Hybrid Sterility Locus on Chromosome X Controls Meiotic Recombination Rate in Mouse

Meiotic recombination safeguards proper segregation of homologous chromosomes into gametes, affects genetic variation within species, and contributes to meiotic chromosome recognition, pairing and synapsis. The Prdm9 gene has a dual role, it controls meiotic recombination by determining the genomic position of crossover hotspots and, in infertile hybrids of house mouse subspecies Mus m. musculus (Mmm) and Mus m. domesticus (Mmd), it further functions as the major hybrid sterility gene. In the latter role Prdm9 interacts with the hybrid sterility X 2 (Hstx2) genomic locus on Chromosome X (Chr X) by a still unknown mechanism. Here we investigated the meiotic recombination rate at the genome-wide level and its possible relation to hybrid sterility. Using immunofluorescence microscopy we quantified the foci of MLH1 DNA mismatch repair protein, the cytological counterparts of reciprocal crossovers, in a panel of inter-subspecific chromosome substitution strains. Two autosomes, Chr 7 and Chr 11, significantly modified the meiotic recombination rate, yet the strongest modifier, designated meiotic recombination 1, Meir1, emerged in the 4.7 Mb Hstx2 genomic locus on Chr X. The male-limited transgressive effect of Meir1 on recombination rate parallels the male-limited transgressive role of Hstx2 in hybrid male sterility. Thus, both genetic factors, the Prdm9 gene and the Hstx2/Meir1 genomic locus, indicate a link between meiotic recombination and hybrid sterility. A strong female-specific modifier of meiotic recombination rate with the effect opposite to Meir1 was localized on Chr X, distally to Meir1. Mapping Meir1 to a narrow candidate interval on Chr X is an important first step towards positional cloning of the respective gene(s) responsible for variation in the global recombination rate between closely related mouse subspecies.减数分裂重组（meiotic recombination）可保障同源染色体正确分离进入配子，影响物种内的遗传变异，并参与减数分裂的染色体识别、配对与联会。Prdm9基因具有双重功能：它通过确定交叉热点（crossover hotspots）的基因组位置来调控减数分裂重组；在小家鼠（Mus m. musculus，Mmm）与欧洲小家鼠（Mus m. domesticus，Mmd）亚种的不育杂交后代中，它同时作为主要的杂交不育基因发挥作用。就后者功能而言，Prdm9与X染色体（Chromosome X，Chr X）上的杂交不育X2（Hstx2）基因组位点通过尚未阐明的机制发生互作。本研究在全基因组层面探究了减数分裂重组率及其与杂交不育的潜在关联：研究人员利用免疫荧光显微镜技术，在一系列亚种间染色体替换品系中，对MLH1 DNA错配修复蛋白（MLH1 DNA mismatch repair protein）的焦点进行了定量分析——该蛋白是双向交叉互换的细胞学标记物。研究发现，7号染色体（Chr 7）与11号染色体（Chr 11）这两条常染色体可显著改变减数分裂重组率，但最强的调控因子被命名为减数分裂重组1（Meir1），其定位在X染色体上4.7 Mb的Hstx2基因组区域内。Meir1对重组率的雄性限定性超效作用与Hstx2在杂交雄性不育中的雄性限定性超效功能相一致，因此Prdm9基因与Hstx2/Meir1基因组位点这两个遗传因子均揭示了减数分裂重组与杂交不育之间的关联。此外，研究人员在X染色体上Meir1的远端区域定位到一个强效的雌性特异性减数分裂重组率调控因子，其作用效果与Meir1相反。将Meir1定位到X染色体上的狭窄候选区间，是通过图位克隆技术分离负责近缘小鼠亚种间全局重组率变异的相关基因的重要第一步。