The influence of duplicated sequences on chromosomal stability is poorly understood. To characterize chromosomal rearrangements involving duplicated sequences, we compared the organization of tandem repeats of the DUP240 gene family in 15 Saccharomyces cerevisiae strains of various origins. The DUP240 gene family consists of 10 members of unknown function in the reference strain S288C. Five DUP240 paralogs on chromosome I and two on chromosome VII are arranged as tandem repeats that are highly polymorphic in copy number and sequence. We characterized DNA sequences that are likely involved in homologous or nonhomologous recombination events and are responsible for intra- and interchromosomal rearrangements that cause the creation and disappearance of DUP240 paralogs. The tandemly repeated DUP240 genes seem to be privileged sites of gene birth and death.

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GENE redundancy is apparent in all sequenced genomes. In Saccharomyces cerevisiae, 30% of the genes are present in at least two copies (DUJON 1998). Different mechanisms, acting independently or in combination, have been proposed to explain the origin of the duplicated copies in eukaryotic genomes: duplication of the entire genome (WOLFE and SHIELDS 1997; LANDER et al. 2001), segmental duplications (CLARK 1994; LLORENTE et al. 2000; EMANUEL and SHAIKH 2001), and single gene duplications (SANKOFF 2001). Multigene families are thought to evolve according to two major mechanisms. Studies on tandemly repeated rRNA and U2 snRNA genes have suggested that members of a gene family do not evolve independently of each other but rather evolve in a concerted fashion (LIAO 1999). Sequences of family members become homogenized by interlocus recombination events that preserve gene function. In contrast, multigene families associated with the vertebrate immune system comply with the birth-and-death model of evolution (NEI et al. 1997), in which repeated gene duplication is followed by functional divergence, gene inactivation, or gene deletion.

The S. cerevisiae DUP240 family, which consists of 10 genes with a high level of nucleotide identity (from 50 to 98%) in the reference strain S288C, is one of the largest gene families in yeast (DUJON 1998). Members of this family are scattered on four chromosomes and arranged either as tandem repeats or as isolated genes (Figure 1; FEUERMANN et al. 1997). Five open reading frames (ORFs; YAR027w, YAR028w, YAR029w, YAR031w, and YAR033w) are tandemly repeated on chromosome I; YGL051w and YGL053w are directly repeated on chromosome VII. These loci are named tandem I and tandem VII, respectively. DUP240 orthologs have been identified only in species of the Saccharomyces sensu stricto group. Most DUP240 ORFs encode proteins of 240 amino acids with two potential transmembrane domains. Simultaneous deletion of the 10 DUP240 ORFs in strain S288C does not alter cell viability, and the Dup240 proteins are membrane associated (POIREY et al. 2002).

View larger version (28K): In this window In a new window Download PPT slide   FIGURE 1.— Genetic organization and chromosomal localization of the 10 DUP240 ORFs of the S. cerevisiae strain S288C. ORFs are represented by open boxes; arrows indicate their orientation with respect to the centromere. Percentages represent the level of nucleotide identity between the sequence units indicated by stippled areas.

 
The DUP240 gene family of yeast provides a good system to approach questions of the evolution of duplicated sequences and their influence on chromosomal stability, since its tandem repeats are potential targets for intra- and interchromosomal recombinations that could reshape the chromosome. The presence of a highly conserved sequence unit between the tandem I and tandem VII loci (Figure 1) favors this hypothesis. We supposed that if DNA recombination events occurred at tandemly repeated loci, the analysis of these loci in different strains of the same species should reveal variability in the organization and sequence of the duplicated genes. The polymorphism observed in the solo DUP240 genes is due mainly to the fixation of point mutations and to allelic recombination (LEH-LOUIS et al. 2004). Here we describe results that suggest that polymorphism within the tandem DUP240 loci results mainly from variations in the structural organization of the DUP240 ORFs. The identification of short repetitive DNA sequences that are likely involved in recombination processes suggests that the large chromosomal rearrangements observed at the tandem DUP240 loci are due mainly to nonallelic recombination events. The presence of new DUP240 paralogs and relics in several yeast strains allows us to conclude that the DUP240 family evolved by a gene birth-and-death mechanism.

S. cerevisiae strains and media:

All strains used in this study are listed in Table 1. Only the laboratory strains S288C and 1278b are heterothallic and haploid; the other strains are homothallic. Cells were cultivated at 30° on YPD medium (1% yeast extract, 2% peptone, 2% glucose, and 2% agar). Asci were obtained after 3 days on sporulation medium (1% potassium acetate and 2% agar) and spores were isolated by tetrad dissection using a Singer MSM micromanipulator.

View this table: In this window In a new window   TABLE 1 S. cerevisiae strains

 

Molecular biology techniques:

Genomic DNA was isolated from yeast cells using the procedure described by HOFFMAN and WINSTON (1987). All PCR amplifications were performed with the Expand long template PCR system (Roche, Indianapolis). Sequences of primers used for PCR amplifications were determined on the basis of the published genomic sequence of the yeast strain S288C (GOFFEAU et al. 1997).

DNA sequencing and sequence analyses:

DNA fragments obtained after PCR amplification were purified through MicroSpin S-400 HR columns (Amersham Pharmacia Biotech) and sequenced using AmpliTaq FS DNA polymerase and BIGDYE terminators. Sequence reactions were elaborated on an Applied Biosystems (Foster City, CA) 373XL sequencer. BLASTN analyses were performed in the SGD web site (http://www.yeastgenome.org/) to compare the sequence of the PCR products to the genomic sequence of S288C. Nucleic acid or protein sequences were aligned using programs available in the UWGCG package version 8.1 (DEVEREUX et al. 1984). A phylogenetic analysis was performed with all DUP240 DNA sequences identified at the tandem I and tandem VII loci, using the PHYLIP phylogeny inference package version 3.573 (FELSENSTEIN 1989). Phylogenies were estimated with the DNApars program by the parsimony method. The stability of the individual branches was assessed using the bootstrap method (SAITOU and NEI 1987).

Southern blot analysis:

PCR amplifications were performed from the genomic DNA of all class A strains with primers specific to YAR027w (5' ATGCAAACCCCTTCAGAA 3') and YAR033w (5' CCGTCTTTTTAAGAAGCG 3'). PCR products were purified, after agarose gel electrophoresis, using the GENECLEAN II system (Q-BIOgene). DNA fragments digested by restriction endonucleases were separated by agarose gel electrophoresis and blotted onto Hybond-N⁺ membrane (Amersham Pharmacia Biotech). Digoxygenin (DIG)-labeled DNA probes were prepared using the DIG DNA labeling kit (Roche Diagnostics). PCR products digested with BspEI were hybridized to the YAR029w and YAR031w gene probes, and those digested with PvuII and HaeIII were hybridized to the YAR027w, YAR028w, and YAR033w gene probes. Signal detection was performed using an enzyme-catalyzed color reaction (Roche Diagnostics).

Chromosomal organization of the tandem VII locus:

ORFs in direct repetition are found in all eukaryotic genomes sequenced so far but are rare in the yeast genome. This particular gene organization is interesting for the purpose of studying genome dynamics. It seems relevant to homologous recombination, which is very efficient in yeast. To demonstrate that the tandemly repeated DUP240 loci are potential sites for multiple chromosomal rearrangements, we compared the structural organization of these loci in the reference strain S288C with that in 14 other strains of the same species (Table 1). The synteny between the genes flanking this locus, OLE1 and ERV14 on one side and YGL050w and TIF4632 on the other side (Figure 2), is perfectly conserved for all the tested strains. In contrast, we observed that the sizes of the PCR fragments obtained with the primers 1 and 2 flanking the tandem VII region (Figure 2) are subject to numerous variations (data not shown). We determined the DNA sequence of this region of the genome in the 15 strains and found that there are three classes (Figure 2). Class 1 consists of the two laboratory strains S288C and 1278b in which YGL051w and YGL053w are arranged as tandem repeats. Class 2 strains contain a single DUP240 ORF at their tandem VII locus. A phylogenetic analysis was performed with the DNA sequences of all ORFs identified at both tandem VII and tandem I loci. As shown in Figure 3, the ORFs identified in class 2 strains constitute two new members of the DUP240 multigene family. These new paralogs were named DUP X (CLIB413, CLIB410, YIIc12, and YIIc17 strains) and DUP Y (CLIB219 strain) according to their phylogenetic relationships. Finally, class 3 is composed of 10 strains in which the tandem VII locus is composed of only Ty and solo LTR elements. Among the natural diploid strains we studied, three cases of heterozygosity are observed in the organization of the tandem VII locus (strains R12, YIIc12, and YIIc17; Figure 2).

View larger version (29K): In this window In a new window Download PPT slide   FIGURE 2.— Genetic organization of the tandem VII locus in the 15 studied yeast strains (not to scale). Genes and ORFs are represented by open boxes. Names of DUP240 ORFs are indicated in boldface type. Genes that surround the tandem VII locus are specified only for the reference strain S288C. Solo long terminal repeats and tRNA genes are denoted by shaded boxes and circles, respectively. Complete Ty sequences appear as hatched areas. The orientation of genetic sequences is indicated by arrows. The tandem VII locus was sequenced in the studied strains after PCR amplification with primers 1 and 2 (arrows above ERV14 and YGL050w). Strains of classes 1, 2, and 3 contain two, one, and no DUP240 ORFs, respectively, on chromosome VII between ERV14 and YGL050w. Superscript a indicates heterozygous strains. Superscript b indicates strains for which the tandem VII locus is not sequenced; presence or absence of DUP240 ORFs and Ty elements was checked by dot-blot analyses.

 

View larger version (32K): In this window In a new window Download PPT slide   FIGURE 3.— Phylogenetic relationships between all DUP240 ORFs identified at the tandem I and tandem VII loci in the 15 tested yeast strains. DNApars program of the PHYLIP phylogeny inference package was used. Bootstrap values for 100 replicates are indicated. Superscript a indicates chimeric ORFs YAR031-033w. Superscript b indicates that the DUP X ORF was identified in strains CLIB413, CLIB410, YIIc12, and YIIc17; only that of strain CLIB413 is shown.

 

Chromosomal organization of the tandem I locus:

The gene synteny is also conserved upstream (between CDC15 and YAR023c) and downstream (between YAT1 and SWH1) of the tandem I locus. However, the tandem I locus varies extensively among the strains, in both ORF copy number and nucleotide sequence. Analysis of the size of the PCR products generated using primers 3 and 4 (Figure 4) and of the corresponding fragments obtained by their digestion with HaeIII and NheI allowed a ranking of the strains among classes A, B, and C (data not shown).

View larger version (27K): In this window In a new window Download PPT slide   FIGURE 4.— Genetic organization of the tandem I locus in the 15 studied yeast strains (to scale except for the genetic elements upstream from 6 and downstream from 7 in the S288C map). Names of genes and ORFs are indicated inside or above open boxes. Genes that surround the tandem I locus are mentioned only on the map of the reference strain S288C. tRNA genes and long terminal repeats are represented by circles and shaded boxes, respectively. Arrows specify the orientation of genetic sequences. Primers 3 and 4 were used to amplify by PCR the genomic region located between YAR023c and YAT1 in all the studied strains. The characteristics of the obtained PCR products allowed grouping of the strains into class A, B, or C. Superscript a indicates that among strains of classes A and C, only the tandem I loci of YIIc17 and TL229 were sequenced. Superscript b indicates that for the heterozygous strain CLIB413, the tandem I locus was sequenced from two haploid strains (named D1 and E1) derived from the sporulation of the diploid strain.

 
For the class C strains TL213 and TL229, the fragment between YAR023c and YAT1 amplified by the PCR is 2.5 kb long, compared with a size of >10 kb for all the other strains. Both strains are missing the DUP240 ORFs (revealed from the DNA sequence of this DNA fragment from strain TL229, which contained two Ty LTR elements, and confirmed by a dot blot for strain TL213; Figure 4). The eight strains of class A (YIIc17, YIIc12, K1, R12, R13, 1278b, CLIB95, and CLIB388) show an identical fragment profile following digestion of a DNA fragment of this locus with HaeIII and NheI, and thus only the tandem I region of strain YIIc17 was sequenced. The five tandemly repeated DUP240 ORFs present on chromosome I of strain S288C are also present in strain YIIc17 in the same order and orientation (Figure 4). All eight class A strains shared the same Southern blot hybridization pattern using the gene probes YAR027w, YAR028w, YAR029w, YAR031w, and YAR033w (data not shown), so we conclude that the five DUP240 ORFs, present at the tandem I locus of all class A strains, are organized in the same way as in strain YIIc17 (Figure 4).

DNA fragments of the tandem I locus from each of the four strains of class B (CLIB219, CLIB382, CLIB410, and CLIB413) show a different fragment profile after digestion with HaeIII and NheI, indicating that their DUP240 ORFs are organized differently. The DNA sequence of each locus was determined (Figure 4). Strain CLIB413 is heterozygous with regard to the structural organization of the tandem I locus, so we examined both E1 and D1 meiotic products. The E1 tandem I locus is composed of seven DUP240 copies arranged in tandem. Three of them are new paralogs named DUP A, DUP B, and DUP C. They are located upstream of the block YAR028w-YAR029w-YAR031w-YAR033w previously identified in S288C and have several distinctive features. First, DUP A is phylogenetically related to DUP X, the paralog present at the tandem VII locus of the same strain (Figure 3). Second, DUP B is closely related to YAR029w (Figure 3). Whereas YAR029w represents the shortest coding sequence for a member of the DUP240 family, DUP B encodes a 191-amino-acid-long protein, a size closer to the standard size for a member of this family (240 amino acids). Finally, DUP C is similar to YAR031w in its first 262 nucleotides, which are 96% identical to the corresponding sequence of YAR031w. The D1 tandem I locus of CLIB413, in contrast, is composed of three DUP240 copies: YAR028w, YAR029w, and a new paralog designated as YAR031-033w that probably results from an in-frame deletion-fusion event between YAR031w and YAR033w.

The genetic organization of the CLIB410 tandem I locus (Figure 4) is quite similar to that depicted for CLIB413 E1 but with two variations: (i) DUP B-C results probably from an in-frame deletion-fusion event between DUP B and DUP C and (ii) the coding sequence of the YAR033w ORF is 153 bp shorter than its counterpart in CLIB413 E1, because of the presence of a missense mutation in the position of the expected initiation codon.

Strain CLIB382 features seven DUP240 paralogs (Figure 4). A perfect duplication (100% nucleotide identity) of a large part of DUP C is present upstream from DUP A. This duplicated copy of DUP C has been named DUP X-C since the beginning of its coding sequence (the first 66 nucleotides) shares the highest degree of similarity with the DUP X ORF located at the CLIB413 tandem VII locus. In addition, we found a chimeric YAR031-033w ORF truncated as a result of multiple point mutations.

Another type of polymorphism is apparent with the strain CLIB219 since six paralogs and one relic are detectable (Figure 4). Among the six DUP240 ORFs, DUP D and DUP E are new paralogs not yet found in other genomes. DUP D is phylogenetically related to DUP Y, the paralog recovered at the tandem VII locus of the same strain (Figure 3). In contrast, DUP E clearly appears as an outgroup in the phylogenetic tree shown in Figure 3, so no hypothesis about its origin can be deduced. Notably, two missense mutations shorten the YAR033w 5'-coding sequence to 309 bp in length. Finally, analysis of the unusually long intergenic area between DUP A and DUP E (1512 bp instead of 425 bp on average) suggests that an ORF, closely related to YAR028w of CLIB413 and CLIB382, was previously located here, but the accumulation of numerous mutations led to the erosion of its coding sequence, forming a relic (FISCHER et al. 2001).

Identification of DNA sequences potentially implicated in intra- and interchromosomal rearrangements:

With the aim of identifying the basis of the gene organization polymorphisms observed at the tandem I and tandem VII loci, we searched for direct repeats of DNA sequences that could play a role in recombination. The DNA sequences of DUP240 tandem loci were systematically screened for such DNA repeats, but we report only data obtained for strain CLIB413 (Figure 5).

View larger version (29K): In this window In a new window Download PPT slide   FIGURE 5.— Schematic of the DNA sequences potentially implicated in chromosomal rearrangements at the tandem I and tandem VII loci of the heterozygous CLIB413 strain. Intra- and interchromosomal duplicated sequence units are represented by stippled and blue boxes, respectively. Percentages show the level of nucleotide identity between these duplicated units. Red and blue arrows indicate the positions of very short repeated DNA sequences that could be involved in nonhomologous recombinations inducing deletion events. The in-frame deletion-fusion event probably at the origin of the YAR031-033w ORF could also have been achieved by homologous recombination, since a 78-bp sequence (S78) in YAR031w is 97% identical to the corresponding sequence in YAR033w. Red boxes correspond to YAR033w sequences.

 
The presence at the CLIB413 tandem I locus of DNA motifs potentially involved in recombination suggests that the strain was previously homozygous at this locus, with the ORF structure of the E1 allele (Figure 5). Two intrachromosomal recombination events inside one tandem I locus could be the cause of the observed D1 allele ORF organization. A first event of nonhomologous recombination [nonhomologous end joining (NHEJ)], involving a 9-bp microhomology (CATGCAAAC), between DUP A and YAR028w could explain the loss of sequence upstream of the D1 YAR028w ORF; a second recombination event between YAR031w and YAR033w probably allowed the creation of the new paralog YAR031-033w in D1. In this latter case, the in-frame deletion-fusion event could have been achieved either with the TACACCAG direct repeats by an NHEJ mechanism or through homologous recombination between a 78-bp DNA sequence repeat (S78). The high level of nucleotide identity is not restricted to the DUP240 coding sequences but is also observed for some intergenic regions. For example, DUP B-DUP C block is 91.8% identical to the YAR029w-YAR031w block (Figure 5). This suggests that the duplication of a sequence unit encompassing at least two adjacent DUP240 ORFs and their corresponding intergenic region have occurred at the tandem I locus of CLIB413 E1.

We considered the possible occurrence of interchromosomal events between the tandem I and tandem VII loci of CLIB413. Sequence units between these two ectopic loci share a high level of nucleotide identity (90.8 and 98.6%; Figure 5). This suggests that, during genome evolution, exchange(s) of genetic material between the tandem I and tandem VII loci led to the presence of the same gene organization in these two nonallelic loci, probably the one recovered in the tandem I region. Such interchromosomal rearrangements may have been followed by intrachromosomal deletion event(s) at the tandem VII locus to yield the present genetic map comprising only DUP X. This hypothesis is supported by the presence of the microhomology ATATCGATGCGC at the potential deletion junctions (in DUP A and YAR033w and also in DUP X; Figure 5).

Extensive polymorphism for the DUP240 tandem loci:

We documented the high degree of intraspecies polymorphism for the structural organization and sequence of the tandemly repeated DUP240 ORFs in S. cerevisiae. This polymorphism is restricted to the DUP240 loci since the synteny is always conserved in the flanking regions. Interestingly, we also observed some cases of heterozygosity in the gene organization of the tandem loci, a situation rarely reported since most of the genetic studies in yeast are performed on haploid or homozygous diploid cells. Another example is given by BROWN et al. (1998) who analyzed one population of diploid yeast that underwent 450 generations of glucose-limited growth. They found that the predominant cell type at the end of the assay shared a single copy of each of the target genes HXT6 and HXT7 (parental genotype) on one chromosome and multiple duplicated HXT7/HXT6 copies (recombinant genotype) on the homologous chromosome.

Expansion and contraction of the DUP240 family:

The DUP240 tandem loci are a breeding ground of new DUP240 paralogs. Indeed, the analysis of duplicated blocks (such as DUP B-DUP C and YAR029w-YAR031w in CLIB413 E1) strongly suggests that new DUP240 ORFs can be generated via the duplication of a sequence unit composed of ORFs and their corresponding intergenic regions. Such blocks have also been observed by BROWN et al. (1998) with the HXT genes. These authors proposed that the increase in gene copy number results from unequal crossover between sister chromatids, a hypothesis that can also be envisaged in the case of the tandemly repeated DUP240 ORFs. We also identified, at the tandem I locus of some class B strains, different chimeric ORFs (like YAR031-033w), which probably originated from two distinct preexistent DUP240 ORFs by deletion-fusion events. In this latter case, the creation of a new paralog at the DUP240 tandem loci is accompanied by the loss of other DUP240 ORFs. The disappearance of ORFs could also be the result of other evolutionary processes. A deletion event (without fusion) could explain, for example, the situation observed for CLIB413 D1 where three paralogs were apparently lost (Figure 5). Furthermore, we identified one relic of a DUP240 ORF in an unusually long intergenic region (tandem I locus in CLIB219). Such an occurrence of genetic drift by point mutations has also led to the loss of parts of the coding sequence of other DUP240 ORFs. For instance, the YAR029w ORF is a derivative of the DUP B paralog through the fixation of several mutations (missense, nonsense, and frameshift) affecting the 5'-terminal part of the coding sequence.

The DUP240 tandem loci probably act as hot spots for ectopic recombination:

We identified DNA motifs that may represent the signature of the molecular events at the origin of chromosomal rearrangements in the DUP240 tandem regions. The absence of a DUP240 ORF at the tandem I and/or tandem VII loci (strains of classes 3 and C) could be explained by ectopic recombination between two homologous solo LTR sequences that surround each DUP240 tandem locus (Figures 2 and 4). Indeed, Ty elements or solo LTRs are well known to induce chromosomal deletion, duplication, translocation, and inversion events by allelic or ectopic recombination in yeast (ROEDER et al. 1984; KUPIEC and PETES 1988; RACHIDI et al. 1999). It is likely that ectopic recombination also plays a major role in the creation of the newly identified DUP240 paralogs with a chimeric structure. The high level of nucleotide identity among most members of the DUP240 family further suggests that a homologous recombination mechanism is involved in the in-frame deletion-fusion events at the origin of these chimeric ORFs. Nevertheless, we cannot exclude a nonhomologous recombination (NHEJ) mechanism, possibly involving microhomology stretches (2–20 bp; MEZARD et al. 1992; KRAMER et al. 1994; MEZARD and NICOLAS 1994). Involvement of very short DNA tandem repeats in deletions leading to new genes encoding a fusion protein was experimentally demonstrated previously in yeast by WELCKER et al. (2000). Thus, DUP240 paralogs could represent another example of multigene families involved in a recombination hot spot, such as the previously described murine immunoglobulin (RAYNARD et al. 2002) and human ß-globin genes (SCHNEIDER et al. 2002).

Birth-and-death model of evolution for the DUP240 family:

We have shown previously that the three isolated DUP240 ORFs (YAR023c, YCR007c, and YHL044w) evolve by nucleotide substitutions and allelic recombination events (LEH-LOUIS et al. 2004). The accumulation of multiple point mutations in coding sequences also takes an important part in the evolution of tandemly repeated DUP240 ORFs, but in this case, nonallelic recombination events are the predominant forces at the origin of the extensive structural polymorphism that is observed. For both tandem and solo DUP240 loci, we do not observe homogenization of ORF sequences, but rather, a propensity toward the accumulation of nucleotide substitutions and toward recombination. Therefore, the DUP240 paralogs evolve by a birth-and-death process, which allows an increase in genetic diversity.

We do not believe the DUP240 gene family represents a new form of selfish DNA. The major argument favoring this idea is that the protein encoded by YCR007c, the solo DUP240 ORF present in all tested yeast strains, is under strong selective pressure (LEH-LOUIS et al. 2004). POIREY et al. (2002) suggested that the Dup240 proteins have different specialized functions since they have different subcellular localizations and nonredundant interacting partners. Thus, the DUP240 family is another intriguing example of an S. cerevisiae family of nonessential genes with a high level of nucleotide identity but nevertheless distinct functions, like the hexose transporter gene family (KRUCKEBERG 1996; WIECZORKE et al. 1999). Considering that DUP240 orthologs have been identified only in species of the Saccharomyces sensu stricto group, a working hypothesis is that the birth of a new DUP240 paralog could provide a new function probably highly specialized and specific to these species. The DUP240 gene family can be considered as a genetic marker of evolution and is a model to study genome plasticity.

We thank especially Marc Sultan for technical assistance and Stéphane Vuilleumier and Mikael Dubow for careful reading of the manuscript. We are grateful to Michel Aigle, Claude Gaillardin, and Huu-Vang Nguyen for providing S. cerevisiae strains and Philippe Hammann and Malek Alioua for automated DNA sequencing in the Strasbourg Centre National de la Recherche Scientifique (CNRS)/Institut de Biologie Moléculaire des Plantes department facilities. This work was supported in part by an E.U. Comprehensive Yeast Genome Database grant (QLRI CT 1999 01333) and by the Génolevures-2 sequencing consortium GDR CNRS 2354. B.W. is supported by a grant from the French Ministère de l'Education Nationale, de la Recherche et de la Technologie.

Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession nos. AJ585103, AJ585104, AJ585105, AJ585106, AJ585107, AJ585108, AJ585190, AJ585524, AJ585525, AJ586490, AJ586491, AJ586492, AJ586493, AJ586494, AJ586495, AJ586496, AJ586497, AJ586498, AJ586499, AJ586500, AJ586501, AJ586502, AJ586503, AJ586504, AJ586505, AJ586506, AJ586507, AJ586508, and AJ586612.

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