ABSTRACT
The rapid progress in molecular genetics over the past two decades is chang ing our view of human genome organization, of which chromosomes are the most visible manifestation. We are just learning the importance of hetero geneity in the distribution and function of nucleotide sequences in eukaryotic genomes that have evolved mechanisms to maintain genomic stability over hundreds of millions of years of natural selection. Radiation, chemicals , intrinsic errors in metabolism or in the cell cycle, and foreign DNA such as phages, retroviruses, and adenoviruses act on eukaryotic chromosomes, caus ing polyploidy, aneuploidy, breaks, incomplete replication, and rearrange ments, all of which restructure the genome. Major errors in chromosome distribution or imbalance are eliminated from the time of oogenesis or sper matogenesis, through conception, embryogenesis, and fetal development. As discussed in detail in the chapter by Warburton in this volume, 1 5 % of all conceptions end in mi scarriage ( 1 ) . As high as 70% of first-trimester mis carriages have chromosomal aneuploidy or polyploidy (2) . By the time of birth, less than 0.6% of newborns have a microscopically detectable chro mosome abnormality (3) . Even with this attrition, environmental and genetic
factors continue to modify DNA and chromosomes to contribute to somatic chromosome instability. Some structural rearrangements, such as dicentric chromosomes, rings, and acentric fragments, are mechanically less able to segregate correctly during mitosis and tend to be lost. Entire chromosomes or chromosome sets are also lost or gained by errors in distribution during meiosis or mitosis. In most cases these gains or losses result either in cell death or, more rarely, in mosaici sm. Still more rarely, loss or gain can result in genome instability, and occasional cells lose cell cycle control, leading to cancer.
