Towards a general theory of evolutionary capacitance

描述（由申请人提供）：进化电容器机制，如酵母朊病毒[PSI+]和热休克蛋白HspQO，以潜在形式储存变异，并在以后揭示。电容器似乎是常见的，可能是遗传结构的关键组成部分。电容器有助于解释为什么在遗传和环境背景下的疾病等位基因在不同的背景下可能是无害的。也许是因为电容的生物学与群体遗传学通常研究的突变，重组和选择过程有很大的不同，从理论的角度来看，电容器仍然知之甚少。拟议的工作将开发一种新的群体遗传学理论，以捕捉电容器生物学的本质，在一个有限的人口经历罕见的环境变化事件。该理论将集中在等位基因的入侵概率上，这些等位基因改变了变异被揭示的概率。该理论将被用来预测在何种情况下这些等位基因会受到青睐。它将结合电容器生物学的不寻常方面，例如同时在多个位点揭示变化的事实，并且这种揭示很容易逆转。电容器生物学的另一个不寻常的方面是，隐藏的变异可能受到低水平的选择，而不是没有选择。隐藏状态下的温和选择，通过去除强烈有害的突变体，可以丰富潜在适应性性状的隐藏变异。这种预适应现象将被纳入模型框架，并将评估其对电容介导的适应的影响。电容的理论框架将通过使用3'非翻译区的比较酵母基因组学来加强，以调查过去[PSI+]电容活性和[PSI+]所揭示的变化的预适应的证据。在公共卫生方面，人类疾病复杂的遗传结构往往使基因分析的尝试感到困惑。对进化电容的深入理解可能为未来的此类分析提供新的框架。由于无法在人体中进行电容的直接实验，因此本文所述的理论和预测方法对于理解解释人体变化的电容范围特别重要。

DESCRIPTION (provided by applicant): Evolutionary capacitor mechanisms such as the yeast prion [PSI+] and the heat shock protein HspQO store variation in a latent form and reveal it later. Capacitors appear to be common, and could be key components of genetic architecture. Capacitors help explain why a disease allele in 1 genetic and environmental context could be harmless in a different context. Perhaps because the biology of capacitance is substantially different from the mutation, recombination, and selection processes typically studied by population genetics, capacitors remain poorly understood from a theoretical perspective. The proposed work will develop a novel population genetics theory to capture the essence of capacitor biology in a finite population undergoing rare environmental change events. The theory will focus on the invasion probabilities of alleles that modify the probability with which variation is revealed. The theory will be used to predict the circumstances under which such alleles will be favored. It will incorporate unusual aspects of capacitor biology, such as the fact that variation is revealed at multiple sites simultaneously, and that revelation is easily reversible. Another unusual aspect of capacitor biology is that hidden variation may be subject to low levels of selection rather than no selection. Mild selection in the hidden state, by removing strongly deleterious mutants, may enrich hidden variation for potentially adaptive traits. This phenomenon of preadaptation will be incorporated into the model framework and its impact on capacitor-mediated adaptation will be assessed. The theoretical framework for capacitance will be reinforced by using comparative yeast genomics of 3' untranslated regions to survey the evidence for past [PSI+] capacitance activity and for preadaptation of the variation revealed by [PSI+]. In the context of public health, the complex genetic architecture of human disease often confounds attempts at genetic analysis. A solid understanding of evolutionary capacitance may provide a new framework for such analyses in the future. Since direct experiments on capacitance cannot be performed in humans, the theoretical and predictive approach described here is particularly important for understanding the scope of capacitance in explaining human variation.