UNRAVELLING THE MOLECULAR BASES OF THE MOSAIC VARIEGATED ANEUPLOIDY (MVA) GENETIC DISEASE BY STUDYING THE MECHANISMS CONTROLLING ANEUPLOIDY OCCURRENCE IN THE BUDDING YEAST MODEL SYSTEM

During cell division, chromosomes are faithfully duplicated, so that one copy of each chromosome can be inherited by the two daughter cells, which must carry identical genetic information. If chromosome transmission is not executed precisely, daughter cells would no longer be identical to their mother and would present an abnormal number of chromosomes, generating an aberrant condition called “aneuploidy” that usually lead to several abnormalities. The fidelity of chromosome transmission has important medical implications. For example, aneuploidy is a main cause of spontaneous human miscarriages, since chromosome transmission errors during the process of sperms and egg formation lead to aneuploid embryos that are mostly inviable. Few aneuploidies are compatible with human embryo survival, but most of them cause severe pathologies, including the Patau, Edwards and Down syndromes. Conversely, aneuploidy arising during any of the millions of the cell divisions taking place in our body is usually dealt with by our organism with the elimination of the aberrant cells. However, when the frequency of aneuploidy is too high, it overloads the correction capacity of the organism and can have extreme pathological consequences. This is the case of mosaic variegated aneuploidy (MVA), a rare human genetic syndrome causing clonal areas of aneuploid cells in various tissues, leading to a broad spectrum of clinical manifestations that are usually fatal during childhood. A mechanism called “spindle checkpoint”, whose lack is associated to MVA and other aneuploidy-related pathologies, controls chromosome transmission and prevents aneuploidy occurrence in normal individuals. The purpose of our research is to gain insights into aneuploidy-related pathologies by studying spindle checkpoint regulation in a suitable model organism, in order to develop appropriate prenatal diagnostic methods and therapies.