MBE Advance Access originally published online on November 24, 2005
Molecular Biology and Evolution 2006 23(3):608-614; doi:10.1093/molbev/msj067
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Research Article |
Patterns of Protein Evolution in Tetrahymena thermophila: Implications for Estimates of Effective Population Size
* Department of Biological Sciences, Smith College, Northampton; Program in Organismic and Evolutionary Biology, University of Massachusetts Amherst; and Department of Biological, Geological and Environmental Sciences, Cleveland State University
E-mail: lkatz{at}smith.edu.
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Abstract |
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High levels of synonymous substitutions among alleles of the surface antigen SerH led to the hypothesis that Tetrahymena thermophila has a tremendously large effective population size, one that is greater than estimated for many prokaryotes (Lynch, M., and J. S. Conery. 2003. Science 302:1401–1404.). Here we show that SerH is unusual as there are substantially lower levels of synonymous variation at five additional loci (four nuclear and one mitochondrial) characterized from T. thermophila populations. Hence, the effective population size of T. thermophila, a model single-celled eukaryote, is lower and more consistent with estimates from other microbial eukaryotes. Moreover, reanalysis of SerH polymorphism data indicates that this protein evolves through a combination of vertical transmission of alleles and concerted evolution of repeat units within alleles. SerH may be under balancing selection due to a mechanism analogous to the maintenance of antigenic variation in vertebrate immune systems. Finally, the dual nature of ciliate genomes and particularly the amitotic divisions of processed macronuclear genomes may make it difficult to estimate accurately effective population size from synonymous polymorphisms. This is because selection and drift operate on processed chromosomes in macronuclei, where assortment of alleles, disruption of linkage groups, and recombination can alter the genetic landscape relative to more canonical eukaryotic genomes.
Key Words: genome evolution • effective population size • ciliates • protein evolution • Tetrahymena thermophila
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Characterizing DNA sequence variation in natural populations of Tetrahymena thermophila is essential for elucidating the evolutionary history of this model organism. Tetrahymena thermophila has been a rich resource for discovery, including self-splicing RNAs and telomeres. Yet, as with many model organisms, only a limited amount of data is available on the ecology and natural history of this model eukaryote. For example, the phylogeography of T. thermophila is relatively unexplored, though populations have been observed along the east coast of the United States (specifically, Massachusetts, Vermont, New Hampshire, Maine, Pennsylvania, Florida) and as far west as Illinois (Nanney and Simon 1999
; F. P. Doerder, unpublished data). Tetrahymena thermophila has not been observed on other continents.
The elevated numbers of synonymous substitutions among alleles of the surface antigen gene SerH (Gerber et al. 2002) were interpreted as showing that T. thermophila has a very large effective population size (Lynch and Conery 2003). In fact, in a study analyzing a diversity of organisms from vertebrates to prokaryotes, T. thermophila has the second highest estimate of effective population size (measured as Neµ)—its value falls between estimates from several prokaryotic species with larger census population sizes and geographic distributions (i.e., Procholorococcus sp., Salmonella enterica, and Legionella penumophila) (Lynch and Conery 2003). However, the estimate of Neµ in T. thermophila was made from only a single locus, SerH, and polymorphisms in any single gene may reflect evolutionary processes (i.e., balancing selection) operating on a single locus rather than population history. Furthermore, based on the estimate of Neµ derived from the SerH data, T. thermophila appears to be an exception to the genome complexity argument that states that genome sizes are largest in lineages with small effective population sizes due to the influence of genetic drift (Lynch and Conery 2003). In contrast to observations for other eukaryotic taxa, T. thermophila has an estimated effective population size larger than most prokaryotes (Lynch and Conery 2003) and also a relatively large macronuclear genome (
110 Mb; GenBank accession number AAGF01000000).
The SerH gene is one of a family of Ser genes in Tetrahymena that encodes abundant glycosylphosphatidylinositol-linked surface proteins known as immobilization antigens (Ko and Thompson 1992; Smith et al. 1992). As with the variant surface proteins of many parasitic protists (Kusch and Schmidt 2001), the proteins encoded by these genes are modular, composed of tandem repeats containing even numbers of periodic cysteines. For instance, SerH genes encode H proteins containing 3.5–4.5 repeats each with eight cysteines, whereas the SerL genes encode L proteins containing 2–5 repeats each with six cysteines (Tondravi et al. 1990; Doerder and Gerber 2000). While the sequencing of SerH alleles from T. thermophila populations revealed considerable sequence variation, the overall structure, hydrophobicity and cysteine periodicity were conserved (Gerber et al. 2002). At the nucleotide level, 9.7%–26.7% of sites were polymorphic in pairwise comparisons, and a high rate of synonymous substitution was observed. Though the exact role of the SerH proteins is unknown, their ubiquitous presence on the surface of Tetrahymena and their tight environmental and genetic regulation suggest that they are ecologically important.
The SerH locus is also associated with elevated levels of recombination within macronuclei when compared to other loci (Deak and Doerder 1998). In ciliates, macronuclear genomes are the site of all gene expression while the germline micronucleus is transcriptionally inactive and exchanged during conjugation (reviewed in Jahn and Klobutcher 2002; Yao, Duharcourt, and Chalker 2002; McGrath and Katz 2004). For two SerH1 nonsense mutations separated by 726 nt, recombination forming wild-type and double-mutant alleles occurs in virtually 100% of heterozygous macronuclei, a recombination rate significantly higher than that observed for other macronuclear markers (Lovlie, Haller, and Orias 1988; Longcor et al. 1996). Whereas only micronuclear recombination can generate new hereditary genotypes, macronuclear recombination can yield new gene combinations within an asexual clonal lineage and therefore may be advantageous during asexual periods of the ciliates life cycle.
Our aim was to distinguish between two hypotheses on protein evolution and effective population size in T. thermophila. The first hypothesis is that the high level of polymorphism at SerH, including numerous synonymous substitutions among alleles, is indicative of a large effective population of this ciliate and is paralleled by high levels of polymorphisms at other loci (Gerber et al. 2002). Under the second hypothesis, the elevated level of polymorphism in SerH is anomalous and reflects a nonneutral pattern of molecular evolution in this surface antigen gene. To distinguish between these hypotheses, we analyzed variation in four nuclear genes and one mitochondrial gene from a combination of inbred lines and natural isolates of T. thermophila, some of which contain previously characterized divergent SerH alleles (Gerber et al. 2002).
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Polymerase Chain Reaction, Cloning, and Sequencing
We characterized polymorphisms in three protein-coding and two small-subunit (SSU)-rDNA genes (mitochondrial and nuclear) to assess different regions of the T. thermophila genome. Polymorphisms are expected to accumulate at synonymous sites in protein-coding genes and in regions of low constraint (i.e., some loops) of the rDNAs. Four genes (SSU-rDNA, mt-SSU,
tub, Ef1) were characterized in the Katz laboratory, where samples were sent "blind" to hide source (natural population vs. clonal line). We relied on previously published primers for amplification of tub (Israel et al. 2002), Ef1 (Baldauf 1999), and SSU-rRNA (Medlin et al. 1988). Ciliate specific, degenerate primers for 1.6 kb of mt-SSU were designed in our laboratory: SSU mito 159+ (ATAGCGTMHDGGTGMGTAAWA) and SSU mito 1840 (CCACCRRCARKTTCCCMTACC). All products were amplified using Platinum Taq DNA polymerase (Invitrogen, Carlsbad, Calif., #10966026). A 1-kb fragment of the actin gene was characterized in the Doerder laboratory from five natural populations using primers ATGGCTGAAAGTGAATCCC and CTCAGGAGGAGCAACAAC and a high fidelity Z-Taq (Takara, Mirus Bio, Madison, Wisc.) Actin products, analyzed in the Doerder laboratory, were cloned into pGEM-Teasy for sequencing. Resulting sequences were similar to sequences on GenBank (table 1).
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Sequence Analysis
The sequences obtained in this study were aligned using the multisequence alignment algorithms and ClustalW (Thompson, Higgins, and Gibson 1994
) as implemented in Megalign (DNAStar, Inc., Madison, Wisc.) and then exported into PAUP* version 4.0b10 (Swofford 2002) for estimation of uncorrected pairwise distances. Average pairwise synonymous distances were calculated for the three protein-coding genes using the modified Nei-Gojobori method as implemented in Mega3 (Kumar, Tamura, and Nei 2004).
SerH Analysis
Analysis of the evolution of SerH combined published alleles (table 2) with homologous regions form the T. thermophila genome. SerH loci were identified in the completed T. thermophila macronculear genome by Blast analysis, using the Assembly_2 November 2003 scaffolds available at The Institute for Genomic Research http://tigrblast.tigr.org/er-blast. Identification of SerH ESTs was performed by both inspecting the results of Blast analysis of ESTs from several libraries (http://cbr-rbc.nrc-cnrc.gc.ca/reith/tetra/tetra.html) and by searching for similar ESTs to SerH alleles from natural populations using SeqMan (DNAStar, Inc.). SerH alleles and scaffold regions were aligned by ClustalW in Megalign (DNAStar, Inc.). Genealogical analyses of SerH amino acid repeats and of scaffold regions used both neighbor-joining (NJ) and maximum parsimony algorithms. Mean distances were estimated for NJ analysis. Parsimony analyses treated gaps as a 21st state and used 10 random addition sequences in heuristic searches. Bootstraps were calculated using 100 replicates under all models.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Our data indicate that the degree of DNA polymorphism at the SerH locus (Gerber et al. 2002
) is unusually high and not representative of other genes in T. thermophila as we found low levels of polymorphisms in four macronuclear genes, alpha-tubulin (tub), elongation factor 1 (Ef1), actin, and small-subunit ribosomal RNA (SSU-rDNA), as well as the mitochondrial small-subunit rRNA (mt-SSU). Genomic DNAs from natural populations and clonal lines were chosen for this study because they are known to contain divergent SerH alleles (table 1; Gerber et al. 2002). For all genes except actin, DNAs were isolated from one natural population (ANF5906-1) and three inbred lines (B, B3, and A; table 1). We found less than 0.25% divergence among clones representing three nuclear genes (SSU-rDNA, tub, and Ef1) and one mitochondrial gene (mt-SSU; table 3). Furthermore, there is no evidence of elevated diversity either within the natural population or between inbred lines. In fact, all four of these loci have roughly the same level of polymorphisms, and at least some of the low level of polymorphisms is likely due to either experimental (polymerase chain reaction/sequencing) error or are variants in the polyploid macronucleus. Similarly, a comparison of a 969-bp fragment of actin genes from five different natural isolates (four from Allegheny National Forest and one from New Hampshire) confirms the findings as we uncovered only five polymorphic sites and an average pairwise divergence of 0.27% (table 3). These data are in stark contrast to the high divergence, 20.69% nucleotide and 31.15% amino acid, observed at the SerH locus in the same populations (table 3; Gerber et al. 2002).
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To provide an explanation for the contrast between the high level of SerH polymorphism and lack of variation at other loci, we reanalyzed the published SerH allele sequences based on the patterns of substitutions in three of the 3.5–4.5 imperfect, cysteine-rich repeat motifs within each allele (table 2; Gerber et al. 2002
). If SerH evolves solely by vertical descent, then the first repeat of alleles should be more similar to one another than to other repeats (fig. 1a). However, if concerted evolution underlies the evolution of repeats, then repeats within alleles will be homogenized and therefore repeats will be more similar to one another than to those of other alleles (fig. 1b).
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Genealogical analyses of the first three of the imperfect repeats in SerH reveal a complex pattern of evolution through both vertical descent and concerted evolution. Repeats within one group of alleles, family I (fig. 1c), are very similar to one another, consistent with concerted evolution driving the diversity of these alleles. Within allele family I, repeats in SerH5 are virtually identical at the amino acid level, and repeats within SerH6 are closely related (fig. 1c). Similarly, the first repeat of the SerH1 allele (SerH1_r1) is recently derived from the second repeat of the same allele (SerH1_r2). In contrast, allele families II–IV arose from independent concerted events followed by a period of vertical transmission—repeats within these families are more similar between alleles than within alleles (fig. 1c). For example, repeats within allele family IV (alleles H7, H9, and H12) have diverged due to vertical transmission following concerted evolution of alleles (fig. 1c). Similarly, allele family II (H8, H10, and H11) also diverged following what appears to be a more ancient concerted event—repeats within this family do not form a monophyletic group (fig. 1c).
Comparisons of coding and presumed untranslated regions (UTRs) of SerH alleles reveal a pattern of evolution consistent with the mixed ancestry of the SerH alleles as there is more polymorphism in coding domains compared across alleles than in both 5' and 3' UTRs (table 4). For example, among published alleles 5' and 3' UTRs diverge by 12.7% and 6.0%, respectively, while nucleotide divergence in coding domains in the same alleles is 20.2% (table 2). This pattern is consistent with a recombination-based mechanisms driving evolution of repeat regions within SerH alleles and implies that the concerted evolution is regulated so as not to involve UTRs.
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Comparisons between SerH alleles characterized from several lines with the single macronuclear scaffold available from one inbred strain indicate that there is even a greater diversity of SerH in the macronuclear genomes of natural populations of T. thermophila. Blast analysis of SerH alleles against the completed T. thermophila macronuclear genome identified five loci related to SerH on a single macronuclear scaffold (fig. 2). Only one of these loci, Scaf_5, is identical in sequence to a published allele (SerH3). This macronuclear locus appears to be the only expressed site in the macronucleus as it is the only match found in comparisons with available T. thermophila EST data. Of the remaining four scaffold regions, one (Scaf_1) shows very low levels of similarity to other macronuclear scaffold regions and to published alleles. The other scaffold regions have complex relationships to published alleles, as revealed by genealogical analysis (fig. 3): intriguingly, the five divergent loci on the sequenced macronuclear chromosomes of a laboratory strain of T. thermophila fall in only two of four classes of alleles. This observation suggests that additional variants of SerH will be found on the macronuclear scaffolds of other strains of T. thermophila.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Contrary to previous analysis (Lynch and Conery 2003
), we find no evidence that T. thermophila has a large effective population size. Instead, the low levels of genetic polymorphism in Ef1, SSU-rRNA, tub, actin, and mt-SSU genes indicate that T. thermophila has a smaller effective population size and that the elevated levels at SerH are aberrant. Based on synonymous differences among alleles in our sampling of three protein-coding genes, we used equations from Lynch and Conery (2003) to calculate Neµ for T. thermophila as 0.0008 (table 3). This estimate of Neµ is less than 100 times smaller than the estimate of 0.18 that was calculated based on polymorphisms in the SerH gene. A smaller effective population size for T. thermophila is consistent with the hypothesis of Lynch and Conery (2003) as this model ciliate also has a relatively large macronuclear genome (110 Mb) and large number of genes (25,000). While a more accurate estimate of Neµ for this ciliate will require a larger, random sample of alleles, the estimate of Neµ in this study (table 3) is in line with estimates for other microbial eukaryotes including Plasmodium falciparum (Neµ = 0.00082) and Encephalitozoon cuniculi (Neµ = 0.003). Both of these eukaryotic microbes are parasitic—they can achieve large census population sizes and have relatively broad geographical distributions (generally tropical and subtropical for P. falciparum; recently commensal with humans for E. cuniculi). Similar estimates of T. thermophila census sizes and current distributions are not available, making it difficult to interpret estimates of effective population size for this model ciliate.
The elevated levels of polymorphism at SerH (table 3) coupled with the mixed patterns of vertical descent and gene conversion of repeats (fig. 1c) indicate that the SerH-coding regions are not evolving neutrally. Instead, the Ser H locus may be evolving under adaptive evolution (e.g., balancing selection) to maintain variation in this surface antigen in populations of T. thermophila. Such a pattern of evolution is analogous to that found in variable surface antigens in Trypanosomes (Donelson 2003) and the V(D)J system of human immune systems (Lewis and Wu 1997; Diaz and M.F. 1998), where balancing selection maintains polymorphisms at loci involved in host-parasite interactions. While the function of the SerH-encoded proteins is unknown, the Ser gene families are regulated by environmental factors, and the resulting proteins are expressed on the surface of the ciliate (Margolin, Loefer, and R.D. 1959; Allen and Gibson 1973). Many more candidate Ser gene families with the same type of modular structure are present in the newly sequenced T. thermophila genome (F. P. Doerder, unpublished data), indicating that these antigen genes may constitute a substantial portion of the Tetrahymena genome.
Finally, the rapid amino acid evolution at the SerH locus is consistent with our hypothesis (Katz et al. 2004) that differential selection on the functional macronucleus and the transcriptionally inactive micronucleus contributes to elevated rates observed in many ciliate proteins (Bhattacharya and Weber 1997; Moreira, Le Guyader, and Philippe 1999; Katz et al. 2004). Ciliates, like animals and a few other eukaryotic lineages, have distinct germline and somatic genomes throughout their life cycles (reviewed in Zufall, Robinson, and Katz 2005). However, only in ciliate macronuclei can differential amplification of chromosomes, recombination, and breakup of linkage groups create variation among macronuclei during asexual divisions. All of these effects are enhanced during asexual divisions by amitosis, the process by which macronuclei divide without accurately distributing sister chromatids between daughter nuclei. We argue that genome processing combined with amitosis can mask the effects of deleterious mutations in ciliate macronuclei (Katz et al. 2004). As a result, proteins such as SerH can explore sequence space during iterative asexual cycles by effectively hiding alleles from selection in macronuclei while accumulating potentially compensatory mutations in the micronucleus. Hence, it may be difficult to infer the effective population size of ciliates because selection on processed macronuclear genomes can affect the rates of fixation of synonymous substitutions when compared to other eukaryotes with more canonical genomes.
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Acknowledgements |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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This work was support by the National Science Foundation grants DEB-0092908 and DEB-0079325 to L.A.K. and funds provided to F.P.D. by the Graduate College and Department of Biological, Geological and Environmental Sciences at Cleveland State University. Thanks to Elyse Lasser for her work in helping to characterize T. thermophila sequences.
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Footnotes |
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1 Present address: Department of Plant, Soil, and Insect Sciences, Fernald Hall, University of Massachusetts at Amherst, Amherst, MA 01003
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