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非整倍体和人类生殖健康

Aneuploidy: a destroyer of human reproduction health

  • 摘要: 非整倍体即染色体数目异常,发生于生殖细胞则可能导致不育不孕、自发流产和先天出生缺陷.精子非整倍体发生率为5%~7%,卵子非整倍体发生率为22%~90%;在早期自然流产中,非整倍体率高达50%.绝大多数临床上常见的非整倍体患儿的异常染色体来自卵子(母亲),而且母亲减数分裂I同源染色体不分离是除13和18号染色体以外的各种常见染色体非整倍体的主要原因.母亲的年龄是迄今唯一被证实的与生殖细胞非整倍体发生密切相关的流行病学因素,减数分裂遗传重组(频率和位点分布)异常可能是导致减数分裂I同源染色体不分离的主要细胞学和遗传学因素,减数分裂前最后一次DNA复制时cohesin复合体的加载及其之后的维持异常则可能是引起减数分裂染色体不分离的分子生物学因素.减数分裂遗传重组和cohesin复合体的加载均发生于女性胚胎发育的8~30周,而非整倍体卵子的形成多发生在35岁以上的女性,因此我们认为导致非整倍体卵子形成的“罪恶种子”早在35年前即已埋下,随着女性年龄增大,其体内保障染色体精确分离的保护机制如纺锤体聚合检验点被“磨损”削弱,而最终导致减数分裂时染色体分离异常.未来的研究应着重探讨遗传重组改变的原因、机理及如何导致减数分裂染色体不分离,了解卵母细胞中cohesin复合体、纺锤体聚合检验点的功能是否随女性年龄增大而减弱及其生物学机制,从而为有效防止非整倍体的发生、减少人类生殖相关非整倍体疾病的发生提供理论基础.

     

    Abstract: Aneuploidy, a numerically chromosomal abnormality, is a major cause of infertility, spontaneous abortion or birth with defects. It occurs at the rate of approximately 5%~7%, 22%~90% and more than 50% in spermatozoa, eggs and early spontaneously aborted fetuses,respectively. The vast majority of frequently observed aneuploidy in humans results from eggs (mothers), and nondisjunction of homologous chromosomes in maternal meiosis I is accused of aneuploid eggs for most chromosomes, except chromosome 13 and 18. Maternal age is the only factor identified epidemically so far for the generation of aneuploid germ cells. Alterations in recombination frequency and location, establishment and maintenance of cohesion between sister chromatids are thought to be responsible for homologous chromosome nondisjunction during meiosis I. Sister chromatids cohesion is established during the last DNA replication before meiosis and homologous chromosomes recombination occurs during meiotic prophase I, both of which happen in fetal ovaries. However, most homologous chromosome nondisjunction takes place in women over the age of 35. This implies that mechanisms incorporating chromosome segregation with recombination and cohesion exist during meiosis, which could be abraded with women aging. Future studies should be focused on what the mechanisms are, and how they work to prevent chromosome missegregation during meiosis.

     

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