MICA: Identification of age-related and age-independent changes to meiotic chromosome structure and their association with aneuploidy in human oocytes

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It has long been known that as a woman ages, her likelihood of having a chromosomally abnormal pregnancy rises, with the risk increasing exponentially in women over the age of 35. This means that many couples who delay conception until they are financially secure suffer subfertility and repeated pregnancy loss, causing distress to the couples, a financial burden on the NHS and economic consequences through sickness absence. This is especially significant in countries such as the UK where the number of women giving birth over the age of 35 has doubled in the last 20 years (Office of National Statistics, 2009 data). Curiously, the vast majority of chromosome problems originate from errors in chromosome segregation in the mother's egg. Correct segregation of pairs of chromosomes is essential so that the embryo eventually contains a complete set. Precisely why the fidelity of chromosome segregation decreases so abruptly in eggs from older women is unclear, but mounting evidence from mouse and human studies suggests that a multitude of factors, both environmental and genetic, contribute to faulty chromosome segregation in the egg. One major reason thought to underlie the high error-rate in eggs is the relatively long time period taken to complete female meiosis; the cellular division that halves the number of chromosomes prior to fertilisation. In contrast to sperm production in males, which initiates in puberty and takes approximately 64 days to complete, the process in females is initiated in the ovary of the developing fetus and is not completed until ovulation, which may be several decades later. It is now widely believed that this extended period before completion of meiosis may account for the high error-rate in eggs ovulated in older women.How may these time-dependent changes in chromosome segregation be explained? One popular hypothesis to explain the so-called 'maternal age effect' is that proteins in the egg, responsible for holding together chromosome pairs together, erode over time. This has been referred to as 'becoming unglued'. One set of proteins, known as Cohesins work together with exchanges of the DNA to form cross-over points that hold pairs of chromosomes together until they separate at the first meiotic division. Cohesins certainly appear to be depleted from chromosomes in aged mouse eggs (compared to younger mice), but it is yet to be seen whether the same is true for humans.Since a subset of the missegregating chromosome pairs are in fact 'non-exchange' pairs, (having no cross-over points), deterioration of cohesin should not, in theory, affect their segregation. Instead, other mechanisms must be invoked to explain their missegregation. Synaptonemal Complex (SC) proteins have been implicated in the segregation of non-exchange chromosomes in many other organisms, so it is possible that deterioration of SC proteins may also be associated with errors in chromosome segregation in human eggs. In support of this hypothesis is the observation that SC proteins are associated with chromosomes in human sperm during both meiotic divisions, way beyond their known role in chromosome synapsis.In this work, we plan to use 'surplus' human eggs that cannot be used for IVF treatment to investigate age-related (as well as age-independent) changes to chromosome structure- do they become 'unglued' with time? Our work will begin by examining changes to Cohesins and Synaptonemal Complex proteins, although a broader study including many more candidate proteins is planned for the long term. Through this work we hope to gain valuable insights into the chromosomal basis of human female fertility and the 'maternal age effect', which can be used to help inform women's reproductive choices.