Genetic and Molecular Analysis of DDK Syndrome

描述（由申请方提供）：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%的所得胚胎在植入前发育期间死亡。DDK雄性和其它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2个紧密连锁的基因座，一个（1）编码DDK母本“因子”（“卵突变体”因子，OmDDK），其存在于卵中，并与位于紧密连锁的父本基因处的非DDK等位基因反式相互作用，以引起致死。我们已经将母体OmDDK因子定位为“Schlafen”（Slfn）基因家族的成员，该基因家族先前被鉴定为T细胞生长和发育调节因子家族。我们还确定了一个独特的单倍型，定义为4个单核苷酸多态性，排除所有，但24 kb的Om区域，与致命的相互作用，非DDK父系基因。有趣的是，我们发现父源基因的DDK形式是祖先形式。我们建议调查的分子机制，通过它的母源因素发挥其致命的影响的“新”形式的父亲的基因。我们还计划研究携带DDK形式和C57 BL/6形式的母体基因的雌性产生2类卵子的机制，即通过C57 BL/6精子受精时存活的卵子和通过C57 BL/6精子受精时死亡的卵子。个体雌性产生2种不同类型卵子的现象，以及不同父系基因反应类型的存在，对人类辅助生殖技术有影响。

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.