High-Resolution Recombination Patterns in a Region of Human Chromosome 21 Measured by Sperm Typing

For decades, classical crossover studies and linkage disequilibrium (LD) analysis of genomic regions suggested that human meiotic crossovers may not be randomly distributed along chromosomes but are focused instead in “hot spots.” Recent sperm typing studies provided data at very high resolution and accuracy that defined the physical limits of a number of hot spots. The data were also used to test whether patterns of LD can predict hot spot locations. These sperm typing studies focused on several small regions of the genome already known or suspected of containing a hot spot based on the presence of LD breakdown or previous experimental evidence of hot spot activity. Comparable data on target regions not specifically chosen using these two criteria is lacking but is needed to make an unbiased test of whether LD data alone can accurately predict active hot spots. We used sperm typing to estimate recombination in 17 almost contiguous ~5 kb intervals spanning 103 kb of human Chromosome 21. We found two intervals that contained new hot spots. The comparison of our data with recombination rates predicted by statistical analyses of LD showed that, overall, the two datasets corresponded well, except for one predicted hot spot that showed little crossing over. This study doubles the experimental data on recombination in men at the highest resolution and accuracy and supports the emerging genome-wide picture that recombination is localized in small regions separated by cold areas. Detailed study of one of the new hot spots revealed a sperm donor with a decrease in recombination intensity at the canonical recombination site but an increase in crossover activity nearby. This unique finding suggests that the position and intensity of hot spots may evolve by means of a concerted mechanism that maintains the overall recombination intensity in the region.

数十年来，经典交叉研究与基因组区域的连锁不平衡（linkage disequilibrium）分析均提示，人类减数分裂交叉并非沿染色体随机分布，反而集中于“重组热点（hot spot）”区域。近期的精子分型（sperm typing）研究以极高的分辨率与精度获取了实验数据，明确了多个重组热点的物理边界，这些数据还被用于检验连锁不平衡模式是否可预测重组热点的位置。此类精子分型研究聚焦于基因组中若干已知或疑似存在重组热点的小区域，其判定依据为连锁不平衡断裂现象，或是此前已证实的重组热点活性实验证据。目前尚缺乏基于上述两项标准之外的标准特意筛选的靶区域的可比数据，但要开展无偏检验，验证仅依靠连锁不平衡数据即可准确预测活性重组热点，这类数据是必不可少的。我们采用精子分型技术，对人类21号染色体（Chromosome 21）上跨度为103kb的17个近乎连续的约5kb片段进行重组率估算，发现在其中两个片段中存在新的重组热点。将我们的数据与基于连锁不平衡统计分析预测的重组率进行比对后发现，整体而言两组数据吻合度较高，但有一处预测的重组热点几乎未检测到交叉事件。本研究将男性高分辨率、高精度的重组实验数据量翻倍，同时支持了日益明晰的全基因组研究图景：重组事件定位于由重组冷区域分隔的小范围区域内。对其中一处新重组热点的详细研究显示，一名精子供体在经典重组位点的重组强度出现下降，但邻近区域的交叉活性有所提升。这一独特发现提示，重组热点的位置与强度可能通过一种可维持该区域整体重组强度的协同机制发生演化。