A novel possible mechanism for the genesis of genomic duplications and its experimental test.

Duplication of genomic regions is an important biological process associated with the appearance of gene families, the origin of alternative splicing, and the etiopathogenesis of genetic diseases. Different mechanisms for the genesis of duplications have been suggested, based mainly on structural analyses. However, experimental confirmation of those mechanisms is scarce, mostly because of a lack of information about the circumstances that triggered the rearrangements. Here, I characterize a duplication of about 300 kbp (kilobase pairs) that occurred in the course of a gene targeting experiment. Considering the structure of the locus and the triggering event, I suggest a likely mechanism for the genesis of this duplication which involves anomalous processing of contiguous Okazaki fragments during lagging strand replication. Most importantly, I provide experimental evidence to substantiate that the proposed mechanism can indeed lead to duplication of genomic segments. The model presented represents a novel mechanistic pathway that can explain a variety of rearrangements, including genomic tandem duplications and deletions.