Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits

Molecular medicine began with Pauling's seminal work, which recognized sickle-cell anemia as a molecular disease, and with Ingram's demonstration of a specific chemical difference between the hemoglobins of normal and sickled human red blood cells. During the four decades that followed, investigations have focused on the gene—how mutations specifically alter DNA and how these changes affect the structure and expression of encoded proteins. Recently, however, the advances of the human genome project and the completion of total genome sequences for yeast and many bacterial species, have enabled investigators to view genetic information in the context of the entire genome. As a result, we recognize that the mechanisms for some genetic diseases are best understood at a genomic level. The evolution of the mammalian genome has resulted in the duplication of genes, gene segments and repeat gene clusters. This genome architecture provides substrates for homologous recombination between nonsyntenic regions of chromosomes. Such events can result in DNA rearrangements that cause disease.