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 chromosomal segregation during cell division. Applying one-color fluorescence in situ hybridization (FISH) to interphase nuclei, we studied the replication patterns of homologous DNA loci associated with human centromeres (alpha-satellite sequences) of chromosome pairs 10, 11, 17, and X in PHA-stimulated lymphocytes of female cancer patients with a familial predisposition to malignancy and normal, healthy women. Concomitantly, we measured the rates of aneuploidy for these chromosomes in the same cells. To elucidate the replication patterns of the various centromeric loci, we analyzed the replication-dependent configuration signals obtained following FISH with four chromosome-specific alpha-satellite probes. Our data showed an association between replication timing of alpha-satellite sequences and centromeric function. Chromosome pairs whose homologous alpha-satellite loci replicated highly synchronously revealed low rates of aneuploidy, whereas chromosome pairs with a slightly asynchronous replication pattern (i.e., short intervals between early- and late-replicating loci) revealed intermediate rates of aneuploidy, and chromosome pairs exhibiting asynchrony with long-time intervals between early- and late-replicating loci showed the highest rate of aneuploidy.