Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease

Unequal homologous recombination between repetitive genetic elements is one mechanism that mediates genome instability. We have characterized a homologous recombination event between two neighboring LINE-1 sequences in the human gene encoding the beta subunit of phosphorylase kinase (PHKB). It has lead to the deletion of 7574 nucleotides of genomic DNA including exon 8 of this gene, giving rise to glycogen storage disease through phosphorylase kinase deficiency. To our knowledge, this is the first example of a mutation due to unequal homologous recombination between LINE-1 elements. The sequence features of the recombining LINE-1 elements and of the recombination junction site, and possible reasons for the more frequent occurrence of unequal homologous recombination between Alu elements are discussed.