Human Molecular Genetics, 2000, Vol. 9, No. 4 653-657
© 2000 Oxford University Press
Transduction of 3'-flanking sequences is common in L1 retrotransposition
Department of Genetics, University of Pennsylvania School of Medicine, 415 CRB, 515 Curie Boulevard, Philadelphia, PA 19104, USA
Received 3 December 1999; Revised and Accepted 22 December 1999.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Active LINE-1 (L1) elements possess the ability to transduce non-L1 DNA flanking their 3' ends to new genomic locations. Occasionally, the 3' end processing machinery may bypass the L1 polyadenylation signal and instead utilize a second downstream polyadeny- lation site. To determine the frequency of L1-mediated transduction in the human genome, we selected 66 previously uncharacterized L1 sequences from the GenBank database. Fifteen (23%) of these L1s had transposed flanking DNA with an average transduction length of 207 nucleotides. Since there are ~400 000 L1 elements, we estimate that insertion of transduced sequences alone may have enlarged the diploid human genome as much as 19 Mb or 0.6%. We also examined 24 full-length mouse L1s and found two long transduced sequences. Thus, L1 retrotransposition in vivo com- monly transduces sequence flanking the 3' end of the element.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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The accumulation of 300 000–600 000 LINE-1 (L1) elements, retrotransposons which lack long terminal repeats and have short target site duplications (TSDs), has been important in expanding the human genome (1). Because of 5' truncations, rearrangements and point mutations, most L1s have lost the ability to retro- transpose autonomously. However, in 1988, two de novo L1 insertions causing hemophilia A were discovered, and subsequently the full-length precursor for one of these was isolated (2,3). Eleven other L1 insertions into genes have now been identified (4,5). Thus, some full-length L1s retain the ability to retrotranspose and cause human disease (Fig. 1). In addition, unequal homologous recombination between L1 elements has led to genetic disorders (6,7).
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L1-mediated transduction is a third mechanism by which L1s alter the genome (Fig. 1). When L1s retrotranspose, they do not carry downstream motifs important for efficient RNA cleavage and poly(A) addition (8), and can acquire them only by insertion into a fortuitous target sequence. Thus, the 3'-processing machinery may skip the L1 polyadenylation signal and instead use a second downstream polyadenylation site. Consequently, active L1 elements may transport non-L1 DNA flanking their 3' ends to new genomic locations. In vivo evidence for such L1-mediated transduction in humans exists, but is limited (9–12).
Active L1s, tagged at the 3' end with an indicator cassette disrupted by an intron, are able to retrotranspose at high frequency in cultured cells (13). Moran et al. (14) re-engineered the indicator cassette to form an exon-trap cassette which would function only when an L1 inserted into a gene. Using this assay, they estimated that 6% of L1s had inserted into introns, roughly the percentage expected if no bias exists against retrotransposition into genes. When the gene-trap cassette was moved 3' to the L1 element but still 5' to an SV40 polyadenylation signal, a high frequency of L1-mediated transduction was observed. The inherent inefficiency of L1 RNA cleavage and polyadenylation at the endogenous poly(A) signal suggested a novel mechanism for exon shuffling. An L1 residing in an intron of a gene might transduce downstream exonic sequence to a new site, possibly within another gene. Of even greater potential evolutionary significance, a retrotransposon could introduce new regulatory sequences near a gene and alter its previous mode of expression.
The retrotransposition assay in cultured cells may not reflect accurately transduction events in vivo. First, the SV40 poly(A) signal has a high affinity for the 3'-processing machinery and is probably a strong competitor of the weaker L1 poly(A) signal (15), stimulating alternative polyadenylation at a rate higher than would occur in vivo. Second, RNA splicing and polyadenylation are closely coupled. The intron in the indicator cassette introduces a 3' splice site upstream of the poly(A) signals, and this could affect polyadenylation (16).
Because of the limitations of the cell culture assay, we estimated in vivo transduction frequency by analysis of L1 sequences present in the GenBank database. We found that among relatively recent L1 retrotransposition events, transduction of 3'-flanking sequence is a common occurrence.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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To demonstrate that L1-mediated transduction has contributed to genome expansion and shuffling, we examined the GenBank database for L1 sequences containing both the 3' 100 nucleotides of the active human L1 consensus sequence and an unambiguous TSD. In all, 66 human L1s, including 49 Ta and 17 non-Ta elements, met these criteria and were examined for evidence of transduction.
Fifteen (23%) of the 66 L1 sequences contain transduced flanking DNA (Table 1). Although we have not identified precursors for these elements, each possesses TSDs at the 3' end of their flanking DNA and the 5' end of the L1 body. The presence of these TSDs is strong evidence for transduction by retro- transposition. In 13 of these 15 sequences, a canonical hexa- nucleotide signal is separated by 11–45 nucleotides from a poly(A) tail at the 3' end of the transduced sequence. Transduced sequences range from 39 to 874 nucleotides, with a mean of 207 nucleotides. Four of the 15 L1s containing transductions are full length with two intact open reading frames (ORFs), and thus are probably recent insertions.
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In our data set, 24 of 66 L1s (36%) are full length. It has been reported previously that the great majority of L1s are 5' truncated (17). Since the sequence used to sample GenBank was derived from the extreme 3' end of the L1, our data set members should be unbiased in length. However, our search necessarily focused on young L1s because of the difficulty in identifying TSDs for older L1s. Perhaps recent insertions are full length more often than older insertions. If true, this phenomenon is not limited to Ta elements (the predominant active L1 subfamily) (18), as there is little difference in the percentage of full-length Ta (30%) and full-length non-Ta elements (41%) in our data set.
Transduction is limited to neither human Ta subfamily members nor young L1s. There is no difference in the percentage of transduction events observed for Ta elements (22%) and non-Ta elements (24%). In addition, ancient human L1-mediated transduction events have been reported (11,12).
Transduction of 3'-flanking sequence by L1s also occurs in the mouse. We analyzed 24 full-length mouse L1s from GenBank, 17 A subfamily members and 7 TF subfamily members. The ratio of full-length A to TF elements is in agreement with data of Saxton et al. (19) who estimated that full-length A-type elements are 2.6 times more abundant than full-length TF-type elements in the genome of mouse strain 129Sv. Two A-type L1s are associated with transduced sequence. One (GenBank accession no. AF021335) has captured 3302 nucleotides originating from the 3' half of a different L1 element, and the second (GenBank accession no. AC004405#1) has transduced 2722 nucleotides (Table 1).
There is evidence that transduction is still occurring in the mouse. First, Martin (20) isolated ribonucleoprotein complexes from mouse F9 cells which contained an L1 transcript having 891 bp of 3'-flanking sequence. Second, element AC004405#1 has intact ORFs and a potential empty site in contig AC003994, suggesting that this is a recent retrotransposition event.
How much has L1-mediated transduction contributed to the human genome? Our data set samples the entire genome because L1 retrotransposition events occur throughout the genome, and in cultured cells little bias exists against insertion into genes (1,14). If there are 400 000 L1s in the haploid human genome, and 23% of retrotransposition events have transduced sequence with a mean length of 207 nucleotides, then transduced sequences alone may have enlarged the haploid human genome by as much as 19 Mb or 0.65%.
This estimate assumes that mean transduced sequence length has remained constant throughout L1 evolution, an assumption which we have not tested because of the difficulty of identifying TSDs for old and highly mutated elements. In fact, one might expect mean transduced sequence length to increase over time. An L1 sequence prone to transduction could extend the length of transduced sequence with each successive round of full-length insertion and subsequent retrotransposition (Fig. 2). There is evidence that this phenomenon occurs. Both human element AC003080 and mouse element AC004405#1 appear to derive from two consecutive transduction events (Fig. 3).
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Our estimate also assumes that transduction frequency has remained constant throughout L1 evolution. As discussed previously, >80% of older L1s are truncated (17), whereas a smaller percentage (64%) of the younger elements in our data set are truncated. Since 3' transductions are associated more frequently with full-length L1s (9 of 24) than with truncated L1s (6 of 42), younger elements may have a higher transduction frequency than older ones. Even if transductions are associated less commonly with truncated L1s, they still occur at a significant frequency (6 of 42, or 15%).
Transduced sequences provide a resource for determining L1 lineages (10). For example, human L1 HS46618 has the same 42 nucleotide transduction as L1 AC003080, suggesting that these two sequences share a recent progenitor (Fig. 3A). Further genome sequencing will reveal the lineage of these and other elements with transduced sequence.
Modification of cell function by L1-mediated transduction remains to be demonstrated. In our study, we have not yet demonstrated shuffling of exons or regulatory sequences because the immediate progenitor elements of the L1s associated with transductions are not in the database. Nevertheless, L1s carrying transduced sequences do insert into genes: at least three (HS406A7, AC003080 and HS466I8#1) of the 15 L1 transductions in our human database have done so. The potential exists for L1s to mobilize several kilobases of exon or regulatory sequence and carry it to other sites, altering gene function and increasing genetic diversity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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For our database search, we selected recently retrotransposed human L1s in three ways. First, we analyzed only elements with unambiguous TSDs. Second, we sampled GenBank with the 3' 100 nucleotides of the consensus sequence of active L1 elements (21,22). Third, the consensus sequence included a trinucleotide polymorphism diagnostic for the Ta L1 subset. We analyzed 102 human sequences, each having 98% or greater identity with the active L1 consensus. Those L1 elements lacking unequivocal TSDs (13 in number), broken by the end of a contig (four) or redundant (four) were discarded, as were entries for previously cloned L1s (15 elements).
In the mouse, L1 subfamilies have arisen by acquiring different 5'-untranslated regions containing unique repeating units, or monomers. To assemble the mouse data set, we probed GenBank with the sequence of a full-length A subfamily member and with the full-length consensus sequence for elements of the TF subfamily known to be active in our retrotransposition assay (23), and with TF and A monomer sequences (24,25). Thus, only full-length mouse sequences are represented in this analysis (except for entry AF021335 which has a large internal deletion).
Our data sets are available at: http://www.med.upenn.edu/genetics/labs/kazazian .
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ACKNOWLEDGEMENTS |
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We thank J. Moran, J. Meyer and E. Luning Prak for comments on the text, and C. Street and A. Harris for editorial assistance. This work was supported by a grant from the NIH to H.H.K. and a Howard Hughes Medical Institute Predoctoral Fellowship to E.M.O.
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FOOTNOTES |
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+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +1 215 898 3582; Fax: +1 215 5737760; Email: kazazian@mail.med.upenn.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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