Bioinformatics Advance Access originally published online on July 31, 2006
Bioinformatics 2006 22(20):2577-2579; doi:10.1093/bioinformatics/btl422
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Sebida: a database for the functional and evolutionary analysis of genes with sex-biased expression
1 Max Planck Institute of Biochemistry, Am Klopferspitz 18 82152 Martinsried, Germany
2 Department of Biology, University of Munich (LMU) Grosshaderner Strasse 2, 82152 Planegg-Martinsried, Germany
*To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDATABASE CONTENTRESULTS AND DISCUSSIONREFERENCES |
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Summary: We describe Sebida, a database of genes with sex-biased expression. The database integrates results from multiple, independent microarray studies comparing male and female gene expression in Drosophila melanogaster, Drosophila simulans and Anopheles gambiae. Sebida uses standard nomenclature, which allows individual genes to be compared across different microarray platforms and to be queried by gene name, symbol, or annotation number. In addition to ratios of male/female expression for each gene, Sebida also contains information useful for evolutionary studies, such as local recombination rate, degree of codon bias and interspecific divergence at synonymous and non-synonymous sites.
Availability: Sebida can be accessed at http://www.sebida.de
Contact: gnad{at}biochem.mpg.de
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDATABASE CONTENTRESULTS AND DISCUSSIONREFERENCES |
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In sexually reproducing species, males and females typically differ in many morphological and behavioral traits. Because sex-specific chromosomes (e.g. the Y chromosome) are typically highly heterochromatic and contain few genes, almost all intersexual differences arise through the differential expression of genes that are physically present in both sexes. With the advent of microarray technologies, it has become possible to detect such sexual dimorphism in gene expression on a genome-wide scale. For example, one of the first applications of microarrays in Drosophila melanogaster was to quantify expression differences between males and females (Jin et al., 2001). Since then, numerous studies have compared gene expression between the sexes in D.melanogaster and other insect species, such as Drosophila simulans and Anopheles gambiae (Arbeitman et al., 2002; Parisi et al., 2003; Ranz et al., 2003; Gibson et al., 2004; Stolc et al., 2004; Hahn and Lanzaro, 2005). These studies revealed that a large fraction of genes in the genome show sex-biased expression. Indeed, depending on the experimental and statistical methods used, up to 60% of genes show significant expression differences between the sexes.
In addition to their obvious interest for developmental biologists studying sexual differentiation, genes with sex-biased expression are also of great interest to evolutionary biologists. This is because they may be enriched for adaptively evolving genes that are subject to forces such as sexual selection or intersexual co-evolution. It is now well documented that sex-biased genes, particularly those with a male expression bias, tend to evolve rapidly in both expression level and DNA/protein sequence (Ranz et al., 2003; Zhang et al., 2004) and there is growing evidence that much of this rapid evolution may be attributable to positive selection (Swanson and Vacquier, 2002; Zhang and Parsch, 2005).
Although data from many microarray studies comparing male and female gene expression in D.melanogaster and other species are available, there is no central resource that presents these data in a format that easily can be compared among experiments or that allows one to access the data on a gene-by-gene basis. This is particularly needed because many experiments use different platforms, nomenclature and analysis methods. Thus, it is difficult to perform meta-analyses on data present in central repositories, such as the Gene Expression Omnibus, or from results presented in the literature. To enable such comparisons, we present Sebida (sex bias database), a database that integrates data from multiple microarray studies comparing male versus female gene expression in D.melanogaster, D.simulans and A.gambiae. In addition to the ratio of male to female expression for each gene, Sebida provides information useful for evolutionary studies, including measures of recombination, codon bias and interspecific divergence.
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DATABASE CONTENT |
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TOPABSTRACTINTRODUCTIONDATABASE CONTENTRESULTS AND DISCUSSIONREFERENCES |
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For D.melanogaster, Sebida includes male versus female gene expression data from experiments using four different microarray platforms. The first was constructed from
6000 cDNAs and was used for competitive hybridizations of cDNA derived from whole males and females (Ranz et al., 2003). The second platform contains 14 000 PCR amplicons corresponding to exons of each gene in genome release 1.0. These arrays were used for competitive hybridizations of cDNA derived from dissected testes and ovaries (Parisi et al., 2003). Additional experiments with these arrays compared expression between whole males and females, gonadectomized males and females and tudor mutants, which lack germline tissues (Parisi et al., 2004). The third platform is constructed of 60mer oligonucleotide probes designed to 13 000 genes in genome release 3.0. These arrays were used to compare gene expression between whole males and females of two different D.melanogaster strains, as well as their hybrids (Gibson et al., 2004). The final platform is a genome-tiling array of 36mer oligonucleotide probes covering both coding and non-coding regions of the genome, including exons of 13 000 genes. These arrays were used to assay expression levels at several developmental stages, including mature adults of both sexes (Stolc et al., 2004). In addition to the D.melanogaster expression data, Sebida also includes male versus female expression data from D.simulans and A.gambiae. For D.simulans, the hybridizations were performed using the cDNA platform described above. In this case, all genes are assumed to be orthologs of D.melanogaster genes, and are indexed under the same name, symbol and CG number. The A.gambiae data come from experiments using Affymetrix microarrays (Hahn and Lanzaro, 2005). These genes are indexed under their Affymetrix gene ID and their Ensembl transcript number.
Male-, female and non-sex-biased genes are known to differ in a number of evolutionary parameters, such as degree of codon bias and rate of molecular evolution. For this reason, we also provide measures of codon bias and interspecific divergence. Codon bias was estimated using two methods: frequency of optimal codon usage (Fop) and effective number of codons (ENC). To estimate rates of synonymous and non-synonymous substitution, we developed a pipeline to find and align coding regions between D.melanogaster and three other Drosophila species, D.simulans, D.yakuba, and D.pseudoobscura. We then used the PAML software package (Yang, 1997) to calculate non-synonymous and synonymous divergence (dN and dS, respectively). A diagram of the alignment pipeline is linked to the Sebida website. Finally, because local recombination rate is known to correlate with factors such as degree of codon bias and evolutionary rate, we have included estimates of local recombination rate for each gene in the D.melanogaster genome.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONDATABASE CONTENTRESULTS AND DISCUSSIONREFERENCES |
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For D.melanogaster, where the different microarray experiments often differed in gene number and/or the male/female expression ratio of the common genes, we used three different approaches to extract ‘high quality’ sets of sex-biased genes. First, we used a 2-fold cut-off to define sex-biased genes and required that a gene show the same bias in at least two of three datasets (Ranz et al., 2003; Parisi et al., 2003; Gibson et al., 2004). This resulted in the classification of 695 male-, 789 female- and 4033 non-sex-biased genes. The second approach used the above consensus strategy, except that instead of a 2-fold cut-off, we used a P-value cut-off for each dataset that corresponded to a false discovery rate (FDR) of 10%. This resulted in 1253 male-, 883 female- and 1585 non-sex-biased genes. Finally, we performed a meta-analysis by applying a Bayesian method (Townsend and Hartl 2002) to the genes shared among the three datasets, again using an FDR of 10%. Of the 2266 common genes, we classified 174, 538 and 1554, as male-, female- and non-sex-biased, respectively. Complete details of the above analyses, as well as downloadable files for each high-quality gene set are available on the Sebida website.
To illustrate the utility of Sebida, we used the 2-fold cut-off gene set for several evolutionary genomic analyses. For example, a BLAST search of the D.melanogaster genome revealed that male-biased genes were most likely to have paralogs (defined as having a BLASTp match with E < 10–9 over at least 70% of the protein length; Fig. 1a). This suggests that they have a higher duplication rate than other genes or that their duplicates are more often maintained by selection. Male-biased genes also showed the greatest divergence between species (Fig. 1b) and the least codon bias (Fig. 1c). These results are consistent with previous studies that used different collections of sex-biased genes (Zhang et al., 2004; Hambuch and Parsch, 2005). In contrast to the former study, we find that female-biased genes evolve faster than non-sex-biased genes. This difference probably is owing to the larger sample size in the current study and the fact that the previous study was limited to EST sequences, which were enriched for highly-expressed genes.
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Acknowledgments |
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The authors thank J. Baines, A. Bauer-Mehren, J. Ranz, N. Stoletzki and two anonymous reviewers. This work was supported by Deutsche Forschungsgemeinschaft grant PA 903/2.
Conflict of Interest: none declared.
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FOOTNOTES |
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Associate Editor: Martin Bishop
Received on April 26, 2006; revised on July 12, 2006; accepted on July 28, 2006
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REFERENCES |
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TOPABSTRACTINTRODUCTIONDATABASE CONTENTRESULTS AND DISCUSSIONREFERENCES |
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Arbeitman, M.N., et al. (2002) Gene expression during the life cycle of Drosophila melanogaster. Science, 297, 2270–2275
Gibson, G., et al. (2004) Extensive sex-specific nonadditivity of gene expression in Drosophila melanogaster. Genetics, 167, 1791–1799
Hahn, M.W. and Lanzaro, G.C. (2005) Female-biased gene expression in the malaria mosquito Anopheles gambiae. Curr. Biol, . 15, R192–193[CrossRef][Web of Science][Medline].
Hambuch, T.M. and Parsch, J. (2005) Patterns of synonymous codon usage in Drosophila melanogaster genes with sex-biased expression. Genetics, 170, 1691–1700
Jin, W., et al. (2001) The contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. Nat. Genet, . 29, 389–395[CrossRef][Web of Science][Medline].
Parisi, M., et al. (2003) Paucity of genes on the Drosophila X chromosome showing male-biased expression. Science, 299, 697–700
Parisi, M., et al. (2004) A survey of ovary-, testis-, and soma-biased gene expression in Drosophila melanogaster adults. Genome Biol, . 5, R40[CrossRef][Medline].
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Stolc, V., et al. (2004) A gene expression map for the euchromatic genome of Drosophila melanogaster. Science, 306, 655–660
Swanson, W.J. and Vacquier, V.D. (2002) The rapid evolution of reproductive proteins. Nat. Rev. Genet, . 3, 137–144[Web of Science][Medline].
Townsend, J.P. and Hartl, D.L. (2002) Bayesian analysis of gene expression levels: statistical quantification of relative mRNA level across multiple strains or treatments. Genome Biol, . 3, RESEARCH0071.
Yang, Z. (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. CABIOS, 13, 555–556.
Zhang, Z., et al. (2004) Molecular evolution of sex-biased genes in Drosophila. Mol. Biol. Evol, . 21, 2130–2139
Zhang, Z. and Parsch, J. (2005) Positive correlation between evolutionary rate and recombination rate in Drosophila genes with male-biased expression. Mol. Biol. Evol, . 22, 1945–1947
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