ASYNCHRONOUS REPLICATION OF HOMOLOGOUS ALPHA-SATELLITE DNA LOCI IN MAN IS ASSOCIATED WITH NONDISJUNCTION

We tested the hypothesis that loss of replication control of DNA loci associated with human centromeres affects the main centromere function , namely, ensuring proper sister chromatid separation and accurate chr omosomal segregation during cell division. Applying one-color fluoresc ence in situ hybridization (FISH) to interphase nuclei, we studied the replication patterns of homologous DNA loci associated with human cen tromeres (alpha-satellite sequences) of chromosome pairs 10, 11, 17, a nd X in PHA-stimulated lymphocytes of female cancer patients with a fa milial predisposition to malignancy and normal, healthy women. Concomi tantly, we measured the rates of aneuploidy for these chromosomes in t he same cells. To elucidate the replication patterns of the various ce ntromeric loci, we analyzed the replication-dependent configuration si gnals obtained following FISH with four chromosome-specific alpha-sate llite probes. Our data showed an association between replication timin g of alpha-satellite sequences and centromeric function. Chromosome pa irs whose homologous alpha-satellite loci replicated highly synchronou sly revealed low rates of aneuploidy, whereas chromosome pairs with a slightly asynchronous replication pattern (i.e., short intervals betwe en early- and late-replicating loci) revealed intermediate rates of an euploidy, and chromosome pairs exhibiting asynchrony with long-time in tervals between early- and late-replicating loci showed the highest ra te of aneuploidy.