Tulane Cancer Center, and Department of Epidemiology, Tulane University Health Sciences Center, New Orleans, Louisiana
Correspondence: E-mail: pdeinin{at}tulane.edu.
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Abstract |
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Key Words: SINE mobile element retrotransposition rodent subfamily microsatellite
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Introduction |
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In mammals, the most active mobile elements are non-LTR retrotransposons. The primary autonomous retrotransposon currently active in mammalian genomes appears to be L1 elements (Lander et al. 2001; Waterston et al. 2002; Deininger et al. 2003; Kazazian 1998; Ostertag and Kazazian 2001).
SINEs (short interspersed repetitive DNA elements) are the most abundant of mammalian mobile elements. These elements, usually 90 to 300 bp in length, are classified as nonautonomous because they are thought to be dependent on LINE elements for their mobility (Ogiwara et al. 1999; Dewannieux, Esnault, and Heidmann 2003). Nearly all SINEs, with the exception of the human Alu and rodent B1 elements (Ullu and Tschudi 1984), are ancestrally derived from tRNA genes (Daniels and Deininger 1985b; Sakamoto and Okada 1985; Okada 1991). ID elements (originally termed R.dre.1) are members of a major SINE repetitive DNA family within the rodent genome and are believed to be derived from an alanine tRNA gene (Daniels and Deininger 1985a; Deininger and Slagel 1988; Sakamoto and Okada 1985). Features of SINEs include an internal RNA polymerase III promoter, an adenine-rich 3' region (which we will term A-tail in this article) of variable length, and flanking direct repeats created at the site of insertion.
The rat ID family has been classified into subfamilies by diagnostic nucleotide changes (Daniels and Deininger 1985b; Kim et al. 1994). These subfamilies are of differing average ages. The oldest subfamily, ID1, parallels the evolution of the single-copy BC1 RNA locus throughout all rodent genomes. The other subfamilies are rat specific and are characterized by at least one shared base change. The latter subfamilies show a relatively young evolutionary age, ranging from 5 Myr to 1.9 Myr, with their relative ages ID2 > ID3 > ID4. The newer families of ID in rat do not follow the evolution of the BC1 locus and appear to have created a new, and much more actively amplifying, lineage (Kim and Deininger 1996; Kass, Kim, and Deininger 1996).
Most SINE elements are thought to be incapable of retroposition, and only a relatively few active elements are responsible for the activity at any given time (Deininger et al. 1992; Schmid and Maraia 1992; Deininger et al. 1996). The features that separate the active copies from their inactive family members have not been experimentally demonstrated. However, circumstantial evidence suggests that a primary moderator of this activity is the length of the homopolymeric adenine flanking regions (Roy-Engel et al. 2002). For instance, the BC1 locus has served as a master locus for rodent ID elements (Kim et al. 1994), and the copy number of those elements in most rodent genomes parallels the length and homogeneity of the A-rich region at the 3' end of the BC1 locus in the respective genomes.
In this article, we explore the ability to identify recently active ID subfamilies within the Rattus norvegicus genome by assessing the length of the A-tails on the elements. In addition, we have shown through genomic PCR analysis that a group of these elements were recently inserted within the R. norvegicus genome, while being absent from the R. rattus genome. Lastly, we present a model that may explain the observed pattern of SINE subfamily activity through time.
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Materials and Methods |
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Bioinformatics
To identify repetitive elements with long A-tails, Blast searches (BlastN) (Altschul et al. 1990) were performed with a homopolymer (A50) as the query sequence on the draft genome databases (rat [build 2], mouse [build 30], or human [build 33]) with low complexity filter disabled and the maximum number of results returned (v b flags) set at 1000. Expect values of 5e19, 6e19, 6e19 was used for the mouse, rat, and human genomes, respectively, to eliminate all but perfect matches. Elements containing a homopolymeric stretch of 50 adenine residues were tabulated and extracted, along with adjacent flanking unique DNA sequence of approximately 1 kb from GenBank accessions, and analyzed by RepeatMasker2 (http://ftp.genome.washington.edu/cgi-bin/RepeatMasker).
ID Elements
To identify potential subfamily relationships and copy numbers, the ID portion of individual elements, without its A-tail, was used to query the R. norvegicus genome. Blast searches were performed using a 1000 value for the number of one-line descriptions (v) and alignments (b), while including an "expect value" (e) of 1e40. This would allow the acquisition of all perfect matches, as well as those that were imperfect by a single nucleotide. These were then collated manually.
The A-tails of individual elements were defined as the first adenine base after the ID body sequence to the first non-A base in the direct repeats that define the insertion. The means of the distributions of A-tail lengths were analyzed with the z-test.
Mouse and Rat B1 Elements
The B1 elements extracted from the A50 mouse search were aligned (DNA Star, Megalign version 5.0 Expert analysis software) to derive a consensus sequence for this group of elements. Insufficient A50 rat B1 elements were found for our purposes, so we used a search for the rat B1 A40 group. After the alignment of the rat and mouse consensus B1 sequences, the positions involving subfamily diagnostic positions, hypermutable CpG positions (Labuda and Striker 1989; Batzer et al. 1990), and a mouse-specific diagnostic (GA) were replaced with N's to create a generic consensus sequence (TGGTGGNNCANNCCTTTAATCCCAGCACTNNGGAGGCAGAGGCAGGNNGATTTCTGAGTTNNAGGCCAGCCTGGTCTACGAAGTNANTTCCAGGACAGCCAGGGCTACACAGAGAAACCCTGTCTC). This query sequence should show minimal bias in a search because of species or subfamily characteristics that allow for a better estimation of insertion time based on divergence from this common consensus. The Blast program using this query sequence on both rat and mouse genomes were then used with various expect values and with the low complexity filter disabled.
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Results |
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We utilized a generic rat/mouse B1 consensus to query these genomes under high stringency to allow only close matches to the consensus, to corroborate the observation that there is a higher proportion of young B1 elements in mouse than in rat. Using an expect value of 1e-24, there were 5,668 Blast sequence matches within this parameter for the mouse genome, compared with 409 Blast matches for the rat genome. Similar proportions were also obtained when using alternative expect values that would allow different mismatch levels relative to the consensus. Thus, the mouse genome contains a higher proportion of B1 elements with high similarity to the consensus, consistent with a higher recent rate of amplification.
We also noted that the B1 elements selected with the A50 query included non-A bases in the consensus of their A-tail region (table 4). They routinely contained a short run of A residues (four to six) followed by one to three C residues and the An stretch in the majority of cases.
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Discussion |
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Long A-tails in Rodent Elements
ID elements have amplified at a high rate specifically within the rat genome, resulting in approximately 10 times as many copies as in the mouse genome (Kim et al. 1994). In the rat, only about 10% of ID elements appear to have been generated by the BC1 master gene (Kim et al. 1994). Thus, although the BC1 RNA gene has dominated the evolution of ID family members in most rodent genomes (Kass, Kim, and Deininger 1996), the rat genome has new subfamilies of elements that have diverged from the BC1 RNA locus. The A50 query identified elements that were dominated by the youngest of these subfamilies, ID4 (table 3). In particular, three of these ID elements were identical in sequence to over 15,000 elements, suggesting that they represented a minor variant of ID4, termed ID4b, that is a currently active subfamily. This current activity was confirmed by identifying that 16/16 of the members of this new subfamily of elements found in the Rattus norvegicus genomic sequence were detected by PCR in Rattus norvegicus but not in Rattus rattus. This suggests that they have all inserted within the last 2 Myr. One of the elements, which matches the #47 group of ID4b elements, was even polymorphic for its presence in Rattus norvegicus, suggesting extremely recent insertion. Thus, this approach appears to have identified at least some of the more active ID elements in the rat genome.
The mouse genome contained 24 long A-tailed B1 elements, whereas the rat had only one. Our observations predict that B1 elements have been more active recently in mouse than rat. This was strongly supported by finding that more than an order of magnitude more mouse elements were found to be a close match to a generic B1 consensus relative to rat B1 elements. There has also been a recent report of a mutation in mouse caused by a very recent B1 insertion (Gilbert et al. 2004). Thus, it appears that in parallel with the ID expansion in the rat, there was a similar increase of B1 elements in mouse. L1 elements showed fairly equal numbers of elements with long A-tails in the rodent genomes in this analysis, and there were only very low levels of B2 or B4 elements identified with long A-tails, suggesting only modest activities of those SINEs.
It is possible that the parallel expansion of ID and B1 in rat and mouse genomes, respectively, reflects only a limited capacity for SINE retroposition in those genomes and competition for those levels between different SINE species. The ID elements may compete more effectively in rat and the B1 in mouse. However, we favor an explanation that involves stochastic change of either ID or B1 elements in those respective genomes that resulted in changes in their amplification potential, as discussed below.
Interrupted A-tails As a Mechanism for Increased Amplification
We have hypothesized that SINE amplification rates are proportional to the length of the A-tail on individual elements (Roy-Engel et al. 2002). We note that the distributions of A-tails for the recently active ID subfamilies are similar in length to those from the active human Alu subfamilies (fig. 3). In fact, the ID elements are longer on the average because they do not contain as many elements on the shorter end of the distribution. However, the A-tails calculated in figure 3 also include the length of the A7GAACC sequence present in most of the recent ID subfamilies. The BC1 RNA gene has an A-rich stretch that is interrupted by a number of other bases, and yet it has served as the master gene for amplification of ID elements throughout rodent evolution (Shen, Batzer, and Deininger 1991; Kim et al. 1994) and is capable of supporting retroposition in a cultured model system (Hagan, Sheffield, and Rudin 2003). This demonstrates that an A-rich sequence is capable of supporting retroposition, and the adenine residues do not necessarily have to be homopolymeric. Furthermore, we have demonstrated that the BC1 imperfect A-tail is still capable of forming an RNP with poly(A) binding protein (West et al. 2002). The interruptions in the A-tails are likely to result in an evolutionary stabilization of the length of the A-tail, as has been observed for other microsatellites (Bacon, Farrington, and Dunlop 2000; Rolfsmeier and Lahue 2000). Simple microsatellites, including A homopolymers, are extremely unstable. Thus, the initially long A-homopolymers rapidly degrade to shorter lengths. If these shorter lengths are less capable of amplification, then the elements containing them would not propagate as well. If the interruptions in the A-homopolymers result in their stabilization, then the elements containing them are likely to maintain their amplification capability, resulting in the spread of the interrupted A-tails. It seems likely that an imperfect A-tail would not be as favorable as a perfect A-tail of the same length but that if it increases the length by 11 bases per element on the average, it may provide a selective advantage to those elements.
The A-tails on many of the recently amplified mouse B1 elements also included an interruption, with a consensus of A5CCAn(table 4). Although there is some diversity, consistent with the rapid evolution of simple A-tails to more complex microsatellites (Arcot et al. 1995), they almost all share the A5CCAn motif. A minor variant of this motif, A6CCAn, is also included in the B1 element that resulted in the jittery mouse strain (Gilbert et al. 2004), as well as its two possible progenitors. These data suggest the possibility that the same strategy has been utilized independently by several active SINE families to amplify more effectively in rodent genomes.
There may be some basic property of rodent genomes that favors the interrupted A-tail strategy over human. For instance, if homopolymeric A-tails are less stable in rodent than human, it might be necessary to have the interruptions to help provide stability, thus maintaining SINE activity in rodents. Despite the observation that rat microsatellites are generally longer than those in human, homopolymeric adenine sequences are much less common in rat than human (0.09 versus 0.34%, respectively) (Beckman and Weber 1992). These data are consistent with the possibility that SINEs in rodents have more difficulty maintaining a sufficiently long A-tail and have evolved the A-tail interruptions to avoid tail shortening.
A Model for the Genomic Balance of SINE Retrotransposition
The finding of long A-tails associated with the most recent SINE inserts can be explained by the findings that Alu element insertions have longer stretches of A residues at their 3' end than the element that served as the source of the insertion event (Dewannieux, Esnault and Heidmann 2003; Hagan, Sheffield, and Rudin 2003). However, both of these studies utilized elements with A-tails approximately 50 bases in length and do not provide data on the relative influence of A-tail length and amplification rate. Furthermore, it has been demonstrated that most of the SINE RNA transcripts are from inactive subfamilies of SINEs (Shaikh et al. 1997; Liu et al. 1994; Sinnett et al. 1992) and that even older, inactive Alu subfamilies can be made active by overexpressing them with a long A-tail (Hagan, Sheffield, and Rudin 2003). Along with other data previously presented (Roy-Engel et al. 2002), it is likely that long A-tails are beneficial for SINE amplification.
SINE insertion depends on L1 element activity (Dewannieux, Esnault, and Heidmann 2003). Recently inserted L1 elements have also been shown to have long A-tails that rapidly shrink in size (Ovchinnikov, Troxel, and Swergold 2001; Roy-Engel et al. 2002). However, the A-tail is generated by a true polyadenylation process and, therefore, reflects recent activity, but less likely reflect potential for the element to maintain activity. However, the lack of long A-tailed L1 elements in human compared with the similar numbers in rat and mouse would be consistent with the much higher number of active L1 elements that have been estimated to be present in the mouse genome (Goodier et al. 2001; Kazazian 2000; Naas et al. 1998). It would be reasonable to expect long A-tails at the end of an L1 element to show the same instability as those in the SINEs. We cannot directly estimate the relative activity of human SINEs versus rodent SINEs from our data, because we do not know that A-tails follow similar stabilities in those genomes. However, our data strongly suggest that Alu is much more effective relative to L1 elements in human than are the rodent SINEs relative to rodent L1 elements. This may be consistent with hypotheses that human Alu elements have specific properties that make them particularly effective at amplifying (Dewannieux, Esnault, and Heidmann 2003; Schmid and Maraia 1992). In addition, L1 elements have been proposed to gradually evolve to avoid co-opting of the L1 proteins by SINEs for their own purposes. Thus, there may be periods of evolution in which the existing SINEs interact less effectively with the LINE retrotransposition apparatus or other cellular proteins. The SINEs may then evolve by selection for those elements that can interact better.
We propose a model (fig. 4) in which the rate of retrotransposition is primarily controlled by the length of the A-tails of the SINE elements. In this model, we show that the natural equilibrium for the A-tails of SINEs favors them shrinking to a modest length of about 20 bases (Roy-Engel et al. 2002). We have found a few examples, however, where existing A-tails of Alu elements sporadically grew to a long length. Thus, we believe that existing elements in the genome would have a strong tendency to lose amplification potential but might occasionally be reactivated until other parts of the SINE mutate sufficiently to elminate amplification. The primary means of creating long A-tails on SINEs seems to be through the retrotransposition process itself (Dewannieux, Esnault, and Heidmann 2003; Hagan, Sheffield and Rudin 2003). Thus, if SINE retrotransposition rates are high, lots of elements with long A-tails will be created, resulting in more active retrotransposition. Factors that destabilize the length of homopolymeric adenines in a genome will also result in suppression of SINE activity. Alternatively, factors that stabilize the length of the A-rich region, such as interruptions in the homopolymeric A-tail, would tend to maintain amplification rate.
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Acknowledgements |
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Footnotes |
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References |
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