Analysis of a malsegregating mouse Y chromosome: evidence that the earliest cleavage divisions of the mammalian embryo are non-disjunction-prone
Analysis of a malsegregating mouse Y chromosome: evidence that the earliest cleavage divisions of the mammalian embryo are non-disjunction-prone
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DOI：
10.1093/hmg/10.9.963
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发表时间：
2001-04-15
影响因子：
3.5
通讯作者：
Hassold, TJ
中科院分区：
文献类型：
--
作者：
Bean, CJ;Hunt, PA;Hassold, TJ
尽管人类非整倍体的临床重要性，我们知道的哺乳动物不分离的原因很少，在某种程度上，这反映了这样一个事实，即不像低等生物，分离“受损”的染色体在哺乳动物中几乎不存在。为了解决这个问题，我们研究了BALB/cWt（“Wt”）近交系背景下的小鼠Y染色体，在该系统中，性腺组织中Y染色体的丢失与两性畸形有关。我们的研究结果表明，野生型Y染色体在减数分裂细胞分裂过程中是稳定传递的，但在有丝分裂中以极高的频率不分离。令人惊讶的是，不分离事件在很大程度上限于最早的卵裂分裂，这表明有一个时间的“窗口”，在此期间，野生型Y染色体易受不分离。非分离表型具有顺式和反式两种成分：Wt Y染色体在各种遗传背景下不分离，表明存在内在缺陷;然而，不分离的发生率受到菌株背景的显著影响，表明修饰基因座的存在，从而为哺乳动物不分离的遗传效应提供了证据，这些研究表明，哺乳动物最早期的细胞分裂是不分离倾向，这一解释为体外受精（IVF）衍生的人类植入前胚胎研究中观察到的染色体镶嵌率高提供了解释。此外，我们的观察提高了IVF设置对染色体分离产生不利影响的可能性，并表明遗传质量是任何试图改善或修改用于人类卵子和胚胎的体外程序的重要考虑因素。
Despite the clinical importance of human aneuploidy, we know little of the causes of mammalian non-disjunction, In part, this reflects the fact that, unlike lower organisms, segregation 'impaired' chromosomes are virtually non-existent in mammals. To address this issue, we have studied the mouse Y chromosome on the BALB/cWt ('Wt') inbred background, a system in which loss of the Y chromosome in gonadal tissue has been linked to hermaphroditism. Our results indicate that the Wt Y chromosome is stably transmitted during meiotic cell divisions, but non-disjoins at an extremely high frequency in mitosis. Surprisingly, the nondisjunction events are largely restricted to the earliest cleavage divisions, indicating that there is a temporal 'window' during which the Wt Y chromosome is susceptible to non-disjunction. The non-disjunction phenotype has both cis and trans components: the Wt Y chromosome malsegregates on a variety of genetic backgrounds, demonstrating an intrinsic defect; however, the incidence of non-disjunction is significantly influenced by strain background, indicating the existence of modifying loci and thus providing evidence for a genetic effect on mammalian nondisjunction, These studies suggest that the earliest cell divisions in mammals are non-disjunction-prone, an interpretation which provides an explanation for the high rate of chromosome mosaicism observed in studies of in vitro fertilization (IVF)-derived human preimplantation embryos. Further, our observations raise the possibility that the IVF setting adversely affects chromosome segregation and suggest that genetic quality be an important consideration in any attempt to improve or modify in vitro procedures for use on human eggs and embryos.