Statistical study of human constitutional chromosome rearrangement breakpoint distributions

In this study the question of nonrandomness in the distribution of human constitutional rearrangements was evaluated. The distribution of breakpoints were analysed in three groups of reciprocal translocations and three groups of inversions, subdivided according to method of ascertainment of cases for study. In addition, one data set of structural aberrations obtained from sperm chromosomes was also analysed. The method of statistical analysis, based on the binomial distribution, was developed specifically to allow testing distributions in chromosome segments as small as chromosome bands. The distribution of breakpoints was analysed in all data sets using this method, in addition to testing for overall nonrandomness using goodness of fit statistics. Nonrandomness in breakpoint distributions was found in reciprocal translocations (rcp) and inversions ascertained through abnormalities and through incidental events. However, random distribution was observed in incidentally ascertained de novo rearrangements as well as in sperm chromosome aberrations. The nonrandomness in the distribution of rcp breakpoints can be largely attributed to a bias in ascertainment of cases based on the phenotypic manifestations of chromosomal imbalance resulting from a rearrangement. A dependence of the probability of producing specific types of balanced or unbalanced progeny on the position of breakpoints is a likely explanation for the nonrandomness produced in breakpoint distributions. However, some bands including, 5q35, 7p22, 9p22, 13ql4, and 17q25, were observed in different ascertainment groups, excluding selection bias as a likely explanation for this observation. These bands may represent true sites of nonrandom rearrangement due to some factor associated with an underlying DNA sequence or structural characteristic of chromatin that predisposes to rearrangement at specific sites. The nonrandomness observed in the distribution of inversion breakpoints is most likely the product of a founder effect. Many identical inversions in apparently unrelated individuals have been found suggesting that a few ancestral mutations have become widespread in the population. A large data set of incidentally ascertained de novo inversions is required to distinguish between sites of frequent breakage and nonrandomness produced by the ascertainment of related cases. All evidence considered together, indisputable predisposition to rearrangement at specific sites was not found in this study. Furthermore, an overall random association of constitutional rearrangement breakpoints in bands with known oncogenes and fragile sites was observed. However, the possibility of oncogenes and fragile sites as factors involved in constitutional rearrangements in a few isolated cases cannot be excluded. Nonrandomness was found when distribution of breakpoints in light and dark G bands was compared. An excess of breakpoints in some light G bands was observed even after a conservative correction for a possible pattern recognition bias which may lead to the overascertainment of breakpoints in light G bands.Medicine, Faculty ofMedical Genetics, Department ofGraduat