How are chromosomes segregated correctly during sexual gene reassortment?-understanding how the meiotic chromosome axis functions in gametogenesis

性基因重配过程中染色体如何正确分离？-了解减数分裂染色体轴在配子发生中如何发挥作用

• 批准号: MR/W027313/1
• 负责人: Hajime Murakami
• 金额: $ 171.25万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW027313%2F1
• 关键词: How; chromosomes; segregated; correctly; during

Life begins when an egg and a sperm from parents merge into a single cell, the fertilised egg, which multiplies into many cells to create our body. Sperm and egg each contribute 23 chromosomes, making a total of 46 chromosomes in the fertilised egg. When our body produces sperm or eggs, cells undergo a special cell division called meiosis, which halves the number of chromosomes. Chromosomes consist of long stretches of DNA, which encode the many genes required to make our body. When meiosis occurs, the chromosomes inherited from the mother are reshuffled with those from the father, forming a completely new set of chromosomes with a unique combination of genes. This reshuffling process diversifies gene combinations from generation to generation, creating evolutionary adaptability to environmental changes.The process of reshuffling the genes in the chromosomes is called recombination. Recombination operates by cutting DNA and exchanging sections of the DNA between maternal and paternal chromosomes. If recombination fails, the wrong number of chromosomes, or incorrectly assembled chromosomes, can be passed into sperm and eggs. This type of fault is a leading cause of miscarriage and congenital syndromes including Down, Edward, Patau (trisomy 21, 18, 13) & Turner (monosomy X). Overall, about 0.3% of newborn infants have an incorrect chromosome number. Given its importance, organisms are equipped with various mechanisms to ensure correct meiotic recombination. I am investigating how meiotic recombination is controlled. For this research I use yeast cells, which undergo meiosis just like humans, and are easy to manipulate experimentally.When meiosis begins, cells make a group of proteins that act together as scissors to cut the DNA for recombination. To produce normal sperm and eggs, these DNA scissors need to be well controlled to prevent recombination failures, but the control mechanisms are still enigmatic. Recent findings have led me to hypothesise that proteins called Hop1 and Red1 direct the activity of these scissors, telling them where, when, and how often to cut DNA.Hop1 and Red1 are part of the 'chromosome scaffold' of meiotic cells and are believed to help the scissors bind to chromosomes. I discovered further roles for Hop1 and Red1 in the process. Paradoxically, even though their main role is to promote the recruitment of DNA scissors to chromosomes, I found that Hop1 and Red1 can prevent scissors from randomly binding along chromosomes. Moreover Hop1 and Red1 are needed not just to recruit but also to activate the scissors for cutting DNA. Also, Hop1 and Red1 pay extra attention to short chromosomes, preferentially directing the DNA scissors to short chromosomes to ensure they get cut. Overall I propose that these two 'manager proteins' Hop1 and Red1 direct the scissors to chromosomal locations favourable for correct recombination, while simultaneously preventing the scissors from cutting at dangerous places, both by excluding them from such locations and by allowing the scissors to cut DNA only when both manager proteins are present.This project investigates these new functions of Hop1 and Red1 to test my hypothesis. I will elucidate how these proteins behave in meiotic cells to understand the molecular mechanisms that control recombination. Since these scissors and manager proteins are present in human and yeast, new knowledge from this study will advance our understanding of how our eggs and sperm are made and how their production process can fail. This work will therefore make critical contributions to the understanding of fertility and the formation of new genomes and, to the development of reproductive medicine. For example, once the risk of chromosome abnormalities due to mutations in these manager genes is understood, it will help patients to select the best fertility treatments. Such understanding may also help design strategies to avoid faulty meiosis and consequent health problems completely.

当来自父母的卵子和精子融合成一个细胞，即受精卵时，生命就开始了，受精卵繁殖成许多细胞，形成了我们的身体。精子和卵子各贡献23条染色体，受精卵总共有46条染色体。当我们的身体产生精子或卵子时，细胞会经历一种叫做减数分裂的特殊细胞分裂，染色体的数量会减半。染色体由长段DNA组成，这些DNA编码了构成我们身体所需的许多基因。当减数分裂发生时，从母亲那里继承的染色体与从父亲那里继承的染色体重新洗牌，形成一套全新的染色体，具有独特的基因组合。这种重组过程使基因组合一代一代地多样化，创造了对环境变化的进化适应性。染色体中基因重组的过程称为重组。重组是通过切割DNA并在母系和父系染色体之间交换DNA片段来进行的。如果重组失败，错误数量的染色体，或错误组合的染色体，可以传递到精子和卵子。这种类型的缺陷是流产和先天性综合征的主要原因，包括唐氏、爱德华氏、帕陶氏（21、18、13三体）和特纳氏（X单体）。总的来说，大约0.3%的新生儿有不正确的染色体数目。鉴于其重要性，生物体配备了各种机制来确保正确的减数分裂重组。我在研究如何控制减数分裂重组。在这项研究中，我使用了酵母细胞，它像人类一样经历减数分裂，并且易于实验操作。当减数分裂开始时，细胞产生一组蛋白质，这些蛋白质像剪刀一样切割DNA进行重组。为了产生正常的精子和卵子，这些DNA剪刀需要得到很好的控制，以防止重组失败，但控制机制仍然是谜。最近的发现让我假设，Hop1和Red1蛋白质指导这些剪刀的活动，告诉它们何时、何地、以何种频率切割DNA。Hop1和Red1是减数分裂细胞“染色体支架”的一部分，被认为有助于剪刀与染色体结合。在这个过程中，我发现了Hop1和Red1的进一步作用。矛盾的是，尽管它们的主要作用是促进DNA剪刀向染色体的招募，但我发现Hop1和Red1可以阻止剪刀沿着染色体随机结合。此外，Hop1和Red1不仅需要招募，而且还需要激活切割DNA的剪刀。此外，Hop1和Red1对短染色体格外关注，优先将DNA剪刀指向短染色体，以确保它们被剪断。总的来说，我认为这两种“管理蛋白”Hop1和Red1将剪刀引导到有利于正确重组的染色体位置，同时防止剪刀在危险的地方切割，这两种方法都是通过将它们排除在这些位置之外，并允许剪刀仅在两种管理蛋白存在时才切割DNA。这个项目研究Hop1和Red1的这些新功能来验证我的假设。我将阐明这些蛋白质在减数分裂细胞中的行为，以了解控制重组的分子机制。由于这些剪刀和管理蛋白存在于人类和酵母中，这项研究的新知识将促进我们对卵子和精子如何产生以及它们的生产过程如何失败的理解。因此，这项工作将对了解生育能力和新基因组的形成以及生殖医学的发展作出重要贡献。例如，一旦了解了这些管理基因突变导致染色体异常的风险，将有助于患者选择最佳的生育治疗方法。这样的理解也可以帮助设计策略来完全避免错误的减数分裂和随之而来的健康问题。