Evolution of Transcription Factors in Caenorhabditis

Abstract

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 homeodomain (HD), winged helix (WH) and zinc‐finger (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 basic‐leukine zipper (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 hexapeptide (HP), the N‐terminal arm (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.

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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]