Cohesin: role in germ cell chromosomal segregation

至少10%到25%的人类胎儿有错误的染色体数目（非整倍体）。大多数这些畸形胎儿在子宫内死亡，使其成为已知的早孕流产的主要原因。非整倍体是发育障碍和智力迟钝的主要遗传原因。大量证据表明，这些染色体异常大多源于卵子和精子中遗传物质（染色体）的不平等分配。该计划的重点是两个相关基因，称为Rec8和Rad21，我们最近在人类和老鼠身上发现了这两个基因。由于这些基因对其他物种的染色体分离至关重要，它们存在于酵母和人类等多种物种中，它们可能负责哺乳动物生殖细胞中染色体的准确分离。在本研究中，我们将通过缺失Rec8和Rad21基因的基因工程小鼠的功能缺失研究来确定这些分子在控制染色体分离中的作用。通过分析这些动物细胞的染色体异常，我们将获得关于人类染色体分配障碍本质的关键信息。

At least 10 to 25% of all human fetuses have the wrong number of chromosomes (aneuploidy). Most of these abormal fetuses perish in utero, making it the leading known cause of early pregnancy loss. Aneuploidy is the leading genetic cause of developmental disabilities and mental retardation. Abundant evidence suggests that most of these chromosome abnormalities originate during unequal partitioning of genetic material (chromosomes) in eggs and sperm. The proposed project focuses on two related genes, called Rec8 and Rad21, which we recently discovered in humans and mice. Due to that these genes are essential for chromosome separation in other species and they exists in species as diverse as yeast and humans, they may be responsible for accurate separation of chromosomes in germ cells in mammals. In this proposal, we will determine the role(s) of these molecules in controlling proper chromosome segregation by loss-of-function studies in genetically engineered mice lacking Rec8 and Rad21 genes. By analyzing the chromosomal abnormalities of the cells from these animals, we will gain critical information about the nature of chromosome partitioning disorders in humans.