Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function
© Su and Yuan; licensee BioMed Central Ltd. 2010
Published: 7 October 2010
PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms.
The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With Arabidopsis as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function.
PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out to dissect the PHB gene function. The conserved gene evolution indicated that the study in the model species can be translated to human and mammalian studies.
Prohibitin (PHB) is also known as band_7 domain proteins or SPFH (stomatins, prohibitins, flotillins and HflK/C) domain-containing proteins. PHB genes widely exist in a broad spectrum of species ranging from prokaryotes to eukaryotes [1–4]. Depending on the subcellular localization and other factors, PHB genes could be involved in important but diverse biological functions . In human, PHB genes were found to be associated with the breast cancer phenotype, where PHB localizes in the nucleus of some breast cancer cell lines as a transcriptional regulator interacting with E2F, P53, and retinoblastoma (Rb) to regulate the expression of downstream genes. PHB gene can therefore serve as a tumour suppressor regulating cell-cycle progression and apoptosis [6–9]. Besides cell nucleus, PHBs were also found in lipid raft, an important component of cell membrane [1, 2, 4, 6–11]. The plasma membrane PHBs were believed to serve as a target for small molecules in the inflammatory responses and to regulate the iron channels and membrane receptor [12–14]. Overall, PHB genes play important roles for various biological processes and are associated with different disease phenotypes.
Despite the diverse biological functions, most of molecular level studies for PHB genes were focused on their roles in mitochondria. In yeast and mammalian cells, PHB1 and PHB2 are highly homologous subunits that can interact with each other as a complex [15–17]. The assembled complex with 12 to 16 heterodimers is anchored to the mitochondrial inner membrane to play potentially diverse functions as indicated in various publications. PHB complex could interact with m-AAA protease to regulate the degradation of membrane proteins in mitochondria . The PHB complex could also interact with stomatin-like protein (SLP-2/Stoml2) to regulate the stability of the components of respiratory chain complexes [17, 19, 20]. PHB proteins have also been proposed to directly or indirectly interact with mtDNA to regulate the oxidative phosphorylation (OXPHOS) system and reactive oxygen species (ROS) formation, which could lead to senescence phenotype in plants and C.elegans [21–24]. In additions, PHBs might be involved in maintaining crista morphology to recruit proteins into the inner membrane [25, 26]. Overall, all of the aforementioned molecular studies suggested the regulatory function of PHB genes for cell proliferation [5, 27].
Despite the progresses in the function studies, our understanding of the gene family is still rather limited. First, the function at both molecular and pathway level needs to be better defined. Different mechanisms for gene function have been proposed, but few were thoroughly defined for linking the molecular function with biological function. Second, many members of PHB gene family were not well studied in any given species. The diverse gene expression pattern as shown in the article indicated that the member of PHB gene family could account for very diverse functions. Third, despite the previous analyses of PHB gene function in yeast, mammalian cell, and C. elegans, very few studies have been carried out in plants and prokaryotes. Recent studies indicated that PHB genes may be involved in sensence phenotype and we have also discovered the potential function of some PHB genes in growth and defense processes. In order to lay the grounds for studying PHB gene function in different species, we therefore carried out the comparative gene family analysis of this important gene family to study the evolution-functional relevance of the family.
We therefore carried out a comparative gene family analysis of PHB genes from representative species in different biological kingdoms. Phylogenetic analysis of PHB genes from different kingdoms indicated the deep evolutionary roots of the PHB genes. Horizontal gene transfer between higher and lower species has also been found. The phylogenetic analysis is further confirmed by motif pattern, intron-exon structure, and domain distribution of the gene family that PHB genes within each class generally had conserved gene structure. We then focused on the gene duplication and expression analysis in model plant species Arabidopsis. Segmental duplication is the predominant for PHB genes, which confirms that the gene family is relatively conserved. Expression pattern analysis indicated that PHB genes could involved in a variety of functions ranging from development to abiotic and biotic stress responses. Using expression pattern as an indicator for gene function, we found that paralogs often evolve different functions during the evolution. Overall, PHB gene family is a relatively conserved gene family with rather diverse gene function. The evolution-function relationship indicated that the functional study in one species could provide meaningful information for another species. The study of PHB gene functions in model species could also help to elucidate the PHB gene function in cancer, aging, immunity, and others.
Evolutionary relatedness of PHB genes in species from different biological kingdoms
The species selection for PHB gene family analysis.
number Sequence data source
Oryza sativa L.(rice)
Physcomitrella patens (moss)
Saccharomyces cerevisiae (Baker’s yeast)
Homo sapiens (Human)
However, it is notable that E.coli PHB genes and human genes shared a clade together, implicating the possible horizontal gene transfer between bacteria and amniotic ancestor. The horizontally transferred PHB orthologs might have conserved molecular functions shared between eukaryotes and prokaryotes to allow the gene retention in both bacteria and human [28, 29]. Generally speaking, based on the phylogenetic analysis of PHB genes across different species, the PHB gene are evolutionarily conserved and have deep evolutionary roots. In addition, it is also important to reveal the evolutionary mechanisms for more recent duplications.
Overall, the phylogenetic analyses revealed the seemingly contradictory phenomena, the deep evolutionary origins of the gene family and the recent expansion of the gene family. The results indicated the progressive evolution of PHB gene family because the PHB genes appears early in the evolution, but expanded at different stages during the evolution. In particular, the gene family expansion seems to continue in plant species even after the divergence between monocot and dicot, and the mechanisms for such expansion is examined in the later part of the article. The relatedness has significant functional relevance as we will discuss in the Discussion part.
Motif analysis of PHB genes across three species
Multiple sequence alignment of PHB genes
Besides the motif finding, multiple sequence alignment is another approach to identify the conserved domain for gene function. We focused on the model species Arabidopsis in the multiple sequence alignment. As a model plant with the whole genome sequence available, Arabidopsis gene functions were widely studied. Limited research has been carried out to characterize the PHB gene in plants, and Arabidopsis will serve as a good model species for plant PHB gene function studies. We therefore will focus the rest of the study in Arabidopsis.
Intron/exon structure of PHB genes
Both the gene length and intron phase correlate with the gene family classification and intron numbers to a certain degree. Intron phase 0, 1, and 2 referred to the splicing occurred after the first, second, and third nucleotide of the codon, respectively. As shown in Figure 5, genes with similar intron/exon structures and gene length also had conserved splicing phase patterns [41, 42]. A comparative analysis of human and C. elegans intron/exon structure revealed much more introns in these two species as shown in Additional File 1 and 2. The results indicated that the PHB genes in Arabidopsis may have experienced fewer intron birth events as compared to the species in animae kingdom. Overall, the motif distribution, intron/exon structure, and the conserved domain all correlate well with the phylogenetic analysis and relatedness of the genes [38, 40, 43].
Duplications of PHB genes in Arabidopsis
Besides the segmental duplications, one tandem duplication event was also found on chromosome 5. At5g25250 and At5g25260 were two genes with high similarity of DNA sequence and only 1Kb distance on the chromosome. It is very likely that the gene duplication is due to gene jumping mediated by a transposon . Overall, the gene duplication pattern indicated that segmental duplication is predominant for the PHB genes and tandem duplication is also involved. The gene duplication pattern correlates very well with the relatedness of the gene.
Expression patterns of PHB genes in Arabidopsis
As aforementioned, PHB genes may be involved in diverse gene functions. In order to better understand the PHB gene functions and their relevance to gene evolution, we investigated the gene expression level of PHB genes with Arabidopsis as the model species. The gene expression analysis included both the digital gene expression pattern using Genevestigator and the actual real-time PCR experiments.
Nine development stages were surveyed for the digital gene expression analysis. Generally speaking, PHB genes show significant variations for gene expression in terms of both the expression levels and presence at different conditions (Figure 7A). In addition, no significant gene expression pattern and phylogenetic analysis correlations were found. For example, At1g03860 and At4g28510/ At2g20530 could be paralogs, but they had very different expression patterns. According to the traditional gene fate evolution models, paralogs in a gene family usually have divergent expression patterns, indicating the different biological functions. Because a high gene dosage is often detrimental to the organisms, one of the paralogs often evolves a new function in a process called neofunctionalization or disappears in the evolution [52, 53]. In terms of tissue-specific expression, we found that the paralog genes often have differential gene expression patterns, too (Figure 7B). The PHB genes are also responding to the biotic and abiotic stimulus treatment quite differently (Figure 7C). For example, At5g64870 is highly up-regulated when treated with abiotic stresses such as salt, cold, drought, whilst it is down-regulated under some hormones like ABA (abscisic acid), MeJA (Methyl Jasmonate), GA (gibberellins) and so on. However, other PHB genes did not have similar expression pattern under these treatments.
Overall, the gene expression pattern indicated that PHB genes are involved in diverse biological functions and most of the PHB genes evolve new functions after the gene duplication, which is in contrary to some of the fast expanding gene families like terpene synthase gene family.
Despite the ubiquitous presence of PHB genes in prokaryotes to eukaryotes, the function and evolution of PHB genes have not been thoroughly studied. Most studies of PHB genes focused on individual gene functional analysis in yeast, mammalian, C. elegans and some plants[1–4, 23]. Gene family analysis has become a major approach to study the gene function, evolution, and structure. The comparative analysis of gene family across multiple species allowed us to investigate how the various functions of the gene family members were evolved and how the gene structure was relevant to function [54, 55]. The basic hypothesis is that conserved genes in form of orthologs often have similar functions and structures. The gene family expansion is also relevant to the interaction with herbivore or pathogens. For example, most of the plant gene families involved in insect defense like terpene synthase, cytochrome p450(CYP), WRKY gene families experienced recent and rapid evolution, partially due to the evolutionary competition with insect for chemical defense [55–57]. The analysis of the relevance of gene structure and evolution will allow us to understand how new function of a gene family member evolved and developed. Our results highlighted that PHB genes consist of a conserved family with deep evolutionary root yet diverse biological and molecular functions. The comparative analysis elucidated the evolutionary features of the PHB gene family and helped to guide our further gene function analysis and the study of PHB gene's relevance to human diseases.
Evolution of PHB gene family
Comprehensive and concrete evolutionary analysis of PHB gene family is lacking. In order to investigate the evolution of PHB genes and the evolution-function relationship, we carried out a comprehensive phylogenetic and motif analysis of PHB genes from representative species in different kingdoms. In addition, we focused on the model plant Arabidopsis for further gene structure, duplication, and expression pattern analysis. Our results highlighted several features of PHB gene evolution.
First, the phylogenetic and gene structure analysis of PHB genes indicated that PHB genes are relatively conserved across different species. Most of the PHB genes within a class or subclass shared similar motif structure across plant and animal species. The intron/exon structure and domains for the genes within the same class or subclass are also conserved. Generally speaking, the PHB genes within a class or subclass share clades following the evolutionary lineage. Second, the PHB genes have deep evolutionary origins, where some homologs can even trace back to prokaryote species. The divergence of different class or subclass of PHB genes happened very early in the evolution, and some at prokaryote stage. The deep evolutionary root and conserved evolution both indicated that the PHB genes could account for some conserved molecular functions. Third, the conserved and important function can also be reflected in the gene duplication and functional divergence. Several mechanisms are involved in PHB gene family expansion. Horizontal gene transfer was also indicated between human and prokaryote. In model plant Arabidopsis, some PHB genes had early expansion across species in plants, and they usually have common ancestor before the species diverge . However, most of the gene family expansion was due to the segmental duplication in Arabidopsis. Tandem duplication thus exists but is rear. The pattern is different from some dynamic gene families like Terpene Synthase, P450 and WRKY [54, 58]. The results indicated that PHB genes are not much involved in the competitive evolution for chemical defense and its regulation. In fact, most of the duplicated PHB genes evolved rather different expression pattern, indicating potentially new biological function [52, 53]. The result is also different from some other gene families that different gene fates exist together [54, 58]. It is generally believed that plants can be tolerant to a much higher gene dosage effect as compared to animals. The fact that most of PHB gene duplications end up with paralogs with potentially different functions indicated that PHB genes would be involved in some important biological processes.
Function of PHB gene family
The PHB gene evolution generally reflected the family’s conserved but diverse functions. From a molecular perspective, PHB genes were reported to be involved in cell-cycle progression, iron channel regulation, receptor medicated signaling, and the control of respiratory chain in mitochondria [1, 5, 17, 26]. From a biological perspective, PHB genes were related to aging and senescence in mammalian, yeast, and C.elegans [24, 59, 60]. More importantly, they can be associated with a variety of disease states including inflammation, obesity, and cancer . However, more research still need to be carried out to provide confirmative evidence to link molecular functions to biological functions.
We explored the gene expression pattern of PHB genes in model plant Arabidopsis to derive the functional relevance and evolution-function relationship of PHB genes. Despite the tremendous amount of research in Arabidopsis, very few reports were published for the function of PHB family genes. The limited previous studies indicated that PHB genes could be involved in development, senescence, hormone signaling and stress responses [22, 23, 61–63]. From our expression analysis results, we found that PHB genes have very diverse expression patterns in different development stages and tissues, as well as under different stimulus. The results highlighted the potential diverse biological function of PHB genes. In particular, the evolutionary pressure kept the PHB gene motif structure and intron/exon structure conserved during the evolution within each class or subclass. However, the same evolutionary pressure also seems to force the paralogs to evolve differential regulations with potentially roles for different biological processes. Much more comprehensive work needs to be carried out to study the function of PHB genes at different levels, which will also be important for the disease-related studies.
Comparative analysis for disease study
The functional study will help to elucidate the role of PHB genes in cancer, aging, immunity, neuron degeneration and such. It was widely recognized that PHB genes played crucial roles in various human diseases [5, 12, 17]. Mishra et al. has reviewed the diverse localization, function and disease association of PHB genes . PHB1 is also known as B-cell-receptor-associated protein 37 (BAP 37) and the 3’-UTR region of the mRNA was shown be relevant to the breast cancer phenotype [17, 27]. Despite the diverse function, studies has only been focused on how PHB1 and PHB2, the first two genes found, are relevant to diseases [5, 13, 14, 64, 65]. Our comparative analysis indicated the diverse function of the gene family and the relatively conserved gene structure. The study indicated that the molecular function of PHB genes can be much more thoroughly studied in the model species that genetic tools are more readily available than human. Because of the conserved motif pattern and potential molecular function, the studies in the model species can be readily translational to the human and mammalian studies.
PHB family genes are evolutionarily conserved across multiple species in the biological kingdom from our phylogenetic analysis. Gene structure and motif distributions were consistent with the evolutionary relatedness of PHB genes in Arabidopsis. Different duplication events are involved for gene family expansion, especially the segmental duplications in Arabidopsis. Horizontal gene transfer could also be involved in the birth of new genes in higher organisms. Even though PHB genes are important for a core group of molecular functions and are conserved during evolution, the members of the gene family have evolved to have very diverse biological functions in development and biotic or abiotic stress responses.
Materials and methods
Sequence retrieval and gene family member identification
Protein sequences were first acquired from http://www.ebi.ac.uk/interpro/ under the accession PR001107 Band_7. All sequences downloaded were searched against species specific databases with BLASTP algorism using default parameters. Redundant sequences with different accession numbers in EMBL-EBI yet the same locus id in their specific database were discarded. For example, Arabidopsis protein sequences were retrieved from TAIR http://www.arabidopsis.org/; Rice protein sequences were retrieved from TIGR http://rice.plantbiology.msu.edu/; others data source were as shown in Table 1.
Eleven species including five spermatophytes, chlorophyte, bryophyte, nematoda, bacteria, fungi and mammalian were analyzed in this study.
Multiple sequence alignment and phylogenetic analysis
Protein sequences from different species were selected, multiple sequence alignment was performed by ClustalX (1.83) software, and the alignment result was then imported into GeneDoc (http://www.nrbsc.org/gfx/genedoc/index.html) for further visualization.
The phylogenetic tree was built by MEGA4.0 software [34, 66]. The Neighbor-Joining method was used with the following parameters: pairwise deletion of gaps/missing data; poisson correlation of model; bootstrap 1000 replicates, random seed of phylogeny test. Only clades with the bootstrap value higher than 50 were selected for the bootstrap consensus tree [42, 67].
Intron/exon structure and motif analysis
Arabidopsis PHB gene CDS (Complementary DNA Sequence) and genomic sequences were used to derive intron/exon structure with the online tool Gene Structure Display Server (http://gsds.cbi.pku.edu.cn/chinese.php) . Conserved motif structures within PHB domain for Arabidopsis genes were analyzed by MEME4.3.0 (Multiple Expectation Maximization for Motif Elicitation) with the following parameters; distribution of motif occurrences: any number of repetitions; number of different motifs: 20; minimum motif width: 6; and maximum motif width: 50 [31, 32].
Chromosomal distribution and duplication analysis
Arabidopsis PHB genes’s location on chromosome was mapped by the Chromosome Map Tool at TAIR (http://arabidopsis.org/jsp/ChromosomeMap/tool.jsp). “Paralogons in Arabidopsis thaliana” was used for detecting segmental duplication protein pairs in the recent and old duplication blocks on chromosomes separately, default parameters were set [40, 44, 45]. Only the blocks contained PHB genes were retained, and genes detected were then mapped on the chromosomes and linked to each other by lines manually.
Digital expression pattern analysis
To investigate PHB genes expression profiling in Arabidopsis, Genevestigator V3 (https://www.genevestigator.com/gv/index.jsp) was used . Public high quality AtGenExpress ATH1-22k microarray data was chosen. Meta-profile analysis and hierarchical clustering were used to study gene expression at different development stages, in anatomical tissues and under different stimulus.
Plant growth, RNA extraction and real-time PCR experiments
Arabidopsis thaliana (Col-0) plants were grown under 12h light/ 12h dark photoperiod in a controlled environment chamber, 23 C at day time, 20 C at night. Specific tissues including root, stem, cauline leaf, rosette leaf and flower of six week old seedlings were collected, total RNA was extracted with RNeasy Plant Mini Kit (Qiagen).First strand cDNA was synthesized from 2ug RNA with SuperScript™ III Reverse Transcriptase (Invitrogen), then diluted to 2ng/ul. Primer sequences were designed by Primer Express3.0 (Additional File 3). Real-time PCR reaction was carried out with SYBR Green Master Mix (Applied Biosystems) according to the manufacture’s instruction. ABI 7900 sequence detection system was used. Data analysis was used MeV v4.5.1 followed the method of Xu et al., 2009 .
The research is supported by the start up fund from Texas Agrilife Research to JSY and the Chinese Overseas Scholarship for DC and ZS. We appreciated that Ryan Syrnne helped to proof-read the article.
This article has been published as part of BMC Bioinformatics Volume 11 Supplement 6, 2010: Proceedings of the Seventh Annual MCBIOS Conference. Bioinformatics: Systems, Biology, Informatics and Computation. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2105/11?issue=S6.
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