* School of Molecular and Microbial Biosciences, University of Sydney, Sydney, Australia; Molecular Mycology Research Laboratory, CIDM, Westmead Hospital, Westmead, Australia; and
Department of Medicine, Western Clinical School, University of Sydney, Sydney, Australia
Correspondence: E-mail: w.meyer{at}usyd.edu.au.
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Abstract |
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Key Words: simple sequence repeat microsatellite fungi
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Introduction |
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Because of their high mutability, SSRs are thought to play an active role in genome evolution by creating and maintaining genetic variation (Tautz, Trick, and Dover 1986). The length of SSRs in promoter regions may influence transcriptional activity (Kashi, King, and Soller 1997). They may also affect protein-protein interactions via the length of polyglutamine or polyproline traces encoded by SSRs (Gerber et al. 1994). There is also evidence that some SSRs serve a functional role in regulation of gene expression (Kunzler, Matsuo, and Schaffner 1995) and in the evolution of gene regulation (Huang et al. 2003). Dynamic mutations in trinucleotide repeats within or near specific genes have been found to be associated with several neurodegenerative diseases (Jin and Warren 2000; Sermon et al. 2001) and some human cancers (Wooster et al. 1994). The high levels of polymorphisms observed in SSRs and the relative ease of detection of these polymorphisms via PCR amplification has led to the widespread application of SSRs as genetic markers today.
However, despite this widespread use, little is known about SSRs in fungi. In fact, there are only a limited number of studies on these seemingly important and intruding sets of sequences in fungal species. SSRs have currently only been analyzed in detail from two fungal species: Saccharomyces cerevisiae and Schizosaccharomyces pombe. This study indicated that AT motif is the most abundant in fungal genomes (Toth, Gaspari, and Jurka 2000). SSRs have been used as genetic markers in numerous DNA-fingerprinting and PCR-fingerprinting experiments for strain typing of a variety of filamentous fungi and yeasts without prior knowledge of their abundance and distribution in the investigated fungal genomes (Lieckfeld et al.1992; Meyer et al. 1991, 1997, 1999; Meyer, Maszewska, and Sorrell. 2001; Meyer et al. 2003). A recent study proposes the use of SSRs in a number of cell wall proteins for strain typing of wine yeasts (Marinangeli et al. 2003). Besides being used as molecular markers, recognition of abundance and density of SSRs in fungi may help to understand whether these sequences have any functional and evolutionary significance. The study of absolute numbers of SSRs in fungal genomes may also address whether SSR abundance is a direct function of the genome size in these organisms, as had been suggested for higher eukaryotes (Toth, Gaspari, and Jurka 2000). Such understanding would foster the proper use of SSRs in future studies.
Frequencies of various SSR sequences in different genomes have been estimated originally via hybridization experiments (Tautz and Renz 1984; Panaud, Chen, and McCouch 1995) or database searches (Richard and Dujon 1996; Toth, Gaspari, and Jurka 2000). These studies were mainly based on the overrepresented coding regions and limited by the partial genomic sequences available. Large-scale genome sequencing initiatives on a growing number of organisms are now providing the opportunity to evaluate the abundance and relative distribution of SSRs in different genera based on the whole genome. The specific aim of this study was to determine the abundance and diversity of SSRs in fungal genomes and to compare them with other organisms. We describe in the present study, the genome-wide analysis of SSR sequences from nine completely sequenced fungal species representing phylogenetic diverse fungal genera. Specifically, data are presented for the abundance, density, most common and longest SSRs to see if there is a correlation between fungal SSR content of a certain genome and, genome size as previously reported.
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Methods |
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Results |
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Tetranucleotide Repeats
N. crassa and M. grisea showed the greatest occurrence of tetranucleotides with 758 and 219 repeats, respectively. These organisms also had the highest relative abundance of tetranucleotides with 20 repeats/Mb and 5.8 repeats/Mb, respectively (table 2). The lowest relative abundance was one repeat/Mb in S. cerevisiae, even though E. cuniculi had the lowest frequency. The density of tetranucleotide repeats was found to be much lower than the densities of dinucleotide and trinucleotide repeat motifs. The N. crassa genome had the highest (524 bp/Mb) and the S. cerevisiae the lowest (24 bp/Mb) tetranucleotide densities (table 3). The most frequent tetranucleotide repeat motifs were much less in abundance than the lower-repeated units. The most common tetranucleotide repeat was found to be the (TACC)n motif in N. crassa and M. grisea, which occurs 39 and 32 times, respectively (table 6). The repeat (TAGG)n was also common to these genomes, occurring 23 and 24 times, respectively. Generally, most tetranucleotide repeats were rather short, with a repeat length of less than eight. However, there were some longer motifs represented in the genomes of N. crassa and M. grisea (table 7). The longest tetranucleotides were the (AGGA)51 (204 bp), (ACCT)39 (156 bp), and (ACAT)38 (152 bp) motifs in N. crassa. The motif (TACC)48 (192 bp) was the longest in M. grisea. In the A/T-rich genomes of S. pombe and S. cerevisiae, long tetranucleotides were mostly composed of the bases A and T, contrary to the composition of long dinucleotides in these genomes, which contain at least one G in the core motif (table 7).
Pentanucleotide Repeats
As expected, the occurrence of pentanucleotide repeats was less than that of the tetranucleotide repeats. The highest occurrence of pentanucleotides, with 192 repeats, was found in the genome of N. crassa (table 2). The lowest occurrence was in the genome of C. neoformans, with only three repeat motifs. No pentanucleotides were found in E. cuniculi. The highest relative abundance was found in N. crassa (5.1 repeats/Mb) and the lowest in C. neoformans (0.2 repeats/Mb) (table 2). Overall, the density of pentanucleotide repeats ranged between 156 bp/Mb in N. crassa and 6 bp/Mb in C. neoformans (table 3). Generally, the core composition of pentanucleotide repeats was found to deviate more than for the shorter SSR motifs. This variance is probably related to their length rather than to having a particular base bias. The most common motifs were also found to occur less frequently than for tetranucleotide repeats, as is the case with the most frequent TACAC motif, which occurs only five times in N. crassa (table 6). N. crassa also accommodates the longest pentanucleotide motifs (AAGGA)32, (ACTCT)28, (CTTTT)24, and (CTTGA)18, which extend to 160, 140, 120, and 80 bp, respectively (table 7). Other long pentanucleotides found were (GGCAA)29 (145 bp) in M. grisea, (TTGCT)25 (125 bp) in U. maydis, and (GTATG)18 (90 bp) in F. graminearum.
Hexanucleotide Repeats
Hexanucleotide repeats were also found abundantly in the genomes analyzed. U. maydis, with 196 hexanucleotides, had the highest occurrence, and S. pombe, with only three hexanucleotides in 13.1 Mb of sequence analyzed, had the lowest occurrence. As seen for pentanucleotides, there were no hexanucleotides in E. cuniculi (table 2). Moreover, in the genomes of C. neoformans, M. grisea, S. cerevisiae, and U. maydis, hexanucleotide repeats were more abundant than the pentanucleotides. U. maydis, with 9.9 repeats/Mb, had the highest relative abundance, and S. pombe, with 0.2 repeats/Mb, had the lowest relative abundance of hexanucleotides. The densities of hexanucleotide repeats were found to vary significantly among the nine genomes (table 3). The highest density of hexanucleotide was 442 bp/Mb for U. maydis and the lowest was 10 bp/Mb for S. pombe. The hexanucleotide density in U. maydis was even higher than the tetranucleotide and pentanucleotide densities in this species. The most abundant hexanucleotide repeats were found in the larger and medium-sized genomes, with the most common being the (TGCTGT)8 motif in U. maydis (table 6). The longest hexanucleotide repeats were the (GCCTGA)77, (TAGGGT)62, and (CCTTCT)52 motifs in M. grisea, U. maydis and C. neoformans, respectively (table 7). These hexanucleotide repeats were, in fact, by far the longest among all the SSRs found across these species and compare very well with long repeats occurring in humans and higher eukaryotes (Kruglyak et al. 1998). Overall, the longest hexanucleotides were represented in M. grisea and N. crassa genomes.
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Discussion |
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Our analysis revealed that the abundance of SSRs in fungi is comparatively less frequent than in the human genome. A large portion of the noncoding genome is repetitive DNA, which can be of different types based on the length of the repeated elements. SSRs occupy between 0.08% and 0.67% of the fungal genomes, comparatively less than the 3% for the human genome (International Human Sequencing Consortium 2001). For instance, a SSR occurs every 3.9 kb in the S. cerevisiae genome, in contrast to estimates of the overall SSR density in the human genome, which was one repeat per 0.1 kb of sequence (Simple Sequence Repeats Database: [http://www.ingenovis.com/ssr]). Therefore, it can be assumed that the human genome contains about 39-fold more SSRs than does the S. cerevisiae genome. There is no known explanation for the lower occurrence of SSRs in fungi. If the small genome sizes in fungi are taken into account, it still remains to be explained why there are less SSRs in fungi. Because most SSRs occur in noncoding regions, perhaps a high density of fungal genes in fungi compared with higher eukaryotes would imply that the relative amount of noncoding DNA should be less in fungi, thus leading to lower rates in fungal SSR evolution. In humans, more than 98% of the genome does not code for proteins, and it is thought that most of these regions are made up of SSRs (Matula and Kypr 1999). Therefore, the less amount of noncoding DNA resulting from the smaller genome sizes of fungi may explain the lower occurrence of SSRs in fungi.
Some repeats, such as the dinucleotides, are some of the most sought-after molecular markers in most organisms because of their relatively high mutation rates. The higher AT/TA frequencies in the majority of genomes (table 5) may be a result of the high A/T content of the genomes and the relative ease of strand separation compared with C/G tracts (Gur-Arie et al. 2000). Interestingly, as the core repeat unit increases (for example from dinucleotide to trinucleotide), the percentage of the C or G content in the repeat unit also increases (table 7). These repeats (e.g., (TACC)n and (GGCAA)n in M. grisea) still occur in abundance and with relatively long tracts. The high abundance of GT repeats in mammals has been linked to formation of Z-DNA (Majewski and Ott 2000) and regulation of gene expression (Moore et al. 1991). The abundantly occurring SSRs such as the AT repeats in fungi could serve a similar function as GT repeats may serve in mammals.
Relative Abundance of SSRs and the Genome Size
Our results suggest that the relative abundance of SSRs differs and is not consistent with the genome size (fig. 4). It appears that the SSR abundance is neither inversely nor directly proportional to the genome size of fungi as has been reported for other genomes (Morgante, Hanafey, and Powell 2002; Hancock 1996, 2002). Similarly, the relative abundance of each class of SSRs (mononucleotides to hexanucleotides) also differs among the species. Several unexpected relationships between the genome sizes emerged, including the variance between the members of the ascomycetes. Values observed with different genome sizes indicate there are factors that impose limits upon compositional relative abundance variation in these genomes. This idea is supported by the observation of inconsistency of relative abundance in similar-sized genomes (Toth, Gaspari, and Jurka 2000). A surprising result is that the relative abundance of the SSRs in the larger genome of F. graminearum is significantly closer to that in the A. nidulans than to that in the similar-sized genomes M. grisea and N. crassa. It is not clear why similar-sized genomes such as, M. grisea contain almost fourfold more SSRs than do F. graminearum. A more detailed analysis of differential distribution of SSRs and the genome organization of these fungal species is needed to shed more light on the SSR variance in fungal genomes.
Most Common SSR Motifs
The potential of SSRs, specifically of the most abundant repeats, in contributing to the evolution of genomes has been well documented in various organisms. Thus, the large number of common and long SSRs identified in this survey are also likely to be associated with possible or known functions. It has been reported that (GT)n is the most common repeat motif in animals and invertebrates (Stallings et al. 1991), whereas in plants and insects, the repeats (AT)n and (CT)n are the most common, respectively (Lagercrantz, Ellegren, and Andersson 1993; Paxton et al. 1996). In agreement with the early studies in fungi (Valle 1993; Geistlinger et al. 1997), a majority of sequences rich in A/T were observed, especially in dinucleotide repeats. As discussed, this is possibly a consequence of the high A/T content of fungal genomes. However, C/G-containing repeats are also frequently observed in fungal genomes. For example, in M. grisea and U. maydis, the most common dinucleotides are the CT/TC group, which are also the most abundant dinucleotides in insects (Estoup et al. 1993) and higher invertebrates (Katti, Ranjekar, and Gupta 2001). Most of the common trinucleotides such as (CCG)n, (CGC)n, and (GGC)n in M. grisea do not contain either A or T at all. As in the human genome, the repeat (AAC)n in N. crassa is very common and occurs more than 69 times, and its high frequency may indicate similar function in both genomes. Furthermore, there is no known explanation for the uneven abundance of certain repeats in different genomes. One such SSR is the (CAA)n repeat that appears 152 times in the N. crassa genome but only 17 times in F. graminearum, although they are approximately the same size and have the same amount of the genome analyzed (table 1).
Longest SSR Motifs
Our results revealed that the abundance of various SSR motifs varied considerably among the nine fungal species analyzed. However, the length-frequency distributions of SSRs were relatively constant across all species. The length distributions of all SSRs indicated that the frequency of repeats decreases rapidly with increasing repeat length. This may be because longer repeats have higher mutation rates and, hence, could be less stable (Wierdl, Dominska, and Petes 1997). Furthermore, in this study, SSRs are found on average to be much shorter than in higher organisms. Generally, dinucleotide and trinucleotide repeat stretches tended to be longer than other repeats. In addition, SSRs in larger genomes such as M. grisea and N. crassa seemed to be longer than in smaller fungal genomes. The lack of longer repeats could possibly be explained by their downward mutation bias and short existence time (Harr and Schlötterer. 2000). The SSR with the longest nucleotide stretch belonged to M. grisea and consisted of a (GCCTGA)77 motif of 462 bp. In contrast, the longest repeat in N. crassa, the organism with the most abundant SSRs, is the (TTA)93 repeat, which is 279 bp long (table 7). The M. grisea genome is 16 times larger than the E. cuniculi genome; hence, one would expect it to accommodate much longer SSRs. Our results found that larger genomes harbor the longest repeats, as seen for higher organisms with much larger genome sizes. Overall, N. crassa and M. grisea contained the longest dinucleotide, trinucleotide, tetranucleotide, and pentanucleotide repeats between them (table 7). However, long tracts of hexanucleotide repeats were also found frequently in the medium-sized genomes of C. neoformans and U. maydis. Cross-species comparisons indicate that SSR loci can be conserved over long evolutionary time periods, and the number of repeats never reaches extremely long values (Schlötterer, Amos, and Tautz 1991). On the other hand, differences in length distributions between organisms were explained by different SSR mutation rates (Kruglyak et al. 1998). Furthermore, a lack of very long SSRs has been taken as evidence that selection is also involved in maintaining SSRs within a certain size range (Nauta and Weissing 1996).
In conclusion, our study of SSRs in completely sequenced fungal genomes is a small step toward a better understanding the nature of these important sequences. We presented that the occurrence of SSRs in fungi to be comparatively less frequent than in the human and other eukaryotic genomes. Since the discovery of their polymorphic nature, SSRs have become the main choice of molecular markers for a variety of genetic studies. The abundance and variance of SSR lengths may give a good indication of the expected variability. The data on the composition and length distribution of SSRs obtained in this study and the developed screening software can be used for choosing the optimal repeat motifs for SSR isolation in these and related fungal genera.
The SSR sequences and the exact locations within the genomes of all of the SSR loci reported in this study are available at http: http://www.mmrl.med.usyd.edu.au/ssr.html. This information may become useful for a variety of purposes, including isolation and developing variable markers. The SSR data should also facilitate research on the role of SSRs in genome organization.
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Acknowledgements |
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Footnotes |
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