The centromere is an essential chromosomal element required for the faithful segregation of chromosomes during cell division. Chromosome missegregation causes aneuploidy that can lead to embryo death, birth abnormalities, and cancer. Human centromeres are made up of functionally important repetitive alpha satellite DNA. The large and monotonous tracts of this repetitive DNA do not provide many useful internal genetic markers and have hampered progress in the molecular definition of the detailed functional domains of these centromeres. A new class of alpha satellite-negative centromeres known as neocentromeres have recently been discovered that form ectopically at non-centromeric human genomic locations. Available data indicate that these neocentromeres are functionally identical to the normal centromeres. The absence of highly repeated DNA and the availability of fully sequenced genomic DNA markers make neocentromeres an amenable and useful system for studying complex mammalian centromere properties. The long-term objectives of this project are to elucidate the detailed organisational and functional properties of human neocentromeres, and to compare these properties with those of the normal human centromeres. These objectives will be accomplished by: 1) Mapping the domain organisation profiles of centromeric and pericentromeric components at the neocentromere; 2) Determining the functional significance and pliability of the various domains using available neocentromere-based minichromosomes, and through treatment with chemicals that modify chromatin structures; 3) Studying the silencing effects of neocentromeric domains on endogenous genes at or close to the neocentromere; and 4) Where possible, comparing these neocentromere properties with the properties of the normal centromeres using methods adapted for the repetitive alpha satellite DNA arrays. Sound knowledge on human centromere and neocentromere biology has important fundamental value as well as significant impact on our understanding and management of common diseases that are associated with chromosomal instability or missegregation.
