[论文解读] An age-of-allele test of neutrality for transposable element insertions not at equilibrium

Justin P. Blumenstiel, Miaomiao He+1 more|arXiv (Cornell University)|Sep 16, 2012

Chromosomal and Genetic Variations被引用 1

一句话总结

该论文提出了一种针对转座元件（TE）插入的新型等位基因年龄中性检验方法，该方法不假设转座速率恒定，而是利用TE内部的替换数目来估计插入年龄。通过在考虑种群大小变化的前提下对中性条件下的等位基因频率分布进行建模，该方法解释了黑腹果蝇中约80%的TE等位基因频率方差，揭示了TE上普遍存在负向选择，且正向选择极为罕见。

ABSTRACT

How natural selection acts to limit the proliferation of transposable elements (TEs) in genomes has been of interest to evolutionary biologists for many years. To describe TE dynamics in populations, many previous studies have used models of transposition-selection equilibrium that rely on the assumption of a constant rate of transposition. However, since TE invasions are known to happen in bursts through time, this assumption may not be reasonable in natural populations. Here we propose a test of neutrality for TE insertions that does not rely on the assumption of a constant transposition rate. We consider the case of TE insertions that have been ascertained from a single haploid reference genome sequence and have subsequently had their allele frequency estimated in a population sample. By conditioning on the age of an individual TE insertion (using information contained in the number of substitutions that have occurred within the TE sequence since insertion), we determine the probability distribution for the insertion allele frequency in a population sample under neutrality. Taking models of varying population size into account, we then evaluate predictions of our model against allele frequency data from 190 retrotransposon insertions sampled from North American and African populations of Drosophila melanogaster. Using this non-equilibrium model, we are able to explain about 80% of the variance in TE insertion allele frequencies based on age alone. Controlling both for nonequilibrium dynamics of transposition and host demography, we provide evidence for negative selection acting against most TEs as well as for positive selection acting on a small subset of TEs. Our work establishes a new framework for the analysis of the evolutionary forces governing large insertion mutations like TEs, gene duplications or other copy number variants.

研究动机与目标

• 为解决现有TE中性检验方法假设转座速率恒定的局限性，该假设可能无法反映现实中转座元件爆发式入侵的实际情况。
• 开发一种利用TE内部序列分歧来估计插入年龄的方法，从而实现在不假设转座-选择平衡的前提下进行中性检验。
• 评估种群大小变化及选择对自然种群中TE等位基因频率分布的影响。
• 通过在中性条件下基于年龄的等位基因频率预测，检测TE插入上同时存在的负向和正向选择。

提出的方法

• 通过统计自插入以来TE序列内部累积的替换数目，来估计单个TE插入的年龄。
• 在种群大小可变的中性模型下，基于估计的插入年龄对TE等位基因频率的概率分布进行条件化处理。
• 使用共祖先过程模型推导中性条件下的预期等位基因频率分布，整合了群体历史（如种群大小变化）。
• 将预测的年龄依赖型等位基因频率分布拟合到黑腹果蝇种群中190个逆转录转座子插入的实证数据。
• 将观察到的等位基因频率与中性预测值进行比较，以检测表明存在选择的偏离。
• 将该方法应用于北美和非洲的黑腹果蝇种群，以评估在不同群体历史背景下的选择效应。

实验结果

研究问题

• RQ1 能否开发一种不依赖于恒定转座速率假设的TE插入中性检验方法？
• RQ2 从TE内部替换数目估算的插入年龄，在多大程度上能预测自然种群中的TE等位基因频率？
• RQ3 种群大小变化及非平衡转座动力学如何影响TE频率数据的解释？
• RQ4 负向和正向选择在黑腹果蝇TE频率变异中各自贡献有多大？

主要发现

• 仅使用插入年龄，该等位基因年龄模型即可解释约80%的TE插入等位基因频率方差，表明其具有强大的预测能力。
• 在控制了非平衡转座和群体历史之后，检测到负向选择作用于大多数TE插入。
• 一小部分TE显示出正向选择的证据，表明TE插入可能带来罕见的适应性优势。
• 即使在标准平衡模型因爆发式转座动力学而失效的情况下，该方法仍能成功识别出选择信号。
• 该框架可推广至其他大型插入突变，如基因重复和拷贝数变异。
• 与假设种群大小恒定相比，引入群体模型显著提高了中性检验的准确性。