Chromosome spatial order in human cells: evidence for early origin and faithful propagation

We have investigated the origin and nature of chromosome spatial order in h uman cells by analyzing and comparing chromosome distribution patterns of n ormal cells with cells showing specific chromosome numerical anomalies know n to arise early in development. Results show that all chromosomes in norma l diploid cells, triploid cells and in cells exhibiting nondisjunction tris omy 21 are incorporated into a single, radial array (rosette) throughout mi tosis. Analysis of cells using fluorescence in situ hybridization, digital imaging and computer-assisted image analysis suggests that chromosomes with in rosettes are segregated into tandemly linked "haploid sets" containing 2 3 chromosomes each. In cells exhibiting nondisjunction trisomy 21, the dist ribution of chromosome 21 homologs in rosettes was such that two of the thr ee homologs were closely juxtaposed, a pattern consistent with our current understanding of the mechanism of chromosomal nondisjunction. Rosettes of c ells derived from triploid individuals contained chromosomes segregated int o three, tandemly linked haploid sets in which chromosome spatial order was preserved, but with chromosome positional order in one haploid set inverte d with respect to the other two sets. The spatial separation of homologs in triploid cells was chromosome specific, providing evidence that chromosome s occupy preferred positions within the haploid sets. Since both triploidy and nondisjunction trisomy 21 are chromosome numerical anomalies that arise extremely early in development (e.g., during meiosis or during the first f ew mitoses), our results support the idea that normal and abnormal chromoso me distribution patterns in mitotic human cells are established early in de velopment, and are propagated faithfully by mitosis throughout development and into adult life. Furthermore, our observations suggest that segregation of chromosome homologs into two haploid sets in normal diploid cells is a remnant of fertilization and, in normal diploid cells, reflects segregation of maternal and paternal chromosomes.