Alu repeats and human disease

Alu elements have amplified in primate genomes through a RNA-dependent mech anism, termed retroposition, and have reached a copy number in excess of 50 0,000 copies per human genome. These elements have been proposed to have a number of functions in the human genome, and have certainly had a major imp act on genomic architecture, Alu elements continue to amplify at a rate of about one insertion every 200 new births. We have found 16 examples of dise ases caused by the insertion of Alu elements, suggesting that they may cont ribute to about 0.1% of human genetic disorders by this mechanism. The larg e number of Alu elements within primate genomes also provides abundant oppo rtunities for unequal homologous recombination events. These events often o ccur intrachromosomally, resulting in deletion or duplication of exons in a gene, but they also can occur interchromosomally, causing more complex chr omosomal abnormalities. We have found 33 cases of germline genetic diseases and 16 cases of cancer caused by unequal homologous recombination between Alu repeats. We estimate that this mode of mutagenesis accounts for another 0.3% of human genetic diseases. Between these different mechanisms, Alu el ements have not only contributed a great deal to the evolution of the genom e but also continue to contribute to a significant portion of human genetic diseases. (C) 1999 Academic Press.