L1 Elements Are A Source of Human Disease
The LINE or L1 element is the major autonomous retrotransposon
in the human genome (1). It belongs to the class of non-LTR or
polyA-containing retrotransposons. The full-length element is
approximately 6 kb in length and contains two ORFs encoding proteins known or
likely to be involved in the retrotransposition process. The human genome
contains approximately 100,000 L1s, the majority of which are inactive due to
mutations and/or truncations of varying degrees at the 5′ end.
Disease-causing L1 insertions have been found in the factor VIII gene, the
dystrophin gene, the beta-globin gene, APC, and the RP2 (retinitis pigmentosa 2)
gene (1,2). It was postulated the precursor elements to these insertions
would be ‘active’: capable of transcription, reverse transcription, and
insertion in a new genomic location.
We have isolated two full-length, active L1 elements, LRE1 and
LRW2, which were each the progenitor element leading to an insertion
mutation. LRE1 gave rise to a truncated copy inserted in the gene encoding
factor VIII (3). LRE2 gave rise to a truncated, chimaeric element in the
dystrophin gene (4). We established an assay to detect and analyze
retrotransposition of L1 elements in cultured mammalian cells (5). This
has been used to compare retrotransposition frequencies of various potentially
active full-length elements (6), and two full-length mouse elements (7), as well
as to determine which regions of the L1 element are critical for
1. Kazazian, H.H. & Moran, J.V. The impact of L1
retrotransposons on the human genome. Nature Genetics 19, 19-24 (1998).
2. Schwahn, U. et al. Positional cloning of the genes for
X-linked retinitis pigmentosa 2. Nature Genetics 19, 327-332 (1998).
3. Dombroski, B.A. et al. Isolation of an Active
Human Transposable Element. Science 254, 1805-1808 (1991).
4. Holmes, S.E. et al. A new retrotransposable human
L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion.
Nature Genetics 7, 143-148 (1994).
5. Moran, J.V. et al. High-frequency
retrotransposition in cultured mammalian cells. Cell 87 917-927 (1996).
6. Sassaman, D.M. et al. Many human L1 elements are
capable of retrotransposition. Nature Genetics 16 37-43 (1997).
7. Naas, T.P. et al. An actively retrotransposing, novel
subfamily of mouse L1 elements. EMBO 17, 590-597 (1998).