The Recombinational Anatomy of a Mouse Chromosome

Among mammals, genetic recombination occurs at highly delimited sites known as recombination hotspots. They are typically 1–2 kb long and vary as much as a 1,000-fold or more in recombination activity. Although much is known about the molecular details of the recombination process itself, the factors determining the location and relative activity of hotspots are poorly understood. To further our understanding, we have collected and mapped the locations of 5,472 crossover events along mouse Chromosome 1 arising in 6,028 meioses of male and female reciprocal F1 hybrids of C57BL/6J and CAST/EiJ mice. Crossovers were mapped to a minimum resolution of 225 kb, and those in the telomere-proximal 24.7 Mb were further mapped to resolve individual hotspots. Recombination rates were evolutionarily conserved on a regional scale, but not at the local level. There was a clear negative-exponential relationship between the relative activity and abundance of hotspot activity classes, such that a small number of the most active hotspots account for the majority of recombination. Females had 1.2× higher overall recombination than males did, although the sex ratio showed considerable regional variation. Locally, entirely sex-specific hotspots were rare. The initiation of recombination at the most active hotspot was regulated independently on the two parental chromatids, and analysis of reciprocal crosses indicated that parental imprinting has subtle effects on recombination rates. It appears that the regulation of mammalian recombination is a complex, dynamic process involving multiple factors reflecting species, sex, individual variation within species, and the properties of individual hotspots.

在哺乳动物中，遗传重组发生在被称为重组热点（recombination hotspots）的高度限定区域内。这类区域通常长度为1~2千碱基对（kb），其重组活性差异可达1000倍甚至更高。尽管我们对重组过程本身的分子细节已有较为充分的认知，但决定重组热点位置及其相对活性的相关机制仍不甚明晰。为深化相关研究认知，我们收集并定位了6028次减数分裂产生的5472次交换事件在小鼠1号染色体上的位置，这些减数分裂事件来源于C57BL/6J与CAST/EiJ小鼠的正反交F1杂种的雌雄个体。本次交换事件定位的最低分辨率为225 kb，其中位于端粒近端24.7 Mb区域内的交换事件被进一步精细定位，以解析单个重组热点。研究发现，重组速率在区域尺度上具有进化保守性，但在局部尺度上则无此特性。重组热点活性类别的相对活性与丰度之间存在显著的负指数关系，即少数活性最高的热点贡献了绝大多数的重组事件。尽管整体上雌性个体的重组率较雄性高出1.2倍，但该性别差异在不同区域存在显著变化。在局部区域内，完全具有性别特异性的重组热点较为罕见。活性最高的重组热点处的重组起始过程在两条亲本染色单体上独立受到调控，且正反交分析表明，亲本印记对重组速率存在细微影响。由此可见，哺乳动物重组的调控是一个复杂且动态的过程，涉及多重影响因素，包括物种特性、性别差异、物种内的个体变异以及单个重组热点的自身属性。