Patterns and causes of signed linkage disequilibria in flies and plants: original data

Most empirical studies of linkage disequilibrium (LD) study its magnitude, ignoring its sign. Here, we examine patterns of signed LD in two population genomic datasets, one from Capsella grandiflora and one from Drosophila melanogaster. We consider how processes such as drift, admixture, Hill-Robertson interference, and epistasis may contribute to these patterns. We report that most types of mutations exhibit positive LD, particularly, if they are predicted to be less deleterious. We show with simulations that this pattern arises easily in a model of admixture or distance biased mating, and that genome-wide differences across site types are generally expected due to differences in the strength of purifying selection even in the absence of epistasis. We further explore how signed LD decays on a finer scale, showing that loss of function mutations exhibit particularly positive LD across short distances, a pattern consistent with intragenic antagonistic epistasis. Controlling for genomic distance, signed LD in C. grandiflora decays faster within genes, compared to between genes, likely a by-product of frequent recombination in gene promoters known to occur in plant genomes. Finally, we use information from published biological networks to explore whether there is evidence for negative synergistic epistasis between interacting radical missense mutations. In D. melanogaster networks, we find a modest but significant enrichment of negative LD, consistent with the possibility of intra-network negative synergistic epistasis.

当前绝大多数针对连锁不平衡（linkage disequilibrium, LD）的实证研究仅关注其强度，而忽略了其符号属性。本研究聚焦两类群体基因组数据集的带符号连锁不平衡模式，数据集分别取自大花荠（Capsella grandiflora）与黑腹果蝇（Drosophila melanogaster）。我们探讨了遗传漂变、基因交流、希尔-罗伯逊干涉（Hill-Robertson interference）、上位性（epistasis）等演化过程对这类模式的潜在塑造作用。研究发现，多数类型的突变均表现出正向连锁不平衡，其中被预测为有害程度较低的突变这一特征尤为显著。通过模拟实验我们证实，该模式在基因交流或距离偏向性交配模型中极易出现；且即便不存在上位性，由于不同位点的纯化选择（purifying selection）强度存在差异，全基因组范围内不同位点类型间的连锁不平衡差异也普遍存在。我们进一步在更精细的尺度上探究带符号连锁不平衡的衰减规律，结果显示功能丧失突变（loss of function mutations）在短距离范围内呈现尤为显著的正向连锁不平衡，这一模式与基因内拮抗上位性假说相符。在控制基因组距离的前提下，大花荠的带符号连锁不平衡在基因内部的衰减速度快于基因间，这一现象大概率是植物基因组中已知存在的基因启动子区域高频重组事件的副产物。最后，我们借助已发表的生物网络数据，探究互作的激进错义突变之间是否存在负向协同上位性（synergistic epistasis）的证据。在黑腹果蝇的网络数据中，我们发现负向连锁不平衡存在适度但显著的富集现象，这与网络内存在负向协同上位性的可能性相符。