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%的胚胎在着床前发育期间死亡。在DDK雄性和其他近交系的雌性之间的反向杂交是完全有活力和可育的。致命性状分离为2个紧密相连的位点，其中一个(1)编码DDK母体“因子”（“卵子突变”因子，OmDDK），该因子存在于卵子中，并与位于紧密相连的父本基因上的非DDK等位基因相互作用，以反式方式导致致命。我们已经将母体OmDDK因子定位为“Schlafen”（Slfn）基因家族的成员，该家族先前被确定为t细胞生长和发育调节因子家族。我们还发现了一个独特的单倍型，由4个单核苷酸多态性定义，除了24kb的Om区域外，其他区域都被排除，与致命的相互作用有关，非ddk父本基因。有趣的是，我们发现父系基因的DDK形式是祖先的形式。我们建议研究母体因子对父本基因“新”形式施加致死效应的分子机制。我们还计划研究同时携带DDK型和C57BL/6型母系基因的雌性产生两类卵子的机制，一类在与C57BL/6精子受精后存活，另一类在与C57BL/6精子受精后死亡。个体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启示意义。

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.