CaCAn

Aneuploidy, the state of cells containing an incorrect number of chromosomes, is associated with defective cellular functions. Aneuploidy occurs frequently during human embryonic development and often causes miscarriages or genetic diseases. However, all chromosomes are not equally likely to become aneuploid in human embryos. It has been proposed that chromosome-specific aneuploidy could arise from different propensities to be mis-segregated during mitosis as a result from the interaction of the mitotic spindle with the chromosome-specific centromeres. Also, during embryonic development, repair mechanisms could eliminate aneuploid cells into extra-embryonic tissues. However, this could not be studied systematically due to lack of tools to generate chromosome-specific aneuploidy. Our project CaCAn proposes to use newly developed biophysical and biochemical approaches to identify the causes and consequences of chromosome-specific aneuploidy in cellulo and in vivo. First, we will probe the topological and mechanical properties of human centromeres using our 2 newly developed methods for centromere enrichment and magnetic manipulation. Second, we will force chromosome-specific aneuploidy by directly pulling on chromosomes to reveal connections between chromosome positions and aneuploidy. Finally, we will study the behavior of aneuploid cells in both mouse and human preimplantation embryos and relate this to the unbalance of specific chromosomes. By providing molecular, physical and cellular insights into the causes and consequences of chromosome-specific aneuploidy, CaCAn will reveal the mechanisms of a fundamental cellular defect that is frequently at the origin of many pathologies.