Recent advance in our understanding of the molecular nature of chromosomal abnormalities

The completion of the human genome project has enabled researchers to characterize the breakpoints for various chromosomalstructural abnormalities including deletions, duplications or translocations. This in turn has shed new light on the molecularmechanisms underlying the onset of gross chromosomal rearrangements. On the other hand, advances in genetic manipulationtechnologies for various model organisms has increased our knowledge of meiotic chromosome segregation, errors which,contribute to chromosomal aneuploidy. This review focuses on the current understanding of germ line chromosomalabnormalities and provides an overview of the mechanisms involved. We refer to our own recent data and those of others toillustrate some of the new paradigms that have arisen in this field. We also discuss some perspectives on the sexual dimorphismof some of the pathways that leads to these chromosomal abnormalities.Journal of Human Genetics (2009) 54, 253–260; doi:10.1038/jhg.2009.35; published online 17 April 2009Keywords: aneuploidy; cruciform; deletion; gross chromosomal rearrangement; low-copy repeat; non-disjunction; palindrome;translocationTHE RANDOM NATURE OF GROSS CHROMOSOMALREARRANGEMENTSThe development of chromosomal structural abnormalities, alsoknown as gross chromosomal rearrangements (GCR), is essentiallydependent on two distinct processes: double-strand breaks (DSB) andDSB repair. DSBs can result from exogenous agents such as ionizingradiation and chemotherapeutic drugs, and also from endogenouslygenerated reactive oxygen species and mechanical stresses on thechromosomes.