Abstract

Recombination is the exchange of genetic material between homologous chromosomes via physical crossovers. High-throughput sequencing approaches detect crossovers genome wide to produce recombination rate maps but are difficult to scale as they require large numbers of recombinants individually sequenced. We present a simple and scalable pooled-sequencing approach to experimentally infer near chromosome-wide recombination rates by taking advantage of non-Mendelian allele frequency generated from a fitness differential at a locus under selection. As more crossovers decouple the selected locus from distal loci, the distorted allele frequency attenuates distally toward Mendelian and can be used to estimate the genetic distance. Here, we use marker selection to generate distorted allele frequency and theoretically derive the mathematical relationships between allele frequency attenuation, genetic distance, and recombination rate in marker-selected pools. We implemented nonlinear curve-fitting methods that robustly estimate the allele frequency decay from batch sequencing of pooled individuals and derive chromosome-wide genetic distance and recombination rates. Empirically, we show that marker-selected pools closely recapitulate genetic distances inferred from scoring recombinants. Using this method, we generated novel recombination rate maps of three wild-derived strains of Drosophila melanogaster, which strongly correlate with previous measurements. Moreover, we show that this approach can be extended to estimate chromosome-wide crossover interference with reciprocal marker selection and discuss how it can be applied in the absence of visible markers. Altogether, we find that our method is a simple and cost-effective approach to generate chromosome-wide recombination rate maps requiring only one or two libraries.

中文翻译：

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从选定位点周围的等位基因频率衰减测量宽范围和染色体范围的重组率的理论和应用。

摘要

重组是通过物理交换在同源染色体之间交换遗传物质。高通量测序方法可检测基因组范围内的交叉基因，以产生重组率图，但由于需要大量单独测序的重组子，因此难以扩展。我们提出了一种简单且可扩展的合并测序方法，以通过利用选择位点的适应性差异产生的非孟德尔等位基因频率，通过实验推断接近全染色体的重组率。随着更多的交叉将选定的基因座与远端基因座解耦，扭曲的等位基因频率朝着孟德尔方向向远端衰减，可用于估计遗传距离。这里，我们使用标记选择产生扭曲的等位基因频率，并从理论上推导标记选择池中等位基因频率衰减，遗传距离和重组率之间的数学关系。我们实施了非线性曲线拟合方法，可从合并个体的批量测序中可靠地估算等位基因频率的衰减，并得出染色体范围的遗传距离和重组率。根据经验，我们表明标记物选择的池紧密概括了从评分重组体推断的遗传距离。使用此方法，我们生成了三种野生来源的拟南芥菌株的新型重组率图。我们实施了非线性曲线拟合方法，可从合并个体的批量测序中可靠地估算等位基因频率的衰减，并得出染色体范围的遗传距离和重组率。根据经验，我们表明标记物选择的池紧密概括了从评分重组体推断的遗传距离。使用此方法，我们生成了三种野生来源的拟南芥菌株的新型重组率图。我们实施了非线性曲线拟合方法，可从合并个体的批量测序中可靠地估算等位基因频率的衰减，并得出染色体范围的遗传距离和重组率。根据经验，我们表明标记物选择的池紧密概括了从评分重组体推断的遗传距离。使用此方法，我们生成了三种野生来源的拟南芥菌株的新型重组率图。果蝇（Drosophila melanogaster）与以前的测量高度相关。此外，我们表明该方法可以扩展为估计具有互逆标记选择的染色体范围内的交叉干扰，并讨论如何在不存在可见标记的情况下应用该方法。总而言之，我们发现我们的方法是一种仅需一个或两个文库即可生成全染色体重组率图的简单且经济高效的方法。