Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Abstract |
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Introduction |
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While novel L1PA1 (Ta) L1 insertions are increasing the genetic diversity of humans, a more far reaching question is that of how large a genetic load L1 activity imposes on its host. A clue that it does was our finding that about 35% of Ta elements are full length (FL L1), as compared with the previous estimates of only about 5%10% FL for total genomic, and thus mostly ancestral, L1 elements (Fanning and Singer 1987
). A possible explanation for this difference is that most of the ancestral FL L1-containing loci were deleterious and were soon lost as a result of negative selection. This implies that either insufficient time has elapsed to clear deleterious FL Ta-containing loci or they are being generated as fast as they are cleared.
To determine if most of the ancestral FL L1-containing loci were cleared from the human genome, we compared the fractions of FL L1 elements on autosomes and on the X and Y chromosomes. If FL ancestral L1 elements were deleterious and subject to purifying selection, we would expect them to have been cleared from autosomes but not from the Y chromosome. This is because nonrecombining regions, which constitute most of the Y chromosome, accumulate deleterious mutations at a higher rate than do recombining regions. The inevitable increase in deleterious mutations in the absence of recombination has been termed Muller's ratchet (Felsenstein 1974
) and has been verified experimentally (Rice 1994
; reviewed by Hurst 1999
). When present in the male, the X chromosome also cannot recombine, and thus the fraction of FL L1 would be intermediate between the Y chromosome and autosomes.
We show here that only 8.5% of the autosomal L1 elements present in four ancestral non-Ta families (L1PA2L1PA5; Smit et al. 1995
) are FL. In contrast,
30% of the members of these ancestral families residing on the Y chromosome are FL, and this value for the X chromosome is
16.5%. Thus, it appears that FL L1-containing loci imposed a significant enough genetic load on its host to have been lost from the human genome.
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Materials and Methods |
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Analysis of L1-Containing Loci by PCR
The states of L1-containing loci in different human populations were determined as described earlier (Boissinot, Chevret, and Furano 2000).
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Results |
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The Sex-Chromosomal L1 Elements Are Typical Members of Their Subfamilies
The L1 elements enumerated in tables 1 and 2
were assigned to their respective L1PA subfamilies by Repeat Masker based on diagnostic characters in the 3' untranslated region (UTR) (Smit et al. 1995
). Although characters elsewhere in the element (e.g., ORF II) are confirmatory of these designations, the highest resolution of the primate L1 families is generally based on the 3' UTR (Smit et al. 1995
; Boissinot, Chevret, and Furano 2000
; unpublished data). To confirm the Repeat Masker family assignments and to be sure that they did not include yet unrecognized subfamilies that might be unusually enriched in FL elements, we performed a phylogenetic analysis of the FL L1PA1L1PA5 elements.
Figure 2 shows a single neighbor-joining tree built on the 3' UTR of the FL L1PA1L1PA5 elements. The FL Y elements were indistinguishable from their counterparts on the X chromosome and the autosomes except for their longer branch lengths. The latter reflects the greater divergence of L1 elements on the Y chromosome than on the other chromosomes (unpublished data). Maximum-parsimony analysis of the entire L1 sequence of arbitrarily selected subsets of FL L1PA1L1PA5 elements produced similar results (fig. 3 ). Figures 1C, 2, and 3 also show that the L1PA3 family consists of two subfamilies: L1PA3b (the older subfamily) and L1PA3a. This division is supported by numerous characters, including an ancestral 124-bp region of the 5' UTR that is present in L1PA3b and the older families but is deleted from the L1PA3a subfamily and the younger families (results not shown).
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The Density of FL L1 Elements on Autosomes Is Correlated with Recombination Rate
Since the sex chromosomes do not contain an excess of short (<500 bp) L1 elements, the excess of FL and long non-FL (>500 bp) L1s is not likely due to preferential insertion of L1 on the sex chromosomes. Perhaps longer or FL copies are more efficiently generated when sex chromosomes rather than autosomes are the targets for insertion. However, to account for our data, this process would have to be more efficient on the Y chromosome than on the X chromosome and more efficient on certain regions of the autosomes than on others (see below).
A more plausible explanation is that FL L1 elements, and, to a lesser extent, long non-FL (>500 bp) elements, are deleterious. Thus, they accumulated on the Y chromosome (and, to a lesser extent, on the X chromosome) because the removal of deleterious mutations by recombination is not available to the Y chromosome or to the X chromosome when it resides in males. On the other hand, the autosomal FL and long non-FL L1 would be more susceptible to removal by recombination than their counterparts on the sex chromosomes. If true, autosomal regions with abnormally low recombination rates should contain more of the putatively deleterious FL L1 inserts than regions with normal recombination rates. The 8 Mb of DNA located near the centromere of chromosome 21 has a very low recombination rate in males (fig. 5 in Hattori et al. 2000) but not in females. Therefore, this "pseudo-X" region of chromosome 21 should be similar to the X chromosome with respect to its L1 composition.
Table 1 shows that the L1 composition of the 8 Mb with a low recombination rate in males resembles the L1 composition of the X chromosome. These two regions of the genome do not significantly differ with respect to the number per megabase of FL, long (>500 bp), and short (<500 bp) L1 elements (table 1 ). Conversely, the X chromosome contains a statistically significant excess of FL and long non-FL elements over the recombining region of chromosome 21 (table 1 ). Therefore, a difference between recombination rates could explain the loss of potentially active FL L1 elements from most autosomal regions and their consequent relative enrichment on the sex chromosomes.
This conclusion is even more compelling when the low (in males) recombining 8-Mb region of chromosome 21 is compared with the adjacent 8 Mb. Not only do these regions share similar GC contents and densities of Alu and short L1 elements, but they also contain the same number of both known and predicted genes. At the DNA sequence level, they differ only in their numbers of FL L1 elements: the low recombining region contains 11, and the normal recombining region contains 2 (table 2 and Hattori et al. 2000).
The Absence of Once-Active L1-Containing Loci in Present Populations
One way to corroborate the elimination of active L1 elements is to demonstrate that loci which once contained them were subsequently lost from the population. About 10% of L1 insertions include adjacent 3' non-L1 flanking sequence that was transduced during retrotransposition (Moran, DeBerardinis, and Kazazian 1999
; Goodier, Ostertag, and Kazazian 2000
; Pickeral et al. 2000
). By determining the origin of a given transduced sequence, we could locate where the active progenitor of such an L1 insertion is, or was. We analyzed 29 elements that terminated in a 3' transduced sequence identified either by others (Goodier, Ostertag, and Kazazian 2000
; Pickeral et al. 2000
) or us and found a match for 20 of them in GenBank (table 3
). Seven of these elements belonged to the older L1PA2 and L1PA3 families, and surprisingly (given the results of table 1
), four were FL. However, three of these four were identified by Pickeral et al. (2000)
, who limited their search to FL elements. Thus, this unexpectedly high yield of FL elements does not reflect any special feature of L1 elements that contain 3' transduced sequences, but it represents an ascertainment bias.
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Discussion |
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The simplest explanation for our results is that FL L1 elements (and, to a lesser extent, long non-FL [>500 bp] elements) are deleterious and consequently are lost as a result of purifying selection. Thus, the relative enrichment of FL (and long non-FL) L1 elements on the Y and X chromosomes would represent yet another example of the accumulation of deleterious mutations on the sex chromosomes (Baker and Wichman 1990
; Steinemann and Steinemann 1992
; Wichman et al. 1992
; Rice 1994
; Kjellman, Sjogren, and Widegren 1995
; Chalvet et al. 1998
; Junakovic et al. 1998
; Hurst 1999
; Smit 1999
; Erlandsson, Wilson, and Paabo 2000
). If the L1 content of the Y chromosome represents the largely unselected products of past L1 family amplifications, then at least one third of the copies generated during the amplification of the ancestral L1PA2L1PA5 L1 families were FL (tables 1 and 2 ), about the same proportion as that of the currently amplifying L1PA1 (Ta) family (Boissinot, Chevret, and Furano 2000
).
Two bases for selection against (retro)transposable elements in eukaryotes have been proposed: the deleterious effects (genetic rearrangements) caused by ectopic (nonallelic) homologous recombination between elements and the deleterious effects (e.g., genetic damage) due to (retro)transposition. Although these effects are not mutually exclusive, arguments have been marshaled to support the predominance of one or the other (e.g., Biemont et al. 1997
; Charlesworth, Langley, and Sniegowski 1997
). Our results suggest that both effects may account for selection against FL and long non-FL elements.
Ectopic Recombination
Here, we distinguish between the recombination that facilitates the removal of deleterious L1-containing loci from the genome from the ectopic homologous recombination between nonallelic L1-containing loci that would make these loci deleterious.
Ectopic L1 recombination has caused genetic rearrangements in humans, including disease-producing genetic deletions (Burwinkel and Kilimann 1998
; Segal et al. 1999
). A presimian ancestral ectopic recombination produced a duplication of the gamma globin gene (Fitch et al. 1991
), and a more recent one in hominids caused the inversion of a region of the Y chromosome (Schwartz et al. 1998
). In addition, ectopic L1 recombination may remodel satellite DNA arrays of human centromeres (Laurent, Puechberty, and Roizes 1999
).
These few cases of L1 ectopic homologous recombination contrast with the far greater numbers that have been documented for the 300-bp Alu SINE family members (e.g., Burwinkel and Kilimann 1998
; Deininger and Batzer 1999
). One explanation is that ectopic recombination between the more widely spaced L1 elements would lead to far more serious deleterious rearrangements (e.g., deletions) than the more closely spaced Alu elements (Burwinkel and Kilimann 1998
; Deininger and Batzer 1999
). Thus, most ectopic L1 recombinants would be so deleterious that they would be rapidly lost from the population.
A direct correlation between the length of the homologous sequences and the rate of ectopic recombination in mammals has been demonstrated experimentally (e.g., Hasty, Rivera-Perez, and Bradley 1991
; Cooper, Schimenti, and Schimenti 1998
). These results are consistent with our finding that <500-bp L1 elements (less prone to ectopic recombination) are apparently not subject to purifying selection, whereas >500-bp L1 elements (more prone to ectopic recombination) are (table 1
). However, the relatively frequent recombination between the 300-bp Alu sequences indicates that ectopic recombination between sequences that are <500 bp is possible, and some pairs of Alu elements have undergone repeated independent recombinations (e.g., Deininger and Batzer 1999
; Hill et al. 2000
).
Additionally, in contrast to ectopic homologous L1 recombination, ectopic nonhomologous (illegitimate) recombination involving L1 and non-L1 DNA is quite common even when an L1 partner is available (e.g., Inoue et al. 1997
; McNaughton et al. 1998
and references therein). Fairly extensive deletions (e.g., 340 kb) can result, and the participation of L1 elements in these events is proportional only to their frequency in the sequences in question (McNaughton et al. 1998
). Thus, one need not invoke ectopic homologous L1 recombination to produce deletions large enough to be seriously deleterious. In addition, the far more frequent occurrence of ectopic nonhomologous L1 recombination over ectopic homologous L1 recombination has been recapitulated experimentally (Richard et al. 1994
).
Deleterious Effects of L1 Retrotransposition
If we assume that the content of FL L1 on the Y chromosome is a minimal estimate of the unselected products of L1 amplification, then >70% (1 - (8.45/31.1)) of the autosomal FL L1 elements generated by the older L1PA2L1PA5 families have been lost. Thus, most of these FL L1-containing loci were deleterious. Although individual L1 insertions could be deleterious by directly inactivating a gene (e.g., Kazazian 2000) or altering the structural or regulatory properties of genic regions, for the most part these effects could be caused by both FL and non-FL elements. In addition, by whatever mechanism a single L1 insertion produces a deleterious effect, such L1-containing alleles should be more likely lost from the X chromosome than from autosomes because of the hemizygosity of the X chromosome in males. However, table 1 shows that this is the opposite of what we observed. In fact, the somewhat lower number of Alu sequences on the X chromosome than on the autosomes may reflect the deleteriousness of these insertions.
In addition to the above considerations, the randomness and sparseness (relative to the size of the genome) of insertions generated by any given L1 family suggest that selection against FL L1 elements is based on their having a global effect, i.e., by their retrotranspositional activity. If so, L1 retrotransposition must be sufficiently deleterious to be subject to purifying selection. An FL L1-containing locus that produced enough retrotransposition in germ line cells to lower fertility or enough retrotransposition in embryos to affect their viability would be rapidly lost from the population. These types of events constitute the phenomenon known as hybrid dysgenesis caused by transposable elements such as the L1-like I elements in Drosophila melanogaster (Busseau et al. 1994
).
Since the long (>500 bp) non-FL L1 elements should not be capable of autonomous retrotransposition, their presumed participation in ectopic recombination could explain selection against these elements. However, perhaps some could produce L1 products, such as L1 RNA or an active reverse transcriptase, that could be deleterious. Regarding the latter, only a region beginning about 600 bp 5' of the RT domain is required to efficiently generate cDNA from cellular RNA transcripts in vivo in a cell culture assay (Dhellin, Maestre, and Heidmann 1997
). However, even >500-bp non-FL elements that were not long enough to encode a functional RT also exhibited a statistically significant sex-chromosomal bias (results not shown). Thus, the potential to produce an active RT does not account for the selection against these elements.
Whether or not something as drastic as a dysgenic phenomenon is the basis for selection against FL L1 elements, the repeated generation of deleterious FL L1-containing loci could nonetheless have affected (and may still affect) the genetic composition of primates, including humans. L1-containing loci that are both deleterious and linked to essential genetic loci could persist in the population, thereby decreasing its overall fitness. In addition, linkage of deleterious L1-containing loci to novel beneficial alleles could prevent the latter's subsequent fixation. Also, the presence of a particularly deleterious L1 on the Y chromosome could effectively eliminate that particular male lineage. How, or whether, such events affect a population may depend less on the spread of any particular deleterious L1-containing locus on the population than on the ability to repeatedly generate such loci.
Finally, the higher density of L1 elements on the X chromosome relative to the autosomes has been taken as evidence that L1 elements are involved in X inactivation (e.g., Bailey et al. 2000 and references therein). However, our results suggest that the excess of L1 elements on the X chromosome relative to autosomes can be explained by the selective loss of deleterious FL and long non-FL L1-containing loci from autosomes. This does not mean that a difference in the densities of L1 on the X chromosome and the autosomes has not been coopted for use in the X inactivation system. However, autosomal genes can be silenced if the autosome contains an active Xist gene. This suggests that an X-chromosome-like density of L1 elements may not be required for this process (Wutz and Jaenisch 2000).
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Conclusions |
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Footnotes |
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1 Keywords: L1/LINE-1
human
sex chromosome
evolution
retrotransposon.
2 Address for correspondence and reprints: Anthony V. Furano, National Institutes of Health, Building 8, Room 203, 8 Center Drive, MSC 0830, Bethesda, Maryland 20892-0830. avf{at}helix.nih.gov
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literature cited |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bailey, J. A., L. Carrel, A. Chakravarti, and E. E. Eichler. 2000. Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. Proc. Natl. Acad. Sci. USA. 97:66346639
Baker, R. J., and H. A. Wichman. 1990. Retrotransposon Mys is concentrated on the sex chromosomes: implications for copy number containment. Evolution. 44:20832088[ISI]
Biemont, C., A. Tsitrone, C. Vieira, and C. Hoogland. 1997. Transposable element distribution in Drosophila. Genetics. 147:19971999
Boissinot, S., P. Chevret, and A. V. Furano. 2000. L1 (LINE-1) retrotransposon evolution and amplification in recent human history. Mol. Biol. Evol. 17:915928
Burwinkel, B., and M. W. Kilimann. 1998. Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease. J. Mol. Biol. 277:513517[ISI][Medline]
Busseau, I., M. C. Chaboissier, A. Pelisson, and A. Bucheton. 1994. I factors in Drosophila melanogaster: transposition under control. Genetica. 93:101116[ISI][Medline]
Cabot, E. L., B. Angeletti, K. Usdin, and A. V. Furano. 1997. Rapid evolution of a young L1 (LINE-1) clade in recently speciated Rattus taxa. J. Mol. Evol. 45:412423[ISI][Medline]
Chalvet, F., C. di Franco, A. Terrinoni, A. Pelisson, N. Junakovic, and A. Bucheton. 1998. Potentially active copies of the gypsy retroelement are confined to the Y chromosome of some strains of Drosophila melanogaster possibly as the result of the female-specific effect of the flamenco gene. J. Mol. Evol. 46:437441[ISI][Medline]
Charlesworth, B., C. H. Langley, and P. D. Sniegowski. 1997. Transposable element distributions in Drosophila. Genetics. 147:19931995
Cooper, D. M., K. J. Schimenti, and J. C. Schimenti. 1998. Factors affecting ectopic gene conversion in mice. Mamm. Genome. 9:355360[ISI][Medline]
DeBerardinis, R. J., J. L. Goodier, E. M. Ostertag, and H. H. Kazazian Jr. 1998. Rapid amplification of a retrotransposon subfamily is evolving the mouse genome. Nat. Genet. 20:288290[ISI][Medline]
Deininger, P. L., and M. A. Batzer. 1999. Alu repeats and human disease. Mol. Genet. Metab. 67:183193[ISI][Medline]
Dhellin, O., J. Maestre, and T. Heidmann. 1997. Functional differences between the human LINE retrotransposon and retroviral reverse transcriptases for in vivo mRNA reverse transcription. EMBO J. 16:65906602
Erlandsson, R., J. F. Wilson, and S. Paabo. 2000. Sex chromosomal transposable element accumulation and male-driven substitutional evolution in humans. Mol. Biol. Evol. 17:804812
Fanning, T. G., and M. F. Singer. 1987. LINE-1: a mammalian transposable element. Biochim. Biophys. Acta. 910:203212[ISI][Medline]
Felsenstein, J.. 1974. The evolutionary advantage of recombination. Genetics. 78:737756
Fitch, D. H., W. J. Bailey, D. A. Tagle, M. Goodman, L. Sieu, and J. L. Slightom. 1991. Duplication of the gamma-globin gene mediated by L1 long interspersed repetitive elements in an early ancestor of simian primates. Proc. Natl. Acad. Sci. USA. 88:73967400[Abstract]
Furano, A. V.. 2000. The biological properties and evolutionary dynamics of mammalian LINE-1 retrotransposons. Prog. Nucleic Acids Res. Mol. Biol. 64:255294[ISI][Medline]
Goodier, J. L., E. M. Ostertag, and H. H. Kazazian Jr. 2000. Transduction of 3'-flanking sequences is common in L1 retrotransposition. Hum. Mol. Genet. 9:653657
Hasty, P., J. Rivera-Perez, and A. Bradley. 1991. The length of homology required for gene targeting in embryonic stem cells. Mol. Cell. Biol. 11:55865591[ISI][Medline]
Hattori, M., A. Fujiyama, and T. D. Tayloret al. (26 co-authors). 2000. The DNA sequence of human chromosome 21. Nature. 405:311319[ISI][Medline]
Hill, A. S., N. J. Foot, T. L. Chaplin, and B. D. Young. 2000. The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific alu-mediated recombination. Hum. Mol. Genet. 9:15251532
Holmes, S. E., B. A. Dombroski, C. M. Krebs, C. D. Boehm, and H. H. J. Kazazian. 1994. A new retrotransposable human L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion. Nat. Genet. 7:143148[ISI][Medline]
Hurst, L. D.. 1999. The evolution of genomic anatomy. Trends Ecol. Evol. 14:108112[ISI][Medline]
Inoue, H., H. Ishii, H. Alder, E. Snyder, T. Druck, K. Huebner, and C. M. Croce. 1997. Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. Proc. Natl. Acad. Sci. USA. 94:1458414589
Junakovic, N., A. Terrinoni, C. Di Franco, C. Vieira, and C. Loevenbruck. 1998. Accumulation of transposable elements in the heterochromatin and on the Y chromosome of Drosophila simulans and Drosophila melanogaster. J. Mol. Evol. 46:661668[ISI][Medline]
Kazazian, H. H. Jr. 2000. L1 Retrotransposons shape the mammalian genome. Science. 289:11521153
Kimberland, M. L., V. Divoky, J. Prchal, U. Schwahn, W. Berger, and H. H. Kazazian Jr. 1999. Full-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells. Hum. Mol. Genet. 8:15571560
Kimura, M.. 1980. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J. Mol. Evol. 16:111120[ISI][Medline]
Kjellman, C., H. O. Sjogren, and B. Widegren. 1995. The Y chromosome: a graveyard for endogenous retroviruses. Gene. 161:163170[ISI][Medline]
Laurent, A. M., J. Puechberty, and G. Roizes. 1999. Hypothesis: for the worst and for the best, L1Hs retrotransposons actively participate in the evolution of the human centromeric alphoid sequences. Chromosome Res. 7:305317[ISI][Medline]
McNaughton, J. C., D. J. Cockburn, G. Hughes, W. A. Jones, N. G. Laing, P. N. Ray, P. A. Stockwell, and G. B. Petersen. 1998. Is gene deletion in eukaryotes sequence-dependent? A study of nine deletion junctions and nineteen other deletion breakpoints in intron 7 of the human dystrophin gene. Gene. 222:4151[ISI][Medline]
Moran, J. V., R. J. DeBerardinis, and H. H. Kazazian Jr. 1999. Exon shuffling by L1 retrotransposition. Science. 283:15301534
Pickeral, O. K., W. Makalowski, M. S. Boguski, and J. D. Boeke. 2000. Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. Genome Res. 10:411415
Rice, W. R.. 1994. Degeneration of a nonrecombining chromosome. Science. 263:230232[ISI][Medline]
Richard, M., A. Belmaaza, N. Gusew, J. C. Wallenburg, and P. Chartrand. 1994. Integration of a vector containing a repetitive LINE-1 element in the human genome. Mol. Cell. Biol. 14:66896695[Abstract]
Saitou, N., and M. Nei. 1987. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4:406425[Abstract]
Saxton, J. A., and S. L. Martin. 1998. Recombination between subtypes creates a mosaic lineage of LINE-1 that is expressed and actively retrotransposing in the mouse genome. J. Mol. Biol. 280:611622[ISI][Medline]
Schwartz, A., D. C. Chan, L. G. Brown, R. Alagappan, D. Pettay, C. Disteche, B. McGillivray, A. de la Chapelle, and D. C. Page. 1998. Reconstructing hominid Y evolution: X-homologous block, created by X-Y transposition, was disrupted by Yp inversion through LINE-LINE recombination. Hum. Mol. Genet. 7:111
Scott, A. F., B. J. Schmeckpeper, M. Abdelrazik, C. T. Comey, B. O'Hara, J. P. Rossiter, T. Cooley, P. Heath, K. D. Smith, and L. Margolet. 1987. Origin of the human L1 elements: proposed progenitor genes deduced from a consensus DNA sequence. Genomics. 1:113125[Medline]
Segal, Y., B. Peissel, A. Renieri, M. de Marchi, A. Ballabio, Y. Pei, and J. Zhou. 1999. LINE-1 elements at the sites of molecular rearrangements in alport syndrome-diffuse leiomyomatosis. Am. J. Hum. Genet. 64:6269[ISI][Medline]
Skowronski, J., T. G. Fanning, and M. F. Singer. 1988. Unit-length line-1 transcripts in human teratocarcinoma cells. Mol. Cell. Biol. 8:13851397[ISI][Medline]
Smit, A. F. A.. 1999. Interspersed repeats and other mementos of transposable elements in mammalian genomes. Curr. Opin. Genet. Dev. 9:657663[ISI][Medline]
Smit, A. F. A., G. Tóth, A. D. Riggs, and J. Jurka. 1995. Ancestral, mammalian-wide subfamilies of LINE-1 repetitive sequences. J. Mol. Biol. 246:401417[ISI][Medline]
Steinemann, M., and S. Steinemann. 1992. Degenerating Y chromosome of Drosophila miranda: a trap for retrotransposons. Proc. Natl. Acad. Sci. USA. 89:75917595[Abstract]
Swofford, D. L.. 1998. PAUP*Phylogenetic analysis using parsimony (* and other methods). Version 4. Sinauer, Sunderland, Mass
Wichman, H. A., R. A. Van Den Bussche, M. J. Hamilton, and R. J. Baker. 1992. Transposable elements and the evolution of genome organization in mammals. Genetica. 86:287293[ISI][Medline]
Wutz, A., and R. Jaenisch. 2000. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell. 5:695705[ISI][Medline]