Partial gene duplication as a cause of human disease

Tandem duplication of large regions of DNA, including duplication of whole genes, provides a substrate for genetic evolution. Tandem duplication of smaller regions involving parts of genes is now recognized as a contributor to the mutation spectrum that results in genetic disease. In this review, more than 30 unrelated partial gene duplications that have been implicated in the genesis of human genetic disease are presented and the pathogenic effects and frequency of such duplications are summarized. The mechanisms of duplication formation are analyzed with special emphasis on the molecular details of the nucleotide sequences at the duplication junctions. Evidence to date suggests that duplication may arise from either homologous (Alu-Alu) recombination or nonhomologous recombination, the latter possibly mediated by topoisomerases. For the dystrophin gene, in which most duplications have been identified, these recombination events are intrachromosomal, suggesting that unequal sister chromatid exchange is the major mechanism.