生命的超立方体：蛋白质稳定性如何限制生物体的复杂性和分子进化的速度
The Hypercube of Life: How Protein Stability Imposes Limits on Organism Complexity and Speed of Molecular Evolution
摘要：
经典的群体遗传学先验地将适合度分配给等位基因，而不考虑这些等位基因编码的蛋白质的分子或功能特性。在这里，我们研究种群动力学在一个模型中，健身可以推断出从蛋白质的物理性质下的生理假设，任何蛋白质的稳定性损失编码的一个必需基因赋予一个致命的表型。在含有γ基因的生物体中突变的积累可以表示为在具有吸收边界的γ维超立方体内的扩散，在每个维度上，吸收边界由蛋白质稳定性的损失确定，在更高的稳定性下，吸收边界由蛋白质序列的缺乏确定。求解扩散方程，其参数来自蛋白质点突变的数据，我们确定了一个普遍的蛋白质稳定性分布，与现有的数据。该理论提供了突变率、最大基因组大小和蛋白质对点突变的热力学响应之间的基本关系。它通过预测当嗜温生物每次复制基因组每个重要部分的突变率超过约6个突变时，以及嗜热生物每次复制每个基因组超过1至2个突变时，种群就会灭绝（通过致命突变），从而建立了分子进化速率的通用速度限制。此外，我们的研究结果表明，在没有纠错的情况下，现代RNA病毒和原始基因组必然非常短。几种RNA病毒的功能接近进化速度极限，而DNA病毒和具有不同基因组长度和突变率的非突变细菌菌株所使用的纠错机制使这些生物体普遍低于自然速度极限约1000倍。
英文摘要：
Classical population genetics a priori assigns fitness to alleles without considering molecular or functional properties of proteins that these alleles encode. Here we study population dynamics in a model where fitness can be inferred from physical properties of proteins under a physiological assumption that loss of stability of any protein encoded by an essential gene confers a lethal phenotype. Accumulation of mutations in organisms containing Gamma genes can then be represented as diffusion within the Gamma dimensional hypercube with adsorbing boundaries which are determined, in each dimension, by loss of a protein stability and, at higher stability, by lack of protein sequences. Solving the diffusion equation whose parameters are derived from the data on point mutations in proteins, we determine a universal distribution of protein stabilities, in agreement with existing data. The theory provides a fundamental relation between mutation rate, maximal genome size and thermodynamic response of proteins to point mutations. It establishes a universal speed limit on rate of molecular evolution by predicting that populations go extinct (via lethal mutagenesis) when mutation rate exceeds approximately 6 mutations per essential part of genome per replication for mesophilic organisms and 1 to 2 mutations per genome per replication for thermophilic ones. Further, our results suggest that in absence of error correction, modern RNA viruses and primordial genomes must necessarily be very short. Several RNA viruses function close to the evolutionary speed limit while error correction mechanisms used by DNA viruses and non-mutant strains of bacteria featuring various genome lengths and mutation rates have brought these organisms universally about 1000 fold below the natural speed limit.
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