Kinsler Grant, Li Yuping, Sherlock Gavin, Petrov Dmitri A
Department of Biology, Stanford University, Stanford, California, United States of America.
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Biol. 2024 Dec 5;22(12):e3002848. doi: 10.1371/journal.pbio.3002848. eCollection 2024 Dec.
Evolution by natural selection is expected to be a slow and gradual process. In particular, the mutations that drive evolution are predicted to be small and modular, incrementally improving a small number of traits. However, adaptive mutations identified early in microbial evolution experiments, cancer, and other systems often provide substantial fitness gains and pleiotropically improve multiple traits at once. We asked whether such pleiotropically adaptive mutations are common throughout adaptation or are instead a rare feature of early steps in evolution that tend to target key signaling pathways. To do so, we conducted barcoded second-step evolution experiments initiated from 5 first-step mutations identified from a prior yeast evolution experiment. We then isolated hundreds of second-step mutations from these evolution experiments, measured their fitness and performance in several growth phases, and conducted whole genome sequencing of the second-step clones. Here, we found that while the vast majority of mutants isolated from the first-step of evolution in this condition show patterns of pleiotropic adaptation-improving both performance in fermentation and respiration growth phases-second-step mutations show a shift towards modular adaptation, mostly improving respiration performance and only rarely improving fermentation performance. We also identified a shift in the molecular basis of adaptation from genes in cellular signaling pathways towards genes involved in respiration and mitochondrial function. Our results suggest that the genes in cellular signaling pathways may be more likely to provide large, adaptively pleiotropic benefits to the organism due to their ability to coherently affect many phenotypes at once. As such, these genes may serve as the source of pleiotropic adaptation in the early stages of evolution, and once these become exhausted, organisms then adapt more gradually, acquiring smaller, more modular mutations.
自然选择驱动的进化预计是一个缓慢且渐进的过程。特别是，推动进化的突变预计是微小且模块化的，逐步改善少数几个性状。然而，在微生物进化实验、癌症及其他系统早期鉴定出的适应性突变，往往能带来显著的适应性提升，并能同时多效性地改善多个性状。我们探讨了这种多效性适应性突变在整个适应过程中是否普遍存在，或者相反，它是否是进化早期阶段的一种罕见特征，这些早期阶段的突变往往针对关键信号通路。为此，我们开展了带条形码的第二步进化实验，这些实验始于从先前的酵母进化实验中鉴定出的5个第一步突变。然后，我们从这些进化实验中分离出数百个第二步突变，测量它们在几个生长阶段的适应性和表现，并对第二步克隆进行全基因组测序。在这里，我们发现，虽然在这种条件下从进化第一步分离出的绝大多数突变体都表现出多效性适应模式——改善发酵和呼吸生长阶段的表现——但第二步突变则转向模块化适应，主要改善呼吸表现，很少改善发酵表现。我们还确定了适应的分子基础从细胞信号通路中的基因转向参与呼吸和线粒体功能的基因。我们的结果表明，细胞信号通路中的基因可能更有可能由于其能够同时连贯地影响许多表型，从而为生物体提供巨大的、适应性多效性的益处。因此，这些基因可能是进化早期多效性适应的来源，一旦这些基因被耗尽，生物体随后就会更逐渐地适应，获得更小、更模块化的突变。
