Inferring physico-chemical constraints at individual sites in protein evolution

描述（由申请人提供）：检测突变已被正向选择驱动固定或受纯化选择限制的位点通常很重要。这种选择压力的基础是不同氨基酸之间的物理化学差异（例如亲水性，极性或体积）。即使当位点处的一些氨基酸变化受到正选择的青睐时（例如，因为用不同极性取代氨基酸可能是有利的），仍然可以预期选择性约束抑制其他氨基酸的改变。 在同一位点发生变化（例如，因为具有不同体积的氨基酸会破坏蛋白质的折叠）。因此，不同的选择压力可以在相同的位置上作用于不同的性质。此外，在一个地点保存重要的物理化学性质在另一个地点可能不重要。在这个项目中，我们将利用我们在进化和选择的计算和统计建模方面的专业知识，开发计算和统计方法，以阐明哪些物理化学性质在哪些地点是重要的。我们的方法将确定不仅功能上重要的网站经历选择，但物理化学的限制下，进化在这些网站和选择压力，导致一些物理化学性质的变化适应性。我们将使用这些方法来研究适应在几个生物医学上重要的背景下，包括免疫逃逸和逆转病毒病原体，病毒传播，和病毒适应不同的主机隔室的生化基础。

DESCRIPTION (provided by applicant): It is often important to detect sites where mutations have been driven to fixation by positive selection, or which are constrained by purifying selection. Underlying such selective pressures are the physico-chemical differences (e.g. in hydropathy, polarity or volume) between different amino acids. Even when some amino acid changes at a site are favored by positive selection (e.g. because substituting an amino acid with different polarity may be favorable), selective constraints can still be expected to suppress other changes at the same site (e.g. because an amino acid with different volume would disrupt the folding of the protein). Thus different selective pressure can act on different properties at the same site. Moreover, a physico-chemical property that is important to conserve at one site may be unimportant at another. In this project we will use our expertise in computational and statistical modeling of evolution and selection to develop computational and statistical methodology to elucidate which physico-chemical properties are important at which sites. Our methods will identify not only functionally important sites experiencing selection, but the physico-chemical constraints under which evolution operates at those sites and the selective pressure causing some physico-chemical properties to change adaptively. We will use these methods to study the biochemical basis of adaptation in several biomedically important contexts, including immune escape and reversion in viral pathogens, viral transmission, and viral adaptation to different host compartments.