Variability in expression of common fragile sites: in search of a new criterion

Fragile sites are nonrandom, heritable sites on chromosomes that can be induced to form gaps, breaks, and rearrangements under specific conditions. There is currently no established criterion to define a common fragile site. We applied seven published criteria to our data from three groups of subjects: (1) three pairs of like-sexed twins, (2) four unaffected von Hippel-Lindau (VHL) family members, and (3) six patients affected with VHL disease. Substantial differences were present in the numbers of sites considered positive by these criteria. While some of this variability can be attributed to technical factors, our data illustrate the problems in comparing results from different studies to assess the significance of fragile sites. A recently published criterion is based upon the Poisson distribution. We found this criterion to be flawed in its presentation, and furthermore, the Poisson distribution did not provide an adequate approximation to our data. We propose here an alternative approach based upon the negative binomial distribution.