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以潜伏形式储存变异，并在以后显示出来。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一种遗传和环境背景下的疾病等位基因在另一种环境下可能是无害的。也许是因为电容的生物学本质上不同于群体遗传学研究的突变、重组和选择过程，从理论角度来看，电容仍然知之甚少。提出的工作将发展一个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群体经历罕见的环境变化事件。该理论将侧重于等位基因的入侵概率，从而改变变异被揭示的概率。该理论将被用来预测在何种情况下这些等位基因将被偏爱。它将包含电容器生物学的不同寻常的方面，例如在多个位点同时揭示变异的事实，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，隐藏的变异可能受制于低水平的选择，而不是没有选择。隐藏状态下的温和选择，通过去除强有害突变体，可能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酵母3'非翻译区域的比较基因组学来调查过去的[PSI+]电容活性和[PSI+]揭示的变异的预适应的证据来加强。在公共卫生的背景下，人类疾病复杂的遗传结构常常使基因分析的尝试变得混乱。对进化电容的深入了解可能为将来的分析提供一个新的框架。由于电容的直接实验不能在人类身上进行，这里描述的理论和预测方法对于理解解释人类变异的电容范围尤为重要。

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.