Recombination Hot Spots and Human Disease

Recombination between homologous DNA sequences occurs in all organisms, and the resultant exchange of information is critical for the survival of species. Recombination is an essential cellular process catalyzed by proteins explicitly expressed for this purpose. It provides an effective means of generating genetic diversity that is important for evolution. The proteins involved in recombination allow cells to retrieve sequences lost when DNA is damaged by radiation or chemicals, by replacing the damaged section with an undamaged strand from a homologous chromosome. The process of homologous recombination has also been used to study gene function by way of gene knockouts. However, recombination and factors involved in recombination may also be a source of harmful mutations and disease.

Specific DNA sequences are known to mediate or enhance the rate of recombination in the genomes of many organisms. Attempts to identify and decipher recombination hot spots have focused on determining the influence of various DNA sequences on the rate and type of DNA rearrangements. The human nuclear genome contains a large number of highly repeated DNA sequence families (Jelinek and Schmid 1982; Hardman 1986; Vogt 1990), broadly classified as tandemly repeated DNA or interspersed repetitive DNA. Because of their role in mediating disease-causing recombination errors, a brief overview of the various repeats is presented.

Tandemly repeated DNA is characterized by blocks or arrays of tandemly repeated DNA sequences. They are subclassified based on the size of the blocks or arrays of tandem repeats into satellite (0.1 to >2 Mb), minisatellite (0.1–2.0 kb), and microsatellite (∼150 bp) DNA. Satellite DNA is further sub-classified based on the size of the repeat unit within these blocks into types 1 (25–48 bp), 2 and 3 (5 bp), α (alphoid DNA; 171 bp), and β (Sau3A family; 68 bp). Minisatellite DNA consists of telomeric …