scholarly journals Selection enhances protein evolvability by increasing mutational robustness and foldability

Science ◽  
2020 ◽  
Vol 370 (6521) ◽  
pp. eabb5962
Author(s):  
Jia Zheng ◽  
Ning Guo ◽  
Andreas Wagner
Keyword(s):  
Natural Selection ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Deleterious Mutations ◽  
Green Fluorescence ◽  
Weak Selection ◽  
Mutational Robustness ◽  
Evolutionary Success ◽  
Selection For ◽  
Underlying Mechanisms

Natural selection can promote or hinder a population’s evolvability—the ability to evolve new and adaptive phenotypes—but the underlying mechanisms are poorly understood. To examine how the strength of selection affects evolvability, we subjected populations of yellow fluorescent protein to directed evolution under different selection regimes and then evolved them toward the new phenotype of green fluorescence. Populations under strong selection for the yellow phenotype evolved the green phenotype most rapidly. They did so by accumulating mutations that increase both robustness to mutations and foldability. Under weak selection, neofunctionalizing mutations rose to higher frequency at first, but more frequent deleterious mutations undermined their eventual success. Our experiments show how selection can enhance evolvability by enhancing robustness and create the conditions necessary for evolutionary success.

scholarly journals Higher-fitness yeast genotypes are less robust to deleterious mutations

Science ◽  
2019 ◽  
Vol 366 (6464) ◽  
pp. 490-493 ◽  
Author(s):  
Milo S. Johnson ◽  
Alena Martsul ◽  
Sergey Kryazhimskiy ◽  
Michael M. Desai
Keyword(s):  
Second Order ◽  
Order Selection ◽  
Deleterious Mutations ◽  
Mutational Robustness ◽  
First Order ◽  
Fitness Effects ◽  
Yeast Strains ◽  
Selection For ◽  
Microbial Systems ◽  
Insertion Mutations

Natural selection drives populations toward higher fitness, but second-order selection for adaptability and mutational robustness can also influence evolution. In many microbial systems, diminishing-returns epistasis contributes to a tendency for more-fit genotypes to be less adaptable, but no analogous patterns for robustness are known. To understand how robustness varies across genotypes, we measure the fitness effects of hundreds of individual insertion mutations in a panel of yeast strains. We find that more-fit strains are less robust: They have distributions of fitness effects with lower mean and higher variance. These differences arise because many mutations have more strongly deleterious effects in faster-growing strains. This negative correlation between fitness and robustness implies that second-order selection for robustness will tend to conflict with first-order selection for fitness.

Marrow Derived Muscle Colonies Are a Clonal Phenomenon.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2692-2692
Author(s):  
Mehrdad Abedi ◽  
Deborah A. Greer ◽  
Bethany A. Foster ◽  
Delia A. Demers ◽  
Gerald A. Colvin ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Mdx Mouse ◽  
Green Fluorescence ◽  
Fluorescent Intensity ◽  
Tibialis Muscle ◽  
Multiple Cycles ◽  
The Individual ◽  
Negative Population ◽  
Marrow Cells

Abstract We have previously established a model of plasticity of marrow to skeletal muscle that is based on transplantation of GFP positive marrow and cardiotoxin injury to the tibialis muscle. In these experiments, we have observed colonies of GFP positive muscle fibers, defined as 3 or more myocytes. We noted that individual GFP positive fibers showed marked heterogeneity of fluorescence. In sharp contrast, colonies of GFP+ cells, showed homogeneous fluorescence. This was confirmed by using confocal microscopy and by measuring the mean fluorescent intensity of the individual cells in the colonies. When the intensity of the green fluorescence in individual fibers was graded to dull, moderate or bright, in 95% of the colonies counted, showed homogenous intensity of green fluorescence while for single GFP fibers dispersed throughout the specimen the probability of 3 cells being the same color was only 14.12%. Therefore the probability of 95% of colonies to have a minimum of 3 homogenous fibers by random association is less than 0.0001. To show that colonies are not from clumps of cells injected into the muscle, we compared the number of the colonies in two different experimental setting where in both GFP positive marrow cells were injected intravenously after 900cGy of radiation followed by cardiotoxin injury to the muscle. Animals who received two cycle of G-CSF mobilization were compared with those who had lineage negative marrow cells directly injected into their muscle, one day after injury. The incidence of muscle colonies remained the same between the groups. The incidence increased in experiments with multiple cycles of mobilization and injury and also in mdx mouse that has spontaneous ongoing regeneration of its muscles. Cotransplantation of marrow cells from yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) transgenics into C57BL/6 mice followed by cardiotoxin injury showed colonies that were either from YFP or CFP cells. No mixed colonies were found. Transplantation of YFP marrow cells before injury followed by CFP cells after injury and vice versa showed colonies only from cells that were infused at the time of transplantation. Colonies were seen only in samples that received CD45, C-Kit and/or Sca positive marrow cells and not in those negative populations. These cells resulted in a GFP+ CD45 negative population 4 weeks after transplantation and produced Myf5+ and MyoD+ myoblasts three days after injury. These data suggests that marrow derived muscle colonies are a clonal phenomenon similar to CFU-S cells in recipient spleens after transplantation.

scholarly journals Higher fitness yeast genotypes are less robust to deleterious mutations

2019 ◽  
Author(s):  
Milo S. Johnson ◽  
Alena Martsul ◽  
Sergey Kryazhimskiy ◽  
Michael M. Desai
Keyword(s):  
Second Order ◽  
Order Selection ◽  
Deleterious Mutations ◽  
Mutational Robustness ◽  
First Order ◽  
Fitness Effects ◽  
Yeast Strains ◽  
Selection For ◽  
Microbial Systems ◽  
Insertion Mutations

AbstractNatural selection drives populations towards higher fitness, but second-order selection for adaptability and mutational robustness can also influence the dynamics of adaptation. In many microbial systems, diminishing returns epistasis contributes to a tendency for more-fit genotypes to be less adaptable, but no analogous patterns for robustness are known. To understand how robustness varies across genotypes, we measure the fitness effects of hundreds of individual insertion mutations in a panel of yeast strains. We find that more-fit strains are less robust: they have distributions of fitness effects (DFEs) with lower mean and higher variance. These shifts in the DFE arise because many mutations have more strongly deleterious effects in faster-growing strains. This negative correlation between fitness and robustness implies that second-order selection for robustness will tend to conflict with first-order selection for fitness.

scholarly journals Natural selection can favor ratchet robustness over mutational robustness

2017 ◽  
Author(s):  
Yinghong Lan ◽  
Aaron Trout ◽  
Daniel Michael Weinreich ◽  
Christopher Scott Wylie
Keyword(s):  
Natural Selection ◽  
Natural Populations ◽  
Deleterious Mutations ◽  
Short Term ◽  
Mutational Robustness ◽  
Fundamental Interest ◽  
Fitness Advantage ◽  
Short And Long Term ◽  
Asexual Populations

AbstractThe vast majority of fitness-affecting mutations are deleterious. How natural populations evolve to cope is a question of fundamental interest. Previous studies have reported the evolution of mutational robustness, that is, natural selection favoring populations with less deleterious mutations. By definition, mutational robustness provides a short-term fitness advantage. However, this overlooks the fact that mutational robustness decreases finite asexual populations’ ability to purge recurrent deleterious mutations. Thus, mutational robustness also results in higher risk of long-term extinction by Muller’s ratchet. Here, we explore the tension between short- and long- term response to deleterious mutations. We first show that populations can resist the ratchet if either the selection coefficient or the ratio of beneficial to deleterious mutations increases as fitness declines. We designate these properties as ratchet robustness, which fundamentally reflects a negative feedback between mutation rate and the tendency to accumulate more mutations. We also find in simulations that populations can evolve ratchet robustness when challenged by deleterious mutations. We conclude that mutational robustness cannot be selected for in the long term, but it can be favored in the short-term, purely because of temporary fitness advantage. We also discuss other potential causes of mutational robustness in nature.

scholarly journals Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1

2021 ◽  
Vol 22 (13) ◽  
pp. 7100
Author(s):  
Yohan Seo ◽  
Sung Baek Jeong ◽  
Joo Han Woo ◽  
Oh-Bin Kwon ◽  
Sion Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
High Throughput Screening ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Small Cell ◽  
Channel Activity ◽  
Small Cell Lung ◽  
Protein Levels

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

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