L1 Elements Are A Source of Human Disease

L1 Elements Are A Source of Human Disease

SE Holmes

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).