Complex evolution of the DAL5 transporter family
© Hellborg et al; licensee BioMed Central Ltd. 2008
Received: 07 September 2007
Accepted: 11 April 2008
Published: 11 April 2008
Genes continuously duplicate and the duplicated copies remain in the genome or get deleted. The DAL5 subfamily of transmembrane transporter genes has eight known members in S. cerevisiae. All are putative anion:cation symporters of vitamins (such as allantoate, nicotinate, panthotenate and biotin). The DAL5 subfamily is an old and important group since it is represented in both Basidiomycetes ("mushrooms") and Ascomycetes ("yeast"). We studied the complex evolution of this group in species from the kingdom of fungi particularly the Ascomycetes.
We identified numerous gene duplications creating sets of orthologous and paralogous genes. In different lineages the DAL5 subfamily members expanded or contracted and in some lineages a specific member could not be found at all. We also observed a close relationship between the gene YIL166C and its homologs in the Saccharomyces sensu stricto species and two "wine spoiler" yeasts, Dekkera bruxellensis and Candida guilliermondi, which could possibly be the result of horizontal gene transfer between these distantly related species. In the analyses we detect several well defined groups without S. cerevisiae representation suggesting new gene members in this subfamily with perhaps altered specialization or function.
The transmembrane DAL5 subfamily was found to have a very complex evolution in yeast with intra- and interspecific duplications and unusual relationships indicating specialization, specific deletions and maybe even horizontal gene transfer. We believe that this group will be important in future investigations of evolution in fungi and especially the evolution of transmembrane proteins and their specialization.
Transmembrane transporters of unicellular organisms, like yeast, are one of the primary links between the outer world and the metabolic pathways inside the cell. The importance of these genes is seen in the substantial proportion of transporter genes within the yeast genome (10%) . In Saccharomyces cerevisiae, for example, over 400 genes encoding transporter proteins have been found .
Different species of yeast require different substrates to be transported, and the number and kind of transporters present in the genome therefore vary between species. The presence or absence of a transporter may provide insight into the niche preference and metabolic ability of a yeast [3–6]. An example is seen in the loss or inactivation of the galactose transporter Gal2p (and six other genes of the galactose metabolism) in several Hemiascomycete species . Similarly, expansion or contraction of gene numbers in various transporter subfamilies can indicate metabolic abilities: for example, peroxisomal and long chain fatty acid transporters have undergone amplification in Y. lipolytica, which is known to grow on fatty acids . More unexpectedly, genes belonging to two heavy metal transporter subfamilies, SIT and CT2, have been amplified 14 and 10 times respectively in Y. lipolytica , possibly as the result of a natural symbiosis with bacteria providing iron-siderophores and/or other natural chelators.
Yeast transporters have been classified into a number of families and subfamilies, based on functional and phylogenetic criteria [8, 10]. Within the Hemiascomycete phylum, 97 small phylogenetic transporter subfamilies have been identified comprising a total of 355 transporters named according to their evolutionary patterns ("ubiquitous," "species specific," "phylum gains and losses," and "homoplasic").
-Gene name and function of the eight members of the DAL5 subfamily in S. cerevisiae.
Encodes an allantoate and ureidosuccinate permease, expression is constitutive but sensitive to nitrogen catabolite repression. Subtelomeric in S. cerevisiae
A membrane pantothenate transporter, regulated by high concentrations of pantothenate. Pantothenate is essential for the biosynthesis of coenzyme A, which is a carrier of activated C2 units in sterol biosynthesis. FEN2 was first identified in a screen for mutants resistant to fenproprimorph, an inhibitor of ergosterol biosynthesis
Encodes a high affinity H+-biotin (vitamin H) permease different from mammals, regulated by high concentrations of biotin. The biotin uptake and biosynthesis is reciprocally regulated by iron, with uptake being activated when iron is scarce
Encodes a high affinity nicotinic acid (vitamin B3) permease. The mRNA levels increase strongly at reduced extracellular concentrations of both nicotinic acid and para-aminobenzoate (PABA) but are not inhibited by high concentrations of the same substrates. Subtelomeric in S. cerevisiae
Encodes a membrane protein in the endoplasmic reticulum that is strongly regulated by thiamine. It is unable to transport thiamine but might be involved in transport of thiamine precursors. The metabolite is probably a compound that can be used by yeast to generate the thiazole precursor HET. The expression level is upregulated by Pdc2 (pyruvate decarboxylase) and Thi2 (thiamine)
Might be involved in the transport of some sulphur compound (which remains to be identified) since the overexpression of the SEO1 gene allowed growth on low concentration of methionine sulphoxide and supressed the ethionine sulphoxide resistance. The gene does not encode a methionine permease Subtelomeric in S. cerevisiae
Might be involved in the intracellular transport of allantoate since its transcripts are overexpressed during nitrogen starvation (similar to DAL5) The protein is localized in the endoplasmic reticulum. Subtelomeric in S. cerevisiae
Putative protein with elevated mRNA expression by sulfur limitation. YIL166c is a non-essential gene. Subtelomeric in S. cerevisiae
To investigate the evolution of this gene family, and track its expansions and contractions across Hemiascomycetes, we have performed a phylogenetic analysis of these genes across a number of Hemiascomycete species for which whole genomes are available. The DAL5 subfamily is a ubiquitous transporter found in all Hemiascomycete species, but with a very complex evolution involving repeated gene losses and duplications.
Results and Discussion
The relationship between the members of the DAL5 subfamily
The relationship of the DAL5 genes
The relationship of the TNA1 genes
The gene tree indicates ancient duplication of this gene, since many species have gene copies in several clusters (C. albicans, 3 gene copies spread over 3 clusters, C. guilliermondi, 5 gene copies spread over 5 clusters, C. lusitaniae, 4 gene copies spread over 4 clusters, D. hansenii, 4 gene copies spread over 4 clusters, S. kluyveri, 3 gene copies spread over 3 clusters, K. lactis, 2 gene copies spread over 2 clusters, C. glabrata, 2 gene copies spread over 2 clusters, A. gossypi, 2 gene copies spread over 2 clusters) with reciprocal losses in the other clusters which result in a non exact match of the taxonomic phylogeny.
The relationship of the YIL166c and YOL163-2w genes
There are two further points of interest in this region of the tree (Figure 5). The first is the presence of a U. maydis (Basidiomycete) gene at the base of the Hemiascomycete YIL166c clade. Although the node has only 60% bootstrap support, the node below this is 100% supported, which results in a confident clade in which a basidiomycete is nested within ascomycetes. This relationship suggests that there has been a horizontal gene transfer event from either Euascomycetes or Hemiascomycetes to this Basidiomycete species. It will be interesting to see if a similar sequence can be detected in any other Basidiomycete species.
Secondly, while most species are represented in most gene clades, the species represented in each of these two clades (YIL166c and YOL163-2w) are substantially different. The YIL166c group contains the sensu stricto species, D. bruxellensis and C. guilliermondi, while the other clade contains the other species from the Hemiascomycetes. The Saccharomyces sensu stricto species, C. guilliermondi and D. bruxellensis have all been found in alcoholic beverages like wine . The presence of these orthologous transporters in these taxa could be due to selection for retention of a transporter specially adapted to an environment of low oxygen and high ethanol concentration. It seems that the genes from these species are true orthologs with a common origin, and have either been lost from the other Hemiascomycetes or horizontally transferred into the "wine species". The gene transfer is either from a species close to U. maydis, which branched off before the Euascomycetes, or the gene in U. maydis is also a horizontally transferred gene, and the horizontal gene transfer occurred from a species in the Euascomycetes clade to U. maydis, and the "wine species". These hypotheses are currently speculative, and much further work would be required to investigate them further.
Another unusual behaviour of the Hemiascomycete orthologs of YIL166c is that this transporter appears to have undergone species-specific duplication in every species in our analysis. Some have been duplicated prior to speciation like C. tropicalis and C. albicans. The intraspecific duplication has resulted in two or three copies for most of the species in the trees except for Y. lipolytica. The pattern of gene duplication in this species is unusual: for each member of the subfamily, Y. lipolytica has either three or more paralogs or no copy of the gene at all. We found no orthologs of YIL166c, YCT1, TH173 and VHT1 in Y. lipolytica, but for FEN2 we found three copies, YOL163w four copies, DAL5 five copies, SEO1 six copies and for TNA1 20 copies, that met our criteria. The selective advantage of these amplifications for Y. lipolytica is not understood, but it could be a compensation for the loss of the other DAL5 transporters or a selective advantage coupled to a sudden change in the environment and/or the hydrocarbon diet. The amplification we observe of anion:cation symporters in Y. lipolytica has also been seen in drug:H+antiporter transporters and quinate:H+symporters .
How have the gene expansions taken place?
Duplications of genes could be on the gene level, segmental, chromosomal or whole genome duplications. The duplications offer the opportunity for copies to evolve different functions, either broader or more specialized. Gene copies that provide an advantage for the organism may be preserved and go to fixation under selection. Others might lose any function, become pseudogenes and ultimately be lost from the genome. In the DAL5 family the number of copies various tremendously within and between species for the different gene family members. This expansion and shrinkage is most evident in Y. lipolytica where we found three to twenty paralogs for five of the nine subfamilies and in the others, no copy of the gene at all. The other species has also expanded into two to four copies for most genes in this subfamily. In some cases it is evident that the duplications occurred before speciation, for example see C. albicans and C. tropicalis for YOL163w, while in other cases there have been recent independent duplications in several species, see Y. lipolytica and A. gossypii in YOL163w (Figure 5). A similar pattern can be observed in the lower part of the tree DAL5 (Figure 3) where a few lineages (D. hansenii, C. albicans and Y. lipolytica) seem to have undergone a recent duplication and at the same time an ancestor of S. cerevisiae and the sensu stricto group deleted their copy.
Most species-specific genes are located near telomeres in Saccharomyces sensu stricto species [16–18]. Four (SEO1, YCT1, DAL5 and YIL166c) of the eight genes (nine in other species) in this subfamily are subtelomeric in S. cerevisiae. It is possible that the complexity that we see in many trees, especially for Y. lipolytica and D. hansenii, is a result of horizontal gene transfer coupled with intraspecific duplications. Maybe the duplications that we see are a result of specialization for different substrates or maybe even for a different function. Most of the permeases are complex in nature, with many different substrates, and for many of the species investigated here the transporter proteins are poorly studied.
Yeast is one of the most important model organisms in biology research including evolution. The yeast lineage, as part of the kingdom of fungi, has revealed both horizontal transfers and whole genome duplication and is a very important group regarding new insights into evolutionary pathways [3, 5, 19]. Crucial genes often show an interesting evolution and transmembrane proteins are often essential for the survival of the yeast cells. The transmembrane DAL5 subfamily includes genes that seem to be very important due to its many duplications in almost all yeast species investigated, but it also includes genes that obviously can be deleted without any harm done to the organism. When we analysed species from the whole kingdom of fungi we found that the DAL5 subfamily has a very complex evolution in yeast, not seen before, with intra- and interspecific duplications and unusual relationships indicating specialization, deletions and maybe even horizontal gene transfer. We believe that the DAL5 subfamily will be important in future investigations of evolution in fungi, especially the evolution of transmembrane proteins and their specialization.
We performed two sets of BLAST searches to obtain the sequences used in this analysis. First, the protein sequences of the eight members of the DAL5 family from Saccharomyces cerevisiae (SEO1, FEN2, VHT1, TNA1, YIL166c, DAL5, YCT1 and TH173) were used as BLASTP queries against an NCBI genomic BLAST database of several fungal species for which whole genomes are available (Ashbya gossypii, Candida albicans, C. glabrata, C. guilliermondii, C. lusitaniae, C. tropicalis, Debaryomyces hansenii, Kluyveromyces lactis, K. waltii, Saccharomyces bayanus, S. castellii, S. cerevisiae, S. kluyveri, S. kudriavzevii, S. mikate, S. paradoxus, Yarrowia lipolytica, Schizosaccharomyces pombe, Aspergillus fumigatus and A. Nidulans). For each of these query proteins, we extracted from the BLASTP results all hits that had E-values better than 1e-6. To confirm that we had obtained all likely homologs of these genes, we compared the sequences of the hits we obtained in each query species to the database of gene family sequences made available by Jason Stajich at http://www.fungalgenomes.org. Any genes in this database which were not present in our BLAST results, and were over 300 bp long, were added to our dataset.
We also used the S. cerevisiae genes as TBLASTN queries against a database of Dekkera bruxellensis contig sequences, which represent approximately 40% of the genome of D. bruxellensis strain CBS 2499 (Woolfit et al 2007).
We initially treated each of the query genes, together with their sets of hits, as separate datasets. As preliminary analyses suggested that the genes SEO1 and VHT1 represented a Hemiascomycete-specific duplication, the results for these two genes were combined, leaving us with seven datasets.
For each of the datasets, the protein sequences were aligned using T_Coffee. The alignments were edited by hand, and any regions of the sequences for which homology could not be confidently established were removed producing alignments of between 410 and 526 residues in length (SEO1-VHT1: 495aa, FEN2: 449aa, DAL5: 416aa, YCT1: 488aa, TH173: 486aa, TNA1: 410aa, YIL166C:526aa). Phylogenetic trees were constructed for each dataset using PHYML, using the JTT model of substitution, and a gamma distribution of rates with four categories. The gamma parameter was estimated from the data. One thousand bootstrap replicates of each tree were run, using the same model parameters.
We then combined all sequences into a single alignment. The seven previously aligned datasets were used as "profiles" and aligned against one another using the profile comparison function in T_Coffee. The resulting alignment of 650 residues was checked manually, and phylogenetic analyses were performed as described above. To confirm that the step-wise method of alignment had not affected our results, gaps were removed, all sequences were realigned using Muscle, and the phylogenetic analysis was repeated. These results were not qualitatively different.
We would like to thank Andre Goffeau for helpful comments on the manuscript, and Jason Stajich for making gene family data available. LIH and JUP thank the Carl Tryggers foundation and FUTURA for financial support.
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