Genetic and Molecular Analysis of DDK Syndrome

描述(由申请人提供)：当DDK近交系的雌性与许多其他近交系的雄性交配时，高达95%的胚胎在植入前发育期间死亡。DDK雄性和其他近交系雌性之间的正反交是完全可行和可育的。致死性状分离为两个紧密连锁的基因座，一个(1)编码卵子中存在的DDK母体“因子”(“卵突变”因子，OmDDK)，它与位于紧密连锁的父系基因上的非DDK等位基因相互作用，导致致死性。我们已经定位了母体OmDDK因子是“Schlafen”(SLFn)基因家族的成员，该家族以前被确定为T细胞生长和发育调节因子家族的成员。我们还鉴定了一种独特的单倍型，由4个单核苷酸多态定义，排除了除24 kb外的所有Om区，与致死性相互作用的非DDK父本基因相关。有趣的是，我们发现父亲基因的DDK形式就是祖先的形式。我们建议研究Om母系因子对父系基因的“新”形式产生致死作用的分子机制。我们还计划研究同时携带DDK和C57BL/6母体基因的雌性产生两类卵子的机制，即那些在与C57BL/6精子受精时存活的卵子，以及那些在与C57BL/6精子受精时死亡的卵子。单个雌性产生两种不同类型的卵子的现象，以及不同父系基因反应类型的存在，对人类辅助生殖技术具有重要意义。

DESCRIPTION (provided by applicant): When females of the DDK inbred strain are mated with males of many other inbred strains, up to 95% of the resulting embryos die during preimplantation development. The reciprocal crosses, between DDK males and females of other inbred strains, are fully viable and fertile. The lethal trait segregates as 2 tightly-linked loci, one (1) encoding a DDK maternal "factor" (the "Ovum mutant" factor, OmDDK) that is present in the egg and that interacts with non-DDK alleles residing at the closely linked paternal gene, in trans, to cause lethality. We have located the maternal OmDDK factor as a member of the "Schlafen" (Slfn) gene family, identified previously as a family of T-cell growth and development regulators. We have also identified a unique haplotype, defined by 4 single nucleotide polymorphisms that exclude all but 24 kb of the Om region, associated with the lethally-interacting, non-DDK paternal gene. Interestingly, we have found that the DDK form of the paternal gene is the ancestral form. We propose to investigate the molecular mechanisms by which the Om maternal factor exerts its lethal effects on the "new" form of the paternal gene. We also plan to investigate the mechanism by which females carrying both the DDK form and the C57BL/6 form of the maternal gene give rise to 2 classes of ova, those that survive when fertilized by a C57BL/6 sperm and those that die when fertilized by a C57BL/6 sperm. The phenomenon of individual females producing ova of 2 different types, as well as the existence of different paternal gene response types, has implications for assisted reproductive technology in humans.