Loci Affecting Hybrid Sterility in Mice

通过杂交不同物种获得的雄性小鼠F1杂交种的不育性由遗传决定。以前的研究表明，在近端染色体17上有四个杂交不育（Hst）基因座，以及在假常染色体区（PAR）中存在配对问题，从而阻止了染色体X和Y的正常分离。我们一直在研究染色体近端X染色体上与杂种不育相关的基因座。利用同源杂交菌株C57 BL/6 J.SPRET-Hprta（AT 24）发现了一个位点Ihtw 1，含有17个来自M.在C57 BL/6背景上的spretus Chr X。Ihtw 1与睾丸重量低有关，并允许部分生育，但只有一半的睾丸小管充满了发育中的精子，而其他小管是空的。我们已经开发了从AT 24的亚同源菌株，并定义了一个临界区间的1个地图单位包含Ihtw 1。利用两个亚同源菌株间的杂交，我们获得了一个睾丸较小的菌株，仅携带来自M. spretus。另一项研究涉及基因座，也在近端染色体X上，在我们对杂交后代（C57 BL/6 J x M）的分析中发现。macedonicus）x C57BL/6J.一半的雄性后代没有进展到减数分裂中期I，这是一个比M更严重的表型。spretus。这项研究还确定了近端Chr 17，其关系到先前描述的Hst基因座上的一个位点需要确定。表型的遗传分离是鉴定和克隆基因的必要的第一步。从M. macedonicus被单独放置在C57 BL/6背景中。这项建议有两个主要目标。在目标1中，我们建议完善Ihtw 1周围的遗传图谱，生成BAC重叠群，并使用来自人类Chr X的邻位区的序列来识别候选基因。目前最好的候选者是Fgf 13，Hspa 9 b，Pdcd 8和Sox 3。设计了一系列测试来鉴定Ihtw 1编码的基因。将使用杂交（AT 24 x M. spretus）x C57 BL/6，并对后代雄性进行全基因组筛选，所述后代雄性的睾丸重量将用于QTL分析。在目标2中，我们将主要关注M。macedonicus减数分裂中期I计划，而不是重点Chr 17，并建议从同源菌株中制备亚同源菌株，以进一步定位相关基因。寻找常染色体抑制基因的表型将使用类似的方法用于Ihtw 1。染色体近端X染色体上的基因座及其抑制子可能在人类雄性不育中起重要作用。它们也可能参与物种形成的早期阶段。

Sterility in male mouse F1 hybrids obtained by crossing different species is genetically determined. Previous studies have implicated four hybrid sterility (Hst) loci on proximal Chr 17, as well as pairing problems in the pseudoautosomal region (PAR) that prevents normal segregation of Chrs X and Y. We have been studying loci associated with hybrid sterility on proximal Chr X. One locus, Ihtw1, was discovered using a congenic hybrid strain C57BL/6J.SPRET-Hprta(AT24), containing 17 map units from M. spretus Chr X on a C57BL/6 background. Ihtw1 is associated with low testis weight and allows partial fertility, but only half of the testicular tubules are filled with developing sperm, while the other tubules are empty. We have developed subcongenic strains from AT24 and defined a critical interval of 1 map unit containing Ihtw1. Using a cross between two subcongenic strains we have obtained a strain with small testes, carrying only the critical interval from M. spretus. Another study involves loci, also on proximal Chr X, found in our analysis of progeny from the cross (C57BL/6J x M. macedonicus) x C57BL/6J. Half of the male progeny from this cross did not progress to meiotic metaphase I, a more severe phenotype than found with M. spretus. This study also identified a locus on proximal Chr 17, whose relationship to the previously described Hst loci needs to be determined. Genetic isolation of the phenotypes is a necessary first step toward identification and cloning of the genes. Congenic strains have been made in which proximal Chrs X and 17 from M. macedonicus have been separately placed in a C57BL/6 background. This proposal has two major goals. In Aim 1 we propose to refine the genetic map around Ihtw1, generate a BAC contig and use the sequence from the orthologous region of human Chr X to identify candidate genes. The current best candidates are Fgf13, Hspa9b, Pdcd8 and Sox3. A series of tests are designed to identify the gene encoded by Ihtw1. A screen for suppressor loci will be continued using the cross (AT24 x M. spretus) x C57BL/6 and performing a genome wide screen on progeny males whose testis weights will be used for QTL analysis. In Aim 2 we will focus mainly on the M. macedonicus meiotic metaphase I project, with less emphasis on Chr 17, and propose to make subcongenic strains from the congenic strains to further localize the genes involved. A search for autosomal suppressors of the phenotype will use an approach similar to that used for Ihtw1. The loci on proximal Chr X and their suppressors may play significant roles in causing sterility in the human male. They are also probably involved in early stages of speciation.