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

人们早就知道，随着女性年龄的增长，她发生染色体异常怀孕的可能性会增加，35岁以上的女性的风险会成倍增加。这意味着，许多推迟怀孕直到经济上有保障的夫妇会遭受生育不足和反复怀孕丢失的痛苦，给夫妇带来痛苦，给国民健康保险制度带来经济负担，并因疾病缺席而产生经济后果。这一点在英国等国家尤为明显，在这些国家，35岁以上生育的妇女数量在过去20年中翻了一番(国家统计局，2009年数据)。奇怪的是，绝大多数染色体问题都源于母体卵子中染色体分离的错误。正确的染色体对分离至关重要，这样胚胎最终才能包含一套完整的染色体。目前尚不清楚为什么老年女性卵子中染色体分离的保真度突然下降，但来自老鼠和人类研究的越来越多的证据表明，环境和遗传因素都是导致卵子染色体分离错误的原因之一。卵子错误率高的一个主要原因被认为是完成雌性减数分裂所需的时间相对较长，即受精前染色体数量减半的细胞分裂。男性的精子产生在青春期开始，大约需要几天的时间才能完成，而女性的精子产生过程是在发育中的胎儿的卵巢开始的，直到排卵才完成，排卵可能要晚几十年。现在人们普遍认为，减数分裂完成之前延长的时间可能是老年女性排卵错误率高的原因。如何解释这些染色体分离的随时间变化？解释所谓的“母体年龄效应”的一个流行假说是，卵子中负责将染色体对聚集在一起的蛋白质会随着时间的推移而被侵蚀。这被称为“脱胶”。一组被称为粘附素的蛋白质与DNA交换一起形成交叉点，这些交叉点将一对染色体保持在一起，直到它们在第一次减数分裂时分离。与年轻的小鼠相比，衰老的小鼠卵子的染色体上确实出现了粘附素的缺失，但人类的情况是否如此还不得而知。由于错误分离的染色体对中的一部分实际上是非交换的(没有交叉点)，从理论上讲，粘附素的恶化应该不会影响它们的分离。相反，必须援引其他机制来解释它们的错误隔离。联会复合体(Synaptonemal Complex，SC)蛋白在许多其他生物中与非交换染色体的分离有关，因此，SC蛋白的恶化也可能与人类卵子中染色体分离的错误有关。支持这一假说的是，在人类精子的两次减数分裂中，SC蛋白与染色体相关，远远超出了它们在染色体突触中的已知角色。在这项工作中，我们计划使用不能用于体外受精治疗的“剩余”人类卵子来研究与年龄相关(以及与年龄无关)的染色体结构变化--它们是否会随着时间的推移而“脱胶”？我们的工作将从检查粘附素和联会复合体蛋白的变化开始，尽管长期计划进行一项包括更多候选蛋白的更广泛的研究。通过这项工作，我们希望能对人类女性生育的染色体基础和“母体年龄效应”获得有价值的见解，以帮助了解女性的生育选择。

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.