Chromosome missegregation - eroding female fertility

Human female germ cells are highly sensitive to aneuploidy, a genetic condition that arises as a consequence of chromosome missegregation events.

Approximately 40% of age-dependent aneuploidies in human oocytes occur as primary chromosome segregation defects at the second meiotic division (MII). We know very little about the nature of these chromosomal segregation errors.

We have identified an efficient post-metaphase II correction process that increases the accuracy of the chromosome segregation process in oocytes in young adult mice.

Importantly, we find that this process is approximately 10-fold less efficient in oocytes in aged mice due to an inability to correctly resolve merotelic kinetochore-microtubule (MT) attachments at anaphase II.

We will here analyse why aberrant attachments are not eliminated at the metaphase II stage and identify differences in the segregation process for lagging chromosomes in oocytes in young adult and aged mice. This knowledge will be of importance to explain the basis for age-dependent aneuploidy instigated during meiosis II.

The synaptonemal complex (SC) is a conserved tripartite protein structure that regulates synapsis and crossover formation between homologous chromosomes in males and females during meiosis I, a mechanism of fundamental nature for sexual reproduction.

The proposed structural studies will uncover the native organization of the mammalian SC, including the localization of individual SC subunits that form this structure.