caenorhabditis. Genetics 181: 1387–1397.

Jovelin R and Phillips PC (2011) Expression level drives the pattern of selective constraints along the insulin/Tor signal transduction pathway in Caenorhabditis. Genome Biology and Evolution 3: 715–722.

Kopelman NM, Lancet D and Yanai I (2005) Alternative splicing and gene duplication are inversely correlated evolutionary mechanisms. Nature Genetics 37: 588–589.

Kwon ES, Narasimhan SD, Yen K and Tissenbaum HA (2010) A new DAF‐16 isoform regulates longevity. Nature 466: 498–502.

Levine M and Tjian R (2003) Transcription regulation and animal diversity. Nature 424: 147–151.

Lynch M (2007) The frailty of adaptive hypotheses for the origins of organismal complexity. Proceedings of the National Academy of Sciences of the USA 104(suppl. 1): 8597–8604.

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

Lynch M and Force AG (2000) The origin of interspecific genomic incompatibility via gene duplication. American Naturalist 156: 590–605.

Lynch VJ and Wagner GP (2008) Resurrecting the role of transcription factor change in developmental evolution. Evolution 62: 2131–2154.

Maduro MF (2009) Structure and evolution of the C. elegans embryonic endomesoderm network. Biochimica et Biophysica Acta 1789: 250–260.

Maduro MF, Hill RJ, Heid PJ et al. (2005) Genetic redundancy in endoderm specification within the genus Caenorhabditis. Developmental Biology 284: 509–522.

Merritt C, Rasoloson D, Ko D and Seydoux G (2008) 3′ UTRs are the primary regulators of gene expression in the C. elegans germline. Current Biology 18: 1476–1482.

Molin L, Mounsey A, Aslam S et al. (2000) Evolutionary conservation of redundancy between a diverged pair of forkhead transcription factor homologues. Development 127: 4825–4835.

Nayak S, Goree J and Schedl T (2005) fog‐2 and the evolution of self‐fertile hermaphroditism in Caenorhabditis. PLoS Biology 3: e6.

Nokes EB, Van Der Linden AM, Winslow C et al. (2009) Cis‐regulatory mechanisms of gene expression in an olfactory neuron type in Caenorhabditis elegans. Developmental Dynamics 238: 3080–3092.

Ramani AK, Calarco JA, Pan Q et al. (2010) Genome‐wide analysis of alternative splicing in Caenorhabditis elegans. Genome Research 21: 342–348.

Reece‐Hoyes JS, Deplancke B, Shingles J et al. (2005) A compendium of Caenorhabditis elegans regulatory transcription factors: a resource for mapping transcription regulatory networks. Genome Biology 6: R110.

Reece‐Hoyes JS, Shingles J, Dupuy D et al. (2007) Insight into transcription factor gene duplication from Caenorhabditis elegans Promoterome‐driven expression patterns. BMC Genomics 8: 27.

Robinson‐Rechavi M, Maina CV, Gissendanner CR, Laudet V and Sluder A (2005) Explosive lineage‐specific expansion of the orphan nuclear receptor HNF4 in nematodes. Journal of Molecular Evolution 60: 577–586.

Rukov JL, Irimia M, Mork S et al. (2007) High qualitative and quantitative conservation of alternative splicing in Caenorhabditis elegans and Caenorhabditis briggsae. Molecular Biology and Evolution 24: 909–917.

Ruvinsky I and Ruvkun G (2003) Functional tests of enhancer conservation between distantly related species. Development 130: 5133–5142.

Shiu SH, Byrnes JK, Pan R, Zhang P and Li WH (2006) Role of positive selection in the retention of duplicate genes in mammalian genomes. Proceedings of the National Academy of Sciences of the USA 103: 2232–2236.

Sluder AE, Mathews SW, Hough D, Yin VP and Maina CV (1999) The nuclear receptor superfamily has undergone extensive proliferation and diversification in nematodes. Genome Research 9: 103–120.

Sommermann EM, Strohmaier KR, Maduro MF and Rothman JH (2010) Endoderm development in Caenorhabditis elegans: the synergistic action of ELT‐2 and ‐7 mediates the specification→differentiation transition. Developmental Biology 347: 154–166.

Tihanyi B, Vellai T, Regos A et al. (2010) The C. elegans Hox gene ceh‐13 regulates cell migration and fusion in a non‐colinear way. Implications for the early evolution of Hox clusters. BMC Developmental Biology 10: 78.

Vaquerizas JM, Kummerfeld SK, Teichmann SA and Luscombe NM (2009) A census of human transcription factors: function, expression and evolution. Nature Reviews Genetics 10: 252–263.

Vavouri T, Semple JI and Lehner B (2008) Widespread conservation of genetic redundancy during a billion years of eukaryotic evolution. Trends in Genetics 24: 485–488.

Wagner A (2008) Neutralism and selectionism: a network‐based reconciliation. Nature Reviews Genetics 9: 965–974.

Wang X, Greenberg JF and Chamberlin HM (2004) Evolution of regulatory elements producing a conserved gene expression pattern in Caenorhabditis. Evolution and Development 6: 237–245.

Further Reading

Carroll SB, Grenier JK and Weatherbee SD (2005) From DNA to Diversity. Molecular Genetics and the Evolution of Animal Design. Malden, Oxford, Victoria: Blackwell Publishing.

Davidson EH (2006) The Regulatory Genome. Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Sydney, Tokyo: Academic Press.

Hoekstra HE and Coyne JA (2007) The locus of evolution: evo devo and the genetics of adaptation. Evolution 61: 995–1016.

Hsia CC and McGinnis W (2003) Evolution of transcription factor function. Current Opinion in Genetics and Development 13: 199–206.

Stern DL and Orgogozo V (2008) The loci of evolution: how predictable is genetic evolution? Evolution 62: 2155–2177.

Wray GA (2007) The evolutionary significance of cis‐regulatory mutations. Nature Reviews Genetics 8: 206–216.

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Jovelin, Richard(Apr 2012) Evolution of Transcription Factors in Caenorhabditis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022882]