title: Allelic heterogeneity in LINE-1 retrotransposition activity.
abstract: De novo LINE-1 (long interspersed element-1, or L1) retrotransposition events are responsible for approximately 1/1,000 disease-causing mutations in humans. Previously, L1.2 was identified as the likely progenitor of a mutagenic insertion in the factor VIII gene in a patient with hemophilia A. It subsequently was shown to be one of a small number of active L1s in the human genome. Here, we demonstrate that L1.2 is present at an intermediate insertion allele frequency in worldwide human populations and that common alleles (L1.2A and L1.2B) exhibit an approximately 16-fold difference in their ability to retrotranspose in cultured human HeLa cells. Chimera analysis revealed that two amino acid substitutions (S1259L and I1220M) downstream of the conserved cysteine-rich motif in L1 open reading frame 2 are largely responsible for the observed reduction in L1.2A retrotransposition efficiency. Thus, common L1 alleles can vary widely in their retrotransposition potential. We propose that such allelic heterogeneity can influence the potential L1 mutational load present in an individual genome.
authors: Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA. moranj@umich.edu
authors: Sheila M
authors: SM
authors: Lutz
authors: Bethaney J
authors: BJ
authors: Vincent
authors: Haig H
authors: HH
authors: Kazazian
authors: Mark A
authors: MA
authors: Batzer
authors: John V
authors: JV
authors: Moran
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D004251:DNA Transposable Elements / Q000235:genetics*; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D005828:Genetics, Population; D006367:HeLa Cells; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008969:Molecular Sequence Data
chemical_list: D004251:DNA Transposable Elements