*Department of Biochemistry and Molecular Biology, University of Oviedo, Oviedo, Spain;
Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland
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Abstract |
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Introduction |
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Annexin A13 (ANXA13) harbors key information about the evolutionary origins and structure-function relationships of the A family of 12 chordate annexins. It is the earliest branching subfamily in vertebrates and is physically nonsyntenic from other human annexins (Braun et al. 1998
; Morgan et al. 1998
). The short isoform of the human protein has a very restricted, intestine-specific expression (Wice and Gordon 1992
), and a longer isoform identified in dog exhibits differential subcellular targeting in polarized kidney epithelial cells (Fiedler et al. 1995
). Expression is observed mainly in small intestine in committed proliferating crypt epithelia and in differentiated villus enterocytes, where it is selectively transported to the apical region (Noda et al. 2001
). It has been proposed that annexin A13 may play a crucial role in the lipid raft-mediated delivery of apical proteins (Lafont et al. 1998
) and that the different isoforms show regional and cofactor specificity in their actions (Lecat et al. 2000
; Plant et al. 2000
). Despite these comprehensive localization studies, further study has been impeded by the low detectability, uncertainty about the relationship between subcellular location and activity, and imprecise understanding of the protein functional determinants, based on limited cDNA sequence data for human and dog.
A cross-genome survey can provide insight and perspective into protein structure-function relationships as well as gene organization, chromosomal environment, species distribution, and evolutionary origin. Phylogenetic analysis of primary sequence conservation is of fundamental value for identifying divergence patterns and functionally important protein residues because these are under selective evolutionary constraint. Computational sequence analysis calibrated to species fossil records can provide confirmatory estimates of evolutionary order, rates, and ages of gene family members. The annexin A13 gene structure is of special interest because it could clarify the initial gene duplication order of this family by its (non)congruency to the other primary clade members, annexin A7 (Shirvan et al. 1994
) and annexin A11 (Bances et al. 2000
). Interspecies homology is being recognized as a useful tool for identifying conserved promoter regions by phylogenetic footprinting of the regulatory elements responsible for tissue-specific expression (Wasserman et al. 2000
). The map location of ANXA13 in human chromosome 8q24 was originally determined using cytogenetic techniques (Morgan et al. 1998
), but comparative species maps are needed to assess chromosomal paralogy. This could help document the evolutionary history and physical integrity of this chromosomal region, confirm primitive species orthologs, and evaluate this locus for genetic traits being investigated by positional cloning. The ancient origins of vertebrate annexins demand a comprehensive analysis of all available molecular markers revealed by sequence phylogeny, gene structures, genetic maps, and divergence parameters to assess the temporal order of initial gene duplications.
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Methods |
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Identification and Sequencing of Genomic Clones
Genomic sequences for human annexin A13 were obtained from two bacterial artificial chromosome clones (CIT-HSP 2334P3 and RPCI11 138L10). These were identified by TBLASTN searches of the BAC-end database (URL http://www.tigr.org) against the annexin A13 protein sequence and supplied by Research Genetics. Genomic fragments containing portions of the annexin A13 gene were generated with appropriate restriction enzymes, identified by cDNA hybridization, subcloned, and sequenced. Mouse genomic clones for annexin A13 were obtained from a mouse 129/SVJ genomic library prepared from spleen DNA ligated to FIX II vector (Stratagene, La Jolla, Calif.). Random-primed [32P]-labeled cDNA for mouse annexin A13 was used for hybridization. Screening procedures, DNA isolation, restriction analysis, gel electrophoresis, Southern blot transfer, and hybridization were performed as described (Sambrook, Fritsch, and Maniatis 1989
). Genomic fragments were subcloned and sequenced by the dideoxy chain termination method.
Human Cell Cultures
The human colon adenocarcinoma cell line HT-29 was obtained from Dr. Dario Acuña (University of Granada, Spain), and cultures were grown in Dulbecco's modified minimal essential medium containing 10% dialyzed fetal bovine serum plus either 25 mM glucose (for rapid proliferation) or 2.5 mM inosine (to induce differentiation). Multipotent HT-29 cells grown in the presence of inosine and absence of glucose were cultured for at least four passages before use. Cells were harvested for RNA preparation at log phase, 3 to 4 days after plating, to perform reverse transcriptionPCR (RT-PCR) reactions for extending cDNA ends by using the SMART RACE amplification kit (Clontech).
Interspecific Mouse Backcross Mapping
Interspecific backcross progeny were generated by mating (C57BL/6J x Mus spretus) F1 females and C57BL/6J males as described (Copeland and Jenkins 1991
). A total of 205 N2 mice was used to map the Anxa13 locus. DNA isolation, restriction enzyme digestion, agarose gel electrophoresis, Southern blot transfer, and hybridization were performed essentially as described (Jenkins et al. 1982
). All blots were prepared with Hybond N+ nylon membrane (Amersham). The pA13M probe was a 950-bp fragment containing the coding region of mouse annexin A13 cDNA, excised with BamHI/SalI and labeled with [
-32P]dCTP using a random primed labeling kit (Stratagene). Washing was done to a final stringency of 0.8x saline/sodium citrate/phosphate (SSCP) and 0.1% sodium dodecyl sulfate at 65°C. Fragments of 13.5, 5.1, 4.4, 3.2, 2.6, 2.4, and 1.2 kb were detected in SphI-digested C57BL/6J DNA, and fragments of 9.2, 4.7, 3.2, 2.6, 2.4, and 1.2 kb were detected in SphI-digested M. spretus DNA. The presence or absence of the 9.2- and 4.7-kb SphI M. spretusspecific fragments, which cosegregated, was followed in backcross mice. The probes and restriction fragment length polymorphisms (RFLPs) for the loci linked to Anxa13 in mouse, including syndecan2 (Sdc2), myelocytomatosis oncogene (Myc), and thyroglobulin (Tgn) have been reported previously (Brannan et al. 1992
; Spring et al. 1994
). Recombination distances were calculated using Map Manager, version 2.6.5. Gene order was determined by minimizing the number of recombination events required to explain the allele distribution patterns.
Bioinformatics
Computer programs used in this study included the FASTA package (Pearson 1990
) for general sequence comparison, LI93 (Li 1993
) for calculation of nucleotide substitutions, TREE-PUZZLE 5.0 (Strimmer and von Haeseler 1996
) for maximum likelihood analysis, and PHYLIP 3.6a2.1 (Felsenstein 1989
) for maximum parsimony. Public net-server programs included BLAST searches of the various sequence databases maintained at the National Center for Biotechnology Information (NCBI, Bethesda, Md; URL http://www.ncbi.mln.nih.gov) and the European Bioinformatics Institute (EBI, Hinxton, UK; URL http://www.ebi.ac.uk). MatInspector (Quandt et al. 1995
) was used for promoter site detection against the TRANSFAC 4.0 database (Heinemeyer et al. 1999
), and RepeatMasker (URL http://ftp.genome.washington.edu/RM/RepeatMasker.html) identified genomic repetitive elements from REPBASE (Jurka 1998
). Mouse genetic map data came from the Mouse Genome Database maintained by Jackson Laboratories (Massachusetts) at ftp://ftp.informatics.jax.org/pub. Zebrafish genetic map data (Postlethwait et al. 2000
; Woods et al. 2000
) were retrieved from the Stanford University database, URL http://cmgm.stanford.edu/
tallab/Frontpage.html.
Public domain EST sequences for annexin A13 were identified and further characterized from the following species and clone source identification numbers: Bos taurus (Bta, cow, gb:BF604919), D. rerio (Dre, zebrafish A13.1 gb:BF938344 and AI437290, zebrafish A13.2 gb:BI845312), Sus scrofa (Ssc, pig, gb:BF198997), and Xenopus laevis (Xla, African clawed frog, gb:BE509061). Genomic sequence data for human chromosome 8 BAC clones RP11-562D1 and RP11-1A23 from the Human Genome Project (HGP 2001)
were deciphered to identify all intact exons and splice sites for the human annexin A13 gene. Homologous Rattus norvegicus (Rno, Norway rat), mouse, and zebrafish exons were matched by BLAST searches of the TRACE draft sequence databases using full-length cDNAs. Genomic annexin A13 sequence from Tetraodon nigoviridis (Tni, pufferfish, gb:AL279602, Genoscope, France) was identified in the database of Genome Survey Sequences (dbGSS) and characterized for exon splice sites by comparison with zebrafish cDNA. Strongylocentrotus purpura (Spu, purple sea urchin) clones 1012-16-M and 14-7-I from the sea urchin genome project (Cameron et al., California Institute of Technology, personal communication) were identified from dbGSS. Other genus-species names for taxa included in the phylogenetic analysis include Ascaris suum (Asu), Arabidopsis thaliana (Ath), Crassostrea virginica (Cvi), Caenorhabditis elegans (Cel), Dictyostelium discoideum (Ddi), Drosophila melanogaster (Dme), Giardia intestinalis (Gin), Hydra vulgaris (Hvu), Neurospora crassa (Ncr), Schistosoma japonicum (Sja), and Schistosoma mansoni (Sma).
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Results |
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Unique Organization of the Annexin A13 Gene
The full-length cDNAs obtained for human and mouse annexin A13 could now be applied to elucidation of the structural organization of the annexin A13 gene, by selective sequencing and analysis of human and mouse genomic clones and comparison with genomic sequence data from public sequencing projects. All intact exons and splice sites were identified in the human gene (table 1
). The 12 coding exons of annexin A13 span 58 kb of genomic sequence, the longest annexin gene after A10. Primer extension and 5' RACE were performed on RNA obtained from mouse intestine and from human colon adenocarcinoma HT-29 cells grown in inosine to confirm the absence of an untranslated primary exon typically present in other annexin genes and to establish the limit of the transcribed region with respect to the nontranscribed, upstream region. Introns are all phase 0 or 1, analogous to the codon insertion positions in other annexins, and they vary in size from 106 bp (intron 6) to 23 kb (intron 2). The 3' terminus contains two variant polyadenylation signals (AATTAAA), and EST statistics indicate only a modest preference for the more distal downstream site. Similar polyadenylation sites and frequencies were observed in mouse cDNA sequences obtained by 3' RACE and represented in 19 ESTs. Mouse and rat annexin A13 genomic clones contain identical exon splice sites (fig. 2
), although cassette exon-intron 2 remain incompletely defined. A genomic clone from pufferfish (Roest-Crollius et al. 2000
) spanned exons 7 through 11, and, together with numerous zebrafish genomic TRACE sequences, fish annexin A13 exhibits gene structure congruency in the tetrad core region (fig. 2
) but with much smaller introns, typically less than 100 bp.
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Regulatory Regions of Annexin A13
Our full-length human and mouse cDNAs (gb:AJ306450, AJ306451) assessed by 5' RACE provided reasonable assurance that we had approached the limits of the transcribed region, but the determination of further upstream homology in orthologous genes is a presumptive indicator of regulatory conservation (Wasserman et al. 2000
). We therefore isolated and sequenced mouse genomic clones containing the putative promoter region and identified homologous rat sequences in the RATTRACE database. These verified strong homology conservation with the human counterpart and confirmed the retention of certain elements that have been implicated in gastrointestinal gene expression (fig. 3
). The identification of cis-element binding sites for putative transcription factors in the promoters of highly expressed annexins has generally been of uncertain value in the absence of direct functional studies, but such predictions can be valuable guides for promoter analysis of a tightly regulated, tissue-specific gene such as annexin A13. We used MatInspector (Quandt et al. 1995
) to detect transcription factor binding sites with high compatibility (>80%) to sequence matrices. Quite remarkably, the numerous potential binding sites for CDX2, hepatic nuclear factor HNF1, related winged helix/forkhead transcription factors FREAC and XFD, Kruppel factor GKLF, and GATA3, read like a model gene promoter for gastrointestine-specific gene expression. In particular, the homeodomain transcription factor and tumor suppressor CDX2 has a well-defined synergistic role with HNF1 in gut organogenesis and functional maintenance (Mitchelmore et al. 2000
), including a temporal and spatial expression very similar to annexin A13 (Silberg et al. 2000
). Annexin A13 clearly has an AT-rich promoter (65% from bp -1,000 to +100 in human) and an unusually low CpG dinucleotide content (0.8%) suggestive of methylation-mediated decay, both compatible with the putative binding sites for these particular transcription factors. This contrasts with other annexin promoters characterized as GC-rich and replete with Sp1 binding sites (Fernandez et al. 1994
; Bances et al. 2000
; Carcedo et al. 2001
).
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Genomic Environment of ANXA13
The draft sequence containing and surrounding annexin A13 in the human genome (HGP 2000) permitted the identification of internal repetitive elements and external gene neighbors that might bear on this gene's regulation, function, and evolutionary history. Two HGP BAC clones have been positioned in contig CTG17737 by the Washington University Genome Sequencing Center and in the NCBI annotation contig NT_008157. Introns of this 58-kb gene sequence contain numerous repetitive elements (fig. 4
), including 17 Alu and 22 mammalian interspersed repeat short-interspersed repetitive elements, 11 L1, five L2, and one L3 long interspersed nuclear elements (LINEs), 11 MaLR and two endogenous retrovirus long terminal repeats, and 11 simple microsatellite repeats. Their significance in gene function, diagnostics, and evolution remains to be determined. BLAST searches of mapped genes against this contig localized other genes in the immediate proximity of chromosome 8q24.12, including a zinc finger homeodomain transcription factor, ZHX1, squalene epoxidase, SQLE, and several predicted open reading frames for unidentified genes MGC3067, FLJ10204, and KIAA0493 (fig. 4
). These genes await functional characterization to determine whether they share regulatory or functional features in common with annexin A13. As closely linked genes, they can serve to verify orthologous regions in other species genomes and may ultimately help to identify an invertebrate ancestor of annexin A13.
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Evolutionary Separation of Annexins A7 and A11 from A13
Phylogenetic analysis was used to confirm annexin A13 orthology for the nine representatives described in figure 1
, whereas sea urchin and urochordate annexin(s) achieved only weak association with invertebrate ANXB members intermediate between annexins A13 and A7 (results not shown). However, the coincidence of exon splice sites for sea urchin and urochordate genomic sequences with annexins A7 and A13 are highly suggestive of an ancestral relationship. Whether they represent direct orthologs or a vertebrate outgroup must be determined from structural and phylogenetic analysis of their complete coding sequences. Bootstrap parsimony analysis of protein alignments comprising full-length representatives from all eukaryotic phyla portrayed the vertebrate annexin A7-A11 bifurcation as the most evolved pair in a protist annexinrooted tree (fig. 6A
). The annexin A13 orthology group branched from a more basal position amidst nonvertebrate members of the animal ANXB family but later than ANXC-fungi, in agreement with a previous analysis (Braun et al. 1998
). This implies that the Pro-Glyrich amino termini of A7 and A11 may not have been inherited from either ANXC1 or C. elegans nex-2 (i.e., they evolved by independent, convergent evolution) or that ANXA13 selectively lost this feature. We infer that annexin A13 possesses a higher proportion of ancestral characters, and its exon splice pattern, closely related to annexins A7 and A11 (fig. 2
), is consistent with the sequential, progressive evolution of all human annexins from this primary progenitor. Phylogenetic and molecular dating of annexin A13-A7-A11 separations within this base clade of the A family annexins further substantiated the fundamental importance of this concept for the origin of human annexins. Evolutionary distances between these genes were estimated by protein maximum likelihood using TREE-PUZZLE to reveal relatively longer interspecies branch lengths for annexin A13 orthologs and roughly equivalent distances of annexins A7 and A11 from their common ancestor (fig. 6B
). The former observation reflects a more rapid evolutionary rate for annexin A13, and the latter is consistent with rapid, successive duplication of annexins A7 and A11 from A13.
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Discussion |
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Although the sequential formation of annexins A13, A7, and A11 could be loosely inferred from phylogenetic analysis of coding regions, the comparative gene structures establish their direct relatedness and probable order of duplication (fig. 2
). The homology of the human, rodent, and fish annexin A13 genes (fig. 2 ) affirms a stable architecture over the latter half of this gene's lifetime, even though chromosome regional homology may be less extensive in fish versus mammal (fig. 5
). Molecular dating implies that annexins A13, A7, and A11 all existed before chordate genome expansion, so that the greatest subsequent upheaval may have been in chromosomal rearrangements, e.g., an intrachromosomal duplication of annexin A7 to A11, syntenic in human chromosome 10 and mouse chromosome 14 (Fernandez et al. 1996
; Morgan et al. 1998
). The available genetic linkage data do not, however, provide direct mechanistic evidence of a segmental chromosome duplication event involving annexins A13 and A7. The extrapolation of genetic maps and gene structures to other species should help to confirm true orthologs in simpler animal models and facilitate the study of annexin genetic function.
The presence of a coding cassette exon in annexin A13 (fig. 2 ) and the conservation of DNA cis-elements for intestine-specific trans-acting protein factors in the human and rodent promoters (fig. 3
) are significant findings. Both are relevant to the intestine-specific regulation of this gene's expression and, together with subcellular localization studies (Lafont et al. 1998
; Massey-Harroche, Mayran, and Maroux 1998
), can help define the cell conditions under which this gene is active. The specific role of promoter regulatory elements for caudal homeobox (CDX), hepatic nuclear factor (HNF), forkhead (FREAC, XFD) transcription factors, and the upstream LINE1 element should be especially pertinent to the role of annexin A13 in gut tissue development and maintenance. The limited expression of annexin A13 outside of intestine, its temporal pattern during tissue development, and comparisons with other species such as fish merit further study to determine how gene regulation is coupled to protein function.
Gene evolution and function are ultimately determined at the level of protein interactions, so that the identification of diagnostic residues for annexin A13 (fig. 1
) can be instructive for functional studies. The findings that the myristoylation site and cassette isoform are conserved in other species are relevant to the proposed apical transport function of annexin A13 in lipid rafts (Plant et al. 2000
), whereas the excess of basic residues and a potential KGD ligand for integrins pose new considerations for nuclear and membrane actions, respectively. The apparent interspecies conservation and amino terminal accessibility of this ligand are analogous to a similarly conserved and accessible KGD-RGD motif in the carboxy termini of annexins A1-A2-A9 (Morgan and Fernandez 1998
). Although the functional significance of this putative ligand requires experimental verification, such a new line of investigation could help to clarify the mechanism and specificity of annexin membranebinding interactions and their sporadic, extracellular localization. Because the intrinsic, common function of all annexins is, however, determined by the homologous tetrad core, its widespread amino acid conservation leaves open the mystery about essential domain interactions. In this regard, annexin A13 overexpression or knockout, especially in a primitive species lacking redundant annexins, offers the enhanced prospect of detecting an altered phenotype. A comprehensive view of the evolutionary genetics of the annexin gene superfamily should eventually provide an indication as to how the member genes contribute individually and collectively to the pathophysiologies and phenotypes of the species that contain them.
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Supplementary Material |
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Acknowledgements |
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Footnotes |
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Abbreviations: ANXA13, annexin A13 gene of human; Anxa13, annexin A13 gene of rodent; anxa13, annexin A13 gene of nonmammal; BAC, bacterial artificial chromosome; CDX, caudal homeobox; dbGSS, database of Genome Survey Sequences; EST, expressed sequence tag; FREAC, forkhead related activator; HNF, hepatic nuclear factor; long interspersed nuclear elements, LINEs; NNS, nonsynonymous nucleotide substitutions; RACE, 5' or 3' rapid amplification of cDNA ends; RT-PCR, reverse transcriptionpolymerase chain reaction.
Keywords: annexin gene family
gene duplication
gene organization
genetic mapping
molecular evolution
phylogenetic analysis
Address for correspondence and reprints: Maria-Pilar Fernandez, Department of Biochemistry and Molecular Biology, Edificio Santiago Gascon, University of Oviedo, E-33006 Oviedo, Spain. pfernandez{at}bioquimica.uniovi.es
.
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