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

MICA：鉴定减数分裂染色体结构的年龄相关和年龄无关变化及其与人类卵母细胞非整倍性的关系

• 批准号: MR/M000664/1
• 负责人: Eva Hoffmann
• 金额: $ 63.37万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM000664%2F1
• 关键词: MICA; Identification; age; related; independent

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.

人们早就知道，随着女性年龄的增长，她发生染色体异常妊娠的可能性会增加，35岁以上女性的风险呈指数级增长。这意味着许多推迟受孕的夫妇在经济上有保障后才怀孕，导致生育能力低下和反复流产，给夫妇带来痛苦，给NHS带来经济负担，并因病缺勤造成经济后果。这在像英国这样的国家尤其重要，在过去的20年里，35岁以上生育的女性数量翻了一番（国家统计局，2009年的数据）。奇怪的是，绝大多数染色体问题源于母亲卵子中染色体分离的错误。染色体对的正确分离是必不可少的，这样胚胎才能最终包含一整套染色体。为什么老年妇女的卵子中染色体分离的保真度突然下降的原因尚不清楚，但来自小鼠和人类研究的越来越多的证据表明，多种因素，包括环境和遗传因素，导致了卵子中染色体分离的错误。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需要相对较长的时间；在受精前使染色体数目减半的细胞分裂。男性的精子产生始于青春期，大约需要64天才能完成，而女性的精子产生过程始于发育中的胎儿的卵巢，直到排卵后才完成，而排卵可能需要几十年的时间。现在人们普遍认为，在减数分裂完成前的这段较长的时间可能是老年妇女排卵错误率高的原因。如何解释这些随时间变化的染色体分离？一个解释所谓“母亲年龄效应”的流行假设是，卵子中负责将染色体结合在一起的蛋白质会随着时间的推移而侵蚀。这被称为“脱胶”。一组被称为内聚蛋白的蛋白质与DNA的交换一起形成交叉点，将成对的染色体固定在一起，直到它们在第一次减数分裂时分离。在年老的老鼠卵子中（与年轻的老鼠相比），内聚蛋白显然已经从染色体中消失了，但人类是否也是如此还有待观察。由于误分离染色体对的一部分实际上是“非交换”染色体对（没有交叉点），因此从理论上讲，内聚蛋白的退化不应影响它们的分离。相反，必须调用其他机制来解释它们的错误隔离。在许多其他生物中，突触复合体（SC）蛋白与非交换染色体的分离有关，因此SC蛋白的退化可能也与人类卵子中染色体分离错误有关。支持这一假设的观察结果是，SC蛋白在两次减数分裂中都与人类精子中的染色体相关，远远超出了它们在染色体突触中的已知作用。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内聚蛋白和突触复合蛋白的变化开始，尽管长期计划进行更广泛的研究，包括更多的候选蛋白。通过这项工作，我们希望对人类女性生育能力的染色体基础和“母亲年龄效应”获得有价值的见解，这可以用来帮助告知女性的生育选择。

项目成果

Methods in Mitosis and Meiosis- 2nd edition

有丝分裂和减数分裂方法 - 第二版

• 发表时间: 2018
• 作者: Hoffmann, E.R.