Extreme Recombination Frequencies Shape Genome Variation and Evolution in the Honeybee, Apis mellifera

Meiotic recombination is a fundamental cellular process, with important consequences for evolution and genome integrity. However, we know little about how recombination rates vary across the genomes of most species and the molecular and evolutionary determinants of this variation. The honeybee, Apis mellifera, has extremely high rates of meiotic recombination, although the evolutionary causes and consequences of this are unclear. Here we use patterns of linkage disequilibrium in whole genome resequencing data from 30 diploid honeybees to construct a fine-scale map of rates of crossing over in the genome. We find that, in contrast to vertebrate genomes, the recombination landscape is not strongly punctate. Crossover rates strongly correlate with levels of genetic variation, but not divergence, which indicates a pervasive impact of selection on the genome. Germ-line methylated genes have reduced crossover rate, which could indicate a role of methylation in suppressing recombination. Controlling for the effects of methylation, we do not infer a strong association between gene expression patterns and recombination. The site frequency spectrum is strongly skewed from neutral expectations in honeybees: rare variants are dominated by AT-biased mutations, whereas GC-biased mutations are found at higher frequencies, indicative of a major influence of GC-biased gene conversion (gBGC), which we infer to generate an allele fixation bias 5 – 50 times the genomic average estimated in humans. We uncover further evidence that this repair bias specifically affects transitions and favours fixation of CpG sites. Recombination, via gBGC, therefore appears to have profound consequences on genome evolution in honeybees and interferes with the process of natural selection. These findings have important implications for our understanding of the forces driving molecular evolution.

减数分裂重组（Meiotic recombination）是一项基础细胞过程，对进化与基因组完整性具有重要意义。然而，对于多数物种的基因组内重组率如何变化，以及这种变化的分子与进化决定因素，我们目前仍知之甚少。西方蜜蜂（Apis mellifera）的减数分裂重组率极高，但其背后的进化成因与效应尚不明确。本研究利用30只二倍体（diploid）西方蜜蜂的全基因组重测序（whole genome resequencing）数据中的连锁不平衡（linkage disequilibrium）模式，构建了基因组内交叉互换（crossing over）率的精细图谱。研究发现，与脊椎动物基因组不同，蜜蜂的重组景观并未呈现强烈的点状聚集特征。交叉互换率与遗传变异（genetic variation）水平呈显著正相关，但与分化（divergence）无关，这表明选择对基因组存在广泛影响。生殖系甲基化基因（germ-line methylated genes）的交叉互换率更低，这提示甲基化（methylation）可能参与抑制重组过程。在控制甲基化效应后，我们未发现基因表达模式与重组率之间存在显著关联。西方蜜蜂的位点频率谱（site frequency spectrum）与中性预期（neutral expectations）严重偏离：稀有变异以AT偏好突变（AT-biased mutations）为主，而GC偏好突变（GC-biased mutations）的出现频率更高，这表明GC偏好基因转换（GC-biased gene conversion, gBGC）发挥了主要影响；经推断，该过程产生的等位基因固定偏倚是人类基因组平均水平的5至50倍。本研究进一步发现，这种修复偏倚仅对转换突变产生影响，并偏好CpG位点（CpG sites）的固定。因此，通过GC偏好基因转换，重组似乎对西方蜜蜂的基因组进化产生了深远影响，并干扰了自然选择（natural selection）过程。上述发现对于我们理解驱动分子进化的各类力量具有重要意义。