* Tokyo Institute of Technology, Faculty of Bioscience and Biotechnology, Department of Biological Sciences, Yokohama, Japan
Museum Zoologi Bogor (Museum Zoologicum Bogoriense), Puslitbang Biologi-LIPI, Cibinong, Indonesia
Kitakyushu Museum and Institute of Natural History, Kitakyushu, Japan
National Institute for Basic Biology, Department of Cell Biology, Aichi, Japan
Correspondence: E-mail: nokada{at}bio.titech.ac.jp.
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Abstract |
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Key Words: t-SINE tRNA-derived subfamilies multiple source gene model Cynocephalus variegatus Dermoptera
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Introduction |
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To replicate via retrotransposition, SINEs use the existing enzymatic retrotranspositional machinery of their LINE partners. RNA-mediated retrotransposition, also known as target-primed reverse transcription (TPRT), represents the pioneering model for the relationship between SINEs and LINEs (Luan et al. 1993). Evidence supporting this LINE retrotransposition model is provided by an analysis of the Bombyx mori R2Bm RNA transcript. Initially, the R2Bm-encoded EN creates a first-strand nick that is utilized by the R2Bm RT, which subsequently reverse-transcribes copy DNA that is inserted at the 28S target site. The TPRT model gave rise to the suggestion that a similar mechanism may be used for SINE retrotransposition. It was proposed and established by our group that most SINEs share the 3' sequence of their partner LINEs (Ohshima et al. 1996; Okada et al. 1997; Terai, Takahashi, and Okada 1998; Kajikawa and Okada 2002). During retrotransposition, RTs encoded by LINEs recognize the corresponding identical 3' ends in SINEs, thus implementing SINE amplification via mobilization. This mechanism accounts for the majority of SINE retrotransposition in most nonmammalian species. The retrotranspositional machinery of the predominant mammalian LINE family, L1, is an exception to the conserved 3' end-specific region for RT recognition in that no 3' endspecific sequence (except the poly-A tail) is needed (Moran et al. 1996; Ostertag and Kazazian 2001). Additionally, Moran et al. (1996) revealed that mammalian L1 elements retrotranspose at high frequency in HeLa cells and that the integration of mammalian retroposons is mediated by L1-encoded RTs (Jurka 1997). Moreover, there is no RNA sequence specificity with respect to retrotransposition mediated by L1 in trans (Esnault, Maestre, and Heidmann 2000). In other words, each L1 element may not only mobilize its own transcribed RNA sequences, but may also mobilize SINE transcripts for retrotransposition via their 3' poly-A sequence. Thus, mammalian SINEs appear to be amplified by L1-encoded RTs via a mechanism that does not require an identical 3' end in the SINE, apart from the poly-A sequence.
SINEs are derived either from tRNA or 7SL RNA, with the majority of SINEs characterized thus far being derived from tRNAs. SINEs are found in a variety of eukaryotic species such as tobacco, the yellow fever mosquito, salmon, and mammals (for a list of references see Shedlock and Okada 2000). Examples of 7SL RNAderived SINEs include the primate Alu families, the rodent B1 family, and two recently described SINE families in Tupaia (Tu type I and type II; Nishihara, Terai, and Okada 2002). SINEs derived from tRNA genes are composed of a tRNA-related region containing RNA polymerase IIIspecific internal promoter sequences, a tRNA-unrelated region, and an AT-rich region (Okada 1991; Okada et al. 1997).
SINE families are classified into subfamilies based on DNA sequence. Because all characterized SINE families and subfamilies are restricted to particular phylogenetic groups, Shedlock and Okada (2000) suggested that they represent powerful noise-free Hennigian synapomorphies (Hennig 1966). Murphy et al. (2001a, 2001b) proposed a phylogeny that divides placental mammals into four major clades, namely Laurasiatheria, Euarchontoglires, Xenarthra, and Afrotheria. SINE families and subfamilies have been described in many lineages of these clades, except in xenarthran species. For example, in laurasiatherians, CHR-1 and CHR-2 represent SINE families specific to cetartiodactylan lineages (cetaceans, hippopotamuses, and ruminants; Shimamura et al. 1997, 1999). The AfroSINE family was created in a common ancestor of afrotherian species, and another AfroSINE subfamily is present only in the genomes of hyraxes, elephants, and sea cows (Nikaido et al. 2003). On the other hand, in Euarchontoglires (rodents, rabbits, primates, flying lemurs, and tree shrews), all recognized Alu-SINE subfamilies are distributed exclusively among primate genomes (Britten et al. 1988; Schmid 1996). As previously stated, 7SL RNAderived SINEs are found in other Euarchontoglires lineages as well (Nishihara, Terai, and Okada 2002). No 7SL RNAderived SINE family has yet been detected in rabbits or flying lemurs. The rabbit genome harbors the C repeat SINE family (Cheng et al. 1984) that appears to be derived from tRNA genes (Sakamoto and Okada 1985), although to date no SINE family has been characterized in the flying lemur genome.
Here, we describe the isolation and characterization of a unique tRNA-derived SINE family in dermopterans (flying lemurs or colugos). All 30 members of this new SINE family are composed exclusively of tRNA-related regions. Therefore, this novel SINE structure was denoted t-SINE. We discuss several aspects of t-SINEs including the evolution of variable subfamily formations, the flying lemurspecific t-SINE distribution, the multiple source gene model as an amplification mechanism, and the enzymatic retrotranspositional machinery of a corresponding LINE partner for the t-SINE family.
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Materials and Methods |
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In Vitro Transcription of Total DNA
In vitro transcription of total genomic dermopterans DNA in HeLa cell extract was performed as described previously (Endoh and Okada 1986).
Construction and Screening of Genomic Libraries, in Vitro Runoff Transcription, and Sequencing of Cloned DNA
Genomic libraries were constructed by complete digestion of dermopteran genomic DNA with HindIII, followed by sedimentation through a sucrose gradient and selection of DNA fragments of up to 2 kbp. The size-fractionated genomic DNA was ligated into HindIII-digested pUC18 plasmids at 37°C overnight. Aliquots of the ligation reactions were transformed into Escherichia coli DH5- cells. Colonies were transferred to membranes for screening. The first three SINE loci were identified by random selection and sequencing of
60 kbp from the genomic library as described by Okada, Shedlock, and Nikaido (2003). Runoff transcripts were generated in vitro using total genomic dermopteran DNA as well as dermopteran plasmid DNA digested with Bpu1102I (GCTNAGC, TaKaRa, Japan) as described by Koishi and Okada (1991). Additional t-SINE loci were screened using internal primers (CYN-AB-F GTGCGCCRCTTGGGAAGC, CYN-AB-R CACTGGCTGAGCGAGGTGC, CYN-C-F GCCTGCCCGTGGCTCACT, CYN-C-R CACCAAGTCAAGGGTTAAGATCC) labeled by primer extension in the presence of [
-32P]dCTP. [
-32P]dATP-labeled internal primer sequences were also used to further investigate the evolution of the Cynocephalus t-SINE family. Hybridization was performed at 42°C overnight in a solution of 6x SSC, 1% SDS, 2x Denhardt's solution, and 100 µg/ml herring sperm DNA and washed at 50°C for 10 min in a solution of 2x SSC and 1% SDS. Positive phage clones that appeared to contain Cynocephalus t-SINE loci were isolated and the inserts sequenced using universal primers M4 and RV (TaKaRa) as well as internal Cynocephalus t-SINE specific primers (see above). Sequencing was performed with an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). Nucleotide sequence data with the following accession numbers were deposited in GenBank: AY278325 through AY278354.
Dot-Blot Analysis and PCR
Genomic DNA of Saguinus oedipus, Lemur catta, Cynocephalus variegatus, Tupaia belangeri, Lepus crawshayi, Mus musculus, Pteropus dasymallus, and Sorex unguiculatus were arrayed onto a GeneScreen Plus membrane (Du Pont-NEN Products, Boston, Mass.) with a dot-blot apparatus (model DP-96, Advantec, Tokyo) and probed with a t-SINE specific oligonucleotide (GACACTGAGGGTTGCGATCCGTT). The total amount of genomic DNA for the dot-blot hybridization was titrated from 1,000 ng to 10 ng. Linearized plasmid DNA (1100 ng) containing a Cynocephalus t-SINE sequence (CYN-CL56) was used as a positive control. The DNA samples were denatured for 10 min in 2 M NaOH prior to hybridization. Hybridization conditions were as described above, except that the washing step was performed two times at 50°C for 10 min.
Genomic DNA of Homo sapiens, Saguinus oedipus, Lemur catta, Cynocephalus variegatus, Tupaia belangeri, Lepus crawshayi, Mus musculus, and Pteropus dasymallus was amplified by polymerase chain reaction (PCR) using internal t-SINE primers (CYN-C-F, CYN-C-R). The PCR conditions were as follows: After initial denaturation for 3 min at 94°C, 33 cycles were performed consisting of 30 s denaturation at 94°C, 50 s annealing at 56°C, and 30 s elongation at 72°C.
Sequence Analyses
Multiple sequence alignments were constructed using ClustalW (Thompson, Higgens, and Gibson 1994), and sequence analyses were performed with BioEdit (Hall 1999). Database searches were performed with BlastN (Altschul et al. 1997). Mouse and human tRNA sequences were obtained from the tRNA compilation of Sprinzl et al. (1998) and the tRNAscan-SE program (Lowe and Eddy 1997) and compared with known t-SINEs of Cynocephalus using DNA analysis software (Genetyx version 10.1). Using Tree-Puzzle 5.0 (Strimmer and von Haeseler 1996), a maximum likelihood analysis based on the HKY85 model was performed (Hasegawa, Kishino, and Yano 1985) using the discrete gamma distribution (eight categories) for site heterogeneity (Yang 1996). Puzzling supports were based on 1,000 replicates.
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Results and Discussion |
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While the 8-bp insertion is also present in the first subunit of the -type, an additional truncated subunit with a length of 47 bp distinguishes the
- from the ß-type. The first and second subunits of the ß- and
-type sequences exhibit high sequence similarity (table 1). This not only supports the close relationship between the ß- and
-type sequences but also strongly suggests that the
-type subfamily is the youngest presented here. The average length of the 16 trimeric
-type sequences is 230 bp, whereas the average length of the 14 dimeric
- and ß-type sequences is <200 bp. Thus, the major discrete transcript shown in figure 1 may represent the trimeric
-type sequence and is likely the most abundant subfamily in the Cynocephalus genome. In a maximum likelihood analysis of all different subunits, the third
-type subunit is presented in a sister group relation to the second subunit of the ß-type (fig. 5). In other words, the sequence similarity of the third
-type subunit and the second ß-type subunit suggests an origin of the trimeric
-type subfamily after a partial duplication of the second subunit of the ß-type. The major tree topology in figure 5 does not change if subfamilies are divided in minor subfamilies (see below).
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A dimeric retroposon structure may be generated in other ways, including retrotransposition of a tRNA pseudogene in the vicinity of a tRNA gene and duplication of retrotransposed tRNA. The latter scenario is possible because the sequence similarity between subunit 1 and
subunit 2 is 73%. However, both subunits show greater similarity to the tRNAIle gene (table 1). The origin of dimeric Alu elements in the primate genome was described as a fusion of a free left Alu monomer (FLAM) with a free right Alu monomer (FRAM) (Jurka and Zuckerkandl 1991; Quentin 1992). An A-rich linker connects these two Alu precursors as well as many other dimeric SINE elements. Because there is no such poly-A linker found between the t-SINE subunits of the flying lemur, the fusion of two tRNAIle retrotransposed monomers may not be relevant. At the same time, the t-SINE transcription seems to be promoted by the first subunit in view of the fact that a critical nucleotide insertion in the B-Box of the second
-type subunit might be responsible for silencing this t-SINE subunit. The same B-Box mutation can be seen in the derived ß- and
-type sequences as well (fig. 3). A possible fusion of a transcriptionally active FLAM with a silenced FRAM was discussed in previous studies concerning the process of Alu dimerization (Jurka and Zuckerkandl 1991; Quentin 1992). The Alu fusion model involves two separate deletions in 7SL genes or 7SL RNAderived SINEs followed by retrotransposition and fusion. Such a model might explain the origin of the dimeric t-SINEs as well. Human Alu-SINEs as well as rabbit C repeats show a common tendency to insert into regions where other SINEs have previously inserted. Whereas human Alu-SINEs are usually inserted at the 3' end into the poly-A region (Slagel et al. 1987), C repeats occasionally insert into the 5' end of previously existing SINE loci (Krane et al. 1991). Many examples regarding C repeats have been identified in which new SINE insertions occur near or within preexisting inserts (Krane et al. 1991). The former situation has occurred in the Cynocephalus genome as well (data not shown). Although there are several possible ways to generate a dimer or trimer structure as seen in t-SINEs, the precise mechanism remains to be resolved. Given that we could not detect t-SINE monomers that had been subjected to multiple rounds of retrotransposition, we can only suggest that a dimer or trimer structure may have some retrotranspositional advantage over a monomeric tRNA-like structure.
Copy Number of t-SINEs in Cynocephalus, Their Taxonomic Distribution, and Phylogenetic Inference
To estimate the t-SINE copy number, the size of the mammalian genome was postulated to be 3 x 109 bp. Given the fact that the first three t-SINE loci were found by random selection and sequencing of 60 kbp of genomic dermopteran DNA, the assumed copy number is 1.5 x 105 t-SINEs per haploid genome. On the other hand, we performed a dot-blot experiment (fig. 6) to examine the t-SINE distribution in Cynocephalus and other mammalian species. Based on the results of this experiment, the assumed t-SINE copy number was estimated as 1 x 106. Because the
-type sequences seem to be the most abundant t-SINE members in the Cynocephalus genome, the sequence designed as a probe was specific to the duplicated third
-type subunit. The high copy number shown by the dot-blot experiment is supposedly caused by the additional hybridization of the probe to the second subunit of ß- and
-type sequences (see above), and probably even to the second
-type subunit as well.
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Members of the Cynocephalus t-SINE Family Are Amplified Through Multiple Sources and Are Potentially Retrotransposed by L1-Encoded RT in trans
Both SINEs and processed retropseudogenes belong to the nonviral superfamily of retroposons. Once processed retropseudogenes are integrated into a genome, they generally do not propagate further. Conversely, SINEs may propagate and generate progeny during evolution. Each SINE copy has the potential to propagate depending on the circumstances in the genome (Schmid and Maraia 1992; Shedlock and Okada 2000). In cases where SINEs are integrated into unfavorable chromosomal locations, it is possible that they accumulate too many mutations and ultimately lose their ability to propagate. Since all propagating SINE loci are dependent on the retrotranspositional LINE machinery, SINEs may also become inactive if their partner LINE family becomes inert. However, if mutations are introduced into a SINE copy but do not influence its ability to propagate, the progeny may be distinguished by these mutations (diagnostic nucleotides). The "mother copy" with these mutations is called a source gene. In the master gene model only a very limited number of master SINE loci are responsible for long-term amplification of non-propagating offspring copies. This model was proposed by earlier studies of Alu subfamilies (Shen et al. 1991; Deininger et al. 1992; Deininger and Batzer 1995). At present, however, most SINEs are believed to amplify according to the multiple source gene model and can be divided into subfamilies (source genes) that are able to propagate. The amplification rate of source genes will increase or decrease over evolutionary time depending on whether accumulated mutations deactivate them faster or slower (Schmid and Maraia 1992; Shedlock and Okada 2000).
For the new t-SINE family described here, we demonstrated the existence of different subfamilies, each containing several members. Moreover, subfamilies can be further divided into sub-subfamilies based on several diagnostic nucleotides. For example, the -type subfamily may be divided into two sub-subfamilies ([
1: CYN-A, CYN-CL1, 39, 56, 177, 181, 433, 438] [
2: CYN-B, CYN-CL8, 46.1, 66, 172, 173, 175, 434]) that are based on several diagnostic nucleotides (fig. 3, sites 25, 26, 29, 66, 171, 209).
2 may be subdivided into
2.1 (CYN-B, CYN-CL8) and
2.2 (CYN-CL46.1, 66, 172, 173, 175, 434) based on one diagnostic nucleotide (fig. 3, site 171). Several
1 sequences cluster together as well (
1.1: CYN-CL56, 181, 433, 438; fig. 3, sites 100103;
1.2: CYN-CL1, 39, 177; fig. 3, sites 46, 143). Finally, it is possible to divide the
-type subfamily in two sub-subfamilies, namely
1 (CYN-C, CYN-CL263, 293.1, 298, 314) and
2 (CYN-CL46.2, 64, 162, 290, 374) based on one diagnostic nucleotide (fig. 3, site 79).
The delineation of subfamilies suggests the existence of a small number of progenitors that were responsible for the amplification of t-SINE members. Thus, for t-SINEs, an amplification process that is equivalent to SINEs having a common structure (containing a tRNA-unrelated region as well) must also exist. In the multiple source gene model, SINE offspring copies serve as multiple sources for subsequent SINE amplifications (Schmid and Maraia 1992; Shedlock and Okada 2000). This evolutionary model appears to be appropriate for the amplification of t-SINEs (fig. 8). Unlike in the master gene model, which implies long-term persistence of individual source genes, t-SINE source genes were shown to be derived from each other. The t-SINE subfamilies were subjected to dimerization, duplication (trimerization), deletions, insertions, and substitutions. Certain source genes were successfully retrotransposed during evolution, and their offspring copies can clearly be recognized to shape subfamily characteristics. Whereas -type sequences were revealed to form the oldest t-SINE subfamily with a 74%80 % identity to the tRNAlle, ß-type t-SINEs were shown to be derived from
-type t-SINEs to which they are 75%76 % identical. The youngest t-SINE subfamily was presented through the
-type sequences, which are 81%92 % identical to the ß-type t-SINE subunits (table 1). The number of t-SINE copies determined in this study is too limited to assume the age of major t-SINE lineages. Because the rate of amplification is expected to be tightly linked to overall copy numbers, and because
-type sequences are the most abundant in the genome of the flying lemur, it is expected that the
-type source gene is highly active and very successful in its retrotransposition of offspring copies. The high retrotranspositional frequency of UnaSINE1 may reflect the affinity of tRNA-derived regions for ribosomes in order to bring the latter into proximity with polysomes that are synthesizing UnaL2 proteins (Kajikawa and Okada 2002). It might further be expected that a trimeric structure consisting exclusively of tRNA-related subunits (as represented in the
-type subfamily) strengthens its affinity for ribosomes. While this hypothesis has not yet been proven, it is apparent that the youngest trimeric-structured t-SINE subfamily members are the most dominant in the flying lemur genome.
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Note Added in Proof |
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Acknowledgements |
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Footnotes |
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