"Line Retrotransposable Element 1; LRE1"
Alternative titles; symbols:
LINE-1.2 RETROTRANSPOSABLE ELEMENT; L1.2
Gene map locus: 22q11-q12
TEXT:
Over 50,000 L1 (Line-1; long inserted element-1) sequences exist
in the human genome; 3,000
to 4,000 of these are full length (6.1 kb), whereas the rest are
truncated at the 5-prime end.
Line-1 is a member of a specific group of transposable elements
called retroposons, which can
be transcribed into RNA, reverse transcribed into cDNA, and then
reintegrated as cDNAs into
the genome at a new location. Line-1 is a class II retroposon; it
does not contain long terminal
repeats, has at least one open reading frame, and has an A-rich
tract at its 3-prime end. The L1
element composes about 5% of the human genome.
Kazazian et al. (1988) found insertion of an L1
element into exon 14 of the factor VIII gene
causing hemophilia in 2 unrelated patients. Both of these insertions
(3.8 and 2.3 kb, respectively)
contained 3-prime portions of the L1 sequence. Both of the insertions
were de novo events.
Dombroski et al. (1991) used an oligonucleotide
probe complementary to a unique region of the
cloned sequence of one of these patients to detect hybridizing fragments
in the DNA and to
isolate a genomic full-length element containing the 2 open reading
frames (ORFs) of the L1
consensus sequence. This element, called L1.2A, contained the 2
nucleotide changes found in
the insertion in the factor VIII gene of patient JH27 (306700.0022).
However, these 2 changes
were absent from the DNA in the parents. Dombroski
et al. (1991) constructed a genomic DNA
library from the mother of JH27 and isolated an allele of L1.2A
(L1.2B). L1.2B was the first
full-length element with 2 intact ORFs. It contained a 27-bp poly(A)
tail and was flanked by a
15-bp target site duplication. The ORF2 of L1.2A encoded reverse
transcriptase activity. The
L1.2 locus was assigned to chromosome 22 by analysis of somatic
cell hybrid DNAs. It was the
first retrotransposable element isolated from human DNA. Dombroski
et al. (1991) mapped the
L1.2 locus to chromosome 22 by PCR analysis of DNA from human-rodent
cell hybrids. Budarf
et al. (1991) localized the assignment to 22q11.1-q11.2
by in situ hybridization. Dombroski et
al. (1991) demonstrated that the L1.2 transposable
element contains 2 open reading frames.
Mathias et al. (1991) showed that the second
open reading frame encodes a protein with reverse
transcriptase activity. Thus, L1 represents a potential source of
the reverse transcriptase activity
necessary for dispersion of the many classes of mammalian retroelements.
It is possible that the
reverse transcriptase coded by LINEs may help Alu sequences move
around in the genome.
Insertions of Alu sequences have been identified as the cause of
mutation in neurofibromatosis
(NF1; 162200.0001) and in hemophilia B (306900). (In
addition, the widely distributed Alu
sequences, representing as much as 3% of the genome, have been identified
as the frequent basis
of disease-producing deletion of exons resulting from homologous
recombination between Alu
sequences located in adjoining introns. Familial hypercholesterolemia
(143890), Fabry disease
(301500), Sandhoff disease (268800), Tay-Sachs disease
(272800), ADA deficiency
(102700), type I hyperlipoproteinemia (238600), and
Glanzmann thrombasthenia (273800) are
only a few of the numerous disorders in which this mechanism appears
to be operative.) The L1
element on chromosome 22 is presumably present at that location
in all humans. Dombroski et
al. (1991) found it in the same (i.e., corresponding)
location in chimpanzees and gorillas which
means that it has been at the same location in the genome for at
least 6 million years.
Brosius and Gould (1992), who referred to the
gene discovered by Dombroski et al. (1991) as
the LINE1 master gene, proposed a 'genomenclature' which would provide
a comprehensive
and, as they pointed out, respectful taxonomy for pseudogenes and
other so-called junk DNA.
They proposed a general terminology that might aid the integrated
study of evolution and
molecular biology. They designated as a 'nuon' any stretch of nucleic
acid sequence that may be
identifiable by any criterion. Since pseudogenes and dispersed repetitive
elements constitute a
vast repertoire of sequences with the capacity to shape an organism
during evolution, they
proposed that this potential to contribute sequences for future
use be reflected in the terms
'potonuons' or 'potogenes.' If such a potonuon has been co-opted
into a variant or novel
function, an evolutionary process termed 'exaptation,' they employed
the term 'xaptonuon.' If a
potonuon remains without function (nonactive nuon), it is a 'nonaptation'
and they termed it
'naptonuon.' They gave a number of examples for potonuons and xaptonuons.
They even used
the term 'xaptoprotein' for examples involving crystallins of the
eye lens which, although having
structural roles in the refractive properties of the lens, are identical
to housekeeping enzymes (see
123660).
Dombroski et al. (1993) isolated the 2 remaining
full-length members of the subfamily of L1
elements closely related to the L1.2B present in the genome of the
mother of hemophilia patient
JH27. Since these elements, L1.3 and L1.4, were very similar
in sequence to L1.2B and
contained both open reading frames 1 and 2 intact, they were thought
also to be active
retrotransposable elements. The results suggested that certain L1
subfamilies may contain
multiple active elements.
Feng et al. (1996) identified an endonuclease
domain at the amino terminus of the second open
reading frame of L1. It is highly conserved among poly(A) retrotransposons
and resembles the
apurinic/apyrimidinic endonucleases. Mutations in conserved amino
acid residues of L1
endonuclease abolished its nicking activity and eliminated L1 retrotransposition.
Feng
et al.
(1996) proposed that L1 endonuclease cleaves the target site for
L1 insertion and primes
reverse transcription. Moran et al. (1996) showed
that both the previously isolated human L1
elements, L1.2 and LRE2, can actively retrotranspose in cultured
mammalian cells. When stably
expressed from an episome in HeLa cells, both elements retrotransposed
into a variety of
chromosomal locations at a high frequency. The retrotransposed products
resembled
endogenous L1 insertions, since they were variably 5-prime truncated,
ended in poly(A) tracts,
and were flanked by target-site duplications or short deletions.
Point mutations in conserved
domains of the L1.2-encoded proteins reduced retrotransposition
by 100- to 1,000-fold.
Remarkably, L1.2 also retrotransposed in a mouse cell line, suggesting
a potential role for
L1-based vectors in random insertional mutagenesis.
Sassaman et al. (1997) demonstrated that many
human L1 elements are capable of
retrotransposition in HeLa cells. They reported studies bringing
to 7 the number of characterized
active human L1 elements. Based on these and other data, they estimated
that 30 to 60 active
L1 elements reside in the average diploid human genome. Boeke
(1997) reviewed the
significance of the fact that LINEs and Alu elements have in common
the presence of poly(A)
tails of varying length, as well as other shared structural features.
A puzzling aspect of L1
retrotransposition is that the transposition machinery behaves in
a cis-acting manner. The
estimate of Sassaman et al. (1997) that 20 to
60 functional L1 elements are to be found in the
diploid genome indicates that in spite of the large number of L1
elements that are transcriptionally
active, only a remarkably small subset (less than 0.01%) are able
to transpose, i.e., are capable
of causing mutations. In humans and mice, only L1 elements encoding
intact open reading frames
are transpositionally competent. This implies the existence of a
mechanism ensuring cis-action.
Human L1 contains 2 ORFs; ORF1 encodes an RNA-binding protein and
ORF2 encodes an
endonuclease-reverse transcriptase protein. Several observations
suggested to Boeke (1997)
that during or immediately after its translation, nascent L1 ORF2
protein interacts with the
poly(A) tail of its own mRNA. Binding to the poly(A) at the 3-prime
end of L1 RNA is likely to
be required for retrotransposition.
Kazazian and Moran (1998) reviewed the 'master'
human mobile element, the L1
retrotransposon. They predicted that new insight is likely to lead
to important practical
applications for these intriguing mobile elements. They referred
to 6 retrotransposed L1
insertions in addition to the original 2 found to disrupt the factor
VIII gene, resulting in hemophilia
A: one was also in factor VIII, causing no deleterious effects (Woods-Samuels
et al., 1989); 3
were in the Duchenne muscular dystrophy gene (DMD; 310200);
1 was in the APC gene
(175100), causing colon cancer (Miki et al.,
1992); and another was in the beta-globin gene
(HBB; 141900).
To determine the frequency of L1-mediated transduction in the human
genome, Goodier et al.
(2000) studied 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. Given that there are approximately 400,000 L1 elements,
the authors estimated that
insertion of transduced sequences alone may have enlarged the diploid
human genome as much
as 19 Mb or 0.6%. They also examined 24 full-length mouse L1s and
found 2 long transduced
sequences. The authors concluded that L1 retrotransposition in vivo
commonly transduces
sequence flanking the 3-prime end of the element.
SEE ALSO:
Dombroski et al. (1991)
REFERENCES: see PubMed: http://www.ncbi.nlm.nih.gov/PubMed/
1. Boeke, J. D. :
LINEs and Alus--the polyA connection. Nature
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2. Brosius, J.; Gould, S. J. :
On 'genomenclature': a comprehensive (and
respectful) taxonomy for
pseudogenes and other 'junk DNA.' Proc.
Nat. Acad. Sci. 89: 10706-10710, 1992.
PubMed ID : 1279691
3. Budarf, M. L.; Collins, J.; Frazer, K.; Cox,
D.; Emanuel, B. S. :
Regional sublocalization of a putative
retrotransposable human LINE element on
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E. J.; Scott, A. F.; Kazazian, H. H., Jr. :
Isolation of the L1 gene responsible for
a retrotransposition event in man.
(Abstract) Am. J. Hum. Genet. 49 (suppl.):
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H., Jr. :
Two additional potential retrotransposons
isolated from a human L1 subfamily
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7. Feng, Q.; Moran, J. V.; Kazazian, H. H., Jr.;
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Human L1 retrotransposon encodes a conserved
endonuclease required for
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Transduction of 3-prime-flanking sequences
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Disruption of the APC gene by a retrotransposal
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15. Woods-Samuels, P.; Wong, C.; Mathias, S. L.;
Scott, A. F.; Kazazian, H. H., Jr.;
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Characterization of a nondeleterious L1
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PubMed ID : 2497061
3. "Initial Sequencing and Analysis of the Human Genome".
George E. Tiller - updated : 4/14/2000
Victor A. McKusick - updated : 3/2/1999
Victor A. McKusick - updated : 4/28/1998
Victor A. McKusick - updated : 5/2/1997
CREATION DATE:
Victor A. McKusick : 10/4/1991
EDIT HISTORY:
terry : 4/14/2000
mgross : 3/15/1999
carol : 3/4/1999
terry : 3/2/1999
carol : 7/22/1998
terry : 4/28/1998
terry : 5/9/1997
mark : 5/2/1997
terry : 4/29/1997
mark : 1/11/1997
terry : 1/9/1997
carol : 8/25/1993
carol : 12/14/1992
supermim : 3/16/1992
carol : 2/22/1992
carol : 2/7/1992
carol : 1/21/1992