Inverted repeats are often described as "hotspots" of eukaryotic and prokaryotic genomic instability. Long inverted repeats are deemed to greatly influence the stability of the genome of various organisms. This is exemplified in E. coli, where genomic sequences with long inverted repeats are seldom replicated, but rather deleted with rapidity. Again, the long inverted repeats observed in yeast greatly favor recombination within the same and adjacent chromosomes, resulting in an equally very high rate of deletion. Finally, a very high rate of deletion and recombination were also observed in mammalian chromosomes regions with inverted repeats. Reported differences in the stability of genomes of interrelated organisms are always an indication of a disparity in inverted repeats. The instability results from the tendency of inverted repeats to fold into hairpin- or cruciform-like DNA structures. These special structures can hinder or confuse DNA replication and other genomic activities. Thus, inverted repeats lead to special configurations in both RNA and DNA that can ultimately cause mutations and disease.
The illustration shows an inverted repeat undergoing cruciform extrusion. DNA in the region of the inverted repeat unwinds and then recombines, forming a four-way junction with two stem-loop structures. The cruciform structure occurs because the inverted repeat sequences self-pair to each other on their own strand.
Extruded cruciforms can lead to frameshift mutations when a DNA sequence has inverted repeats in the form of a palindrome combined with regions of direct repeats on either side. During transcription, slippage and partial dissociation of the polymerase from the template strand can lead to both deletion and insertion mutations.  Deletion occurs when a portion of the unwound template strand forms a stem-loop that gets "skipped" by the transcription machinery. Insertion occurs when a stem-loop forms in a dissociated portion of the nascent (newly synthesized) strand causing a portion of the template strand to be transcribed twice.