Non-B DNA Conformations, Genomic Rearrangements, and Human Disease

Abstract

The history of investigations on non-B DNA conformations as related to genetic diseases dates back to the mid-1960s. Studies with high molecular weight DNA polymers of defined repeating nucleotide sequences demonstrated the role of sequence in their properties and conformations (1). Investigations with repeating homo-, di-, tri-, and tetranucleotide repeating motifs revealed the powerful role of sequence in molecular behaviors. At that time, this concept was heretical because numerous prior investigations with naturally occurring DNA sequences masked the effect of sequence (1). It may be noted that these studies in the 1960s predated DNA sequencing by at least a decade. Early studies were followed by a number of innovative discoveries on DNA conformational features in synthetic oligomers, restriction fragments, and recombinant DNAs. The DNA polymorphisms were a function of sequence, topology (supercoil density), ionic conditions, protein binding, methylation, carcinogen binding, and other factors (2). A number of non-B DNA structures have been discovered (approximately one new conformation every 3 years for the past 35 years) and include the following: triplexes, left-handed DNA, bent DNA, cruciforms, nodule DNA, flexible and writhed DNA, G4 tetrad (tetraplexes), slipped structures, and sticky DNA (Fig. 1). From the outset, it was realized (1, 2) that these sequence effects probably have profound biological implications, and indeed their role in transcription (3) and in the maintenance of telomere ends (4) has recently been reviewed. However, in the past few years dramatic advances from genomics, human genetics, medicine, and DNA structural biology have revealed the role of non-B conformations in the etiology of at least 46 human genetic diseases (Table I) that involve genomic rearrangements as well as other types of mutation events.