Towards a general theory of evolutionary capacitance

描述(由申请人提供)：进化电容机制，如酵母普鲁恩[PSI+]和热休克蛋白HspQO以潜在的形式存储变异，并在稍后揭示。电容器似乎很常见，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是无害的。也许是因为电容的生物学与通常由群体遗传学研究的突变、重组和选择过程有很大的不同，从理论的角度来看，对电容器的理解仍然很少。这项拟议的工作将发展一种新的种群遗传学理论，以在经历罕见环境变化事件的有限种群中捕捉电容器生物学的本质。该理论将重点放在改变变异被揭示的概率的等位基因的入侵概率上。这一理论将被用来预测在什么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同寻常的方面，例如，变异是同时在多个位置揭示的，并且揭示很容易逆转。电容生物学的另一个不同寻常的方面是，隐藏的变异可能受到低水平的选择而不是没有选择的影响。在隐藏状态下的温和选择，通过去除强烈有害的突变，可能会丰富潜在适应性特征的隐藏变异。这种预适应现象将被纳入模型框架，并将评估其对电容器介导的适应的影响。通过使用3‘非翻译区的酵母比较基因组学来调查过去[PSI+]电容活性的证据以及[PSI+]揭示的变异的预适应，将加强电容的理论框架。在公共卫生的背景下，人类疾病的复杂遗传结构经常混淆了基因分析的尝试。对进化电容的坚实理解可能会为未来的此类分析提供一个新的框架。由于电容的直接实验不能在人体内进行，这里描述的理论和预测方法对于理解电容在解释人类变异中的范围特别重要。

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.