De novo LINE-1 (long interspersed element-1, or L1) retrotransposition events are responsible for ∼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 ∼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.
Bibliographical noteFunding Information:
We thank members of the University of Michigan DNA sequencing core for help with sequencing. We thank Dr. Nicolas Gilbert, Ms. Amy Hulme, Mr. Reid Alisch, and other members of the Moran laboratory for critically evaluating the manuscript. M.A.B is supported, in part, by National Science Foundation grant BCS-0218338 and National Institutes of Health (NIH) grant GM59290. H.H.K. is supported, in part, by NIH grant GM45398. J.V.M. is supported, in part, by NIH grant GM60518 and by a grant from the W. M. Keck Foundation. The University of Michigan Cancer Center helped to defray some of the costs of DNA sequencing.