scholarly journals Most cancers carry a substantial deleterious load due to Hill-Robertson interference

2020 ◽  
Author(s):  
Christopher McFarland ◽  
Susanne Tilk ◽  
Christina Curtis ◽  
Dmitri Petrov
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Selection Model ◽  
Fitness Cost ◽  
Deleterious Mutations ◽  
Weak Selection ◽  
Selective Pressures ◽  
Mutational Burden ◽  
Genome Wide ◽  
Average Fitness

Abstract Cancer genomes exhibit surprisingly weak signatures of negative selection. This may be because tumors evolve under weak selective pressures (‘weak selection’) or because genome-wide linkage in cancer prevents most deleterious mutations from being removed due to Hill-Robertson interference3 (‘inefficient selection’). The weak selection model argues that most genes are only important for multicellular function and that selection acts only on a subset of essential genes. In contrast, the inefficient selection model predicts that only cancers with low mutational burdens, where linkage effects are minimal, will exhibit strong signals of negative selection against deleterious passengers and positive selection for beneficial drivers. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, are present in clonal and subclonal mutations, and persist in Copy Number Alterations. A consequence of this inability to remove deleterious passengers is that tumors with elevated mutational burdens, which are expected to harbor substantial protein folding stress, upregulate heat shock pathways. Finally, using evolutionary modeling, we find that Hill-Robertson interference alone can reproduce the patterns of attenuated selection observed in both drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost). Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage.

scholarly journals Most cancers carry a substantial deleterious load due to Hill-Robertson interference

2019 ◽  
Author(s):  
Susanne Tilk ◽  
Christina Curtis ◽  
Dmitri A Petrov ◽  
Christopher D McFarland
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Selection Model ◽  
Fitness Cost ◽  
Deleterious Mutations ◽  
Weak Selection ◽  
Selective Pressures ◽  
Mutational Burden ◽  
Genome Wide ◽  
Average Fitness

AbstractCancer genomes exhibit surprisingly weak signatures of negative selection1,2. This may be because tumors evolve under weak selective pressures (‘weak selection’) or because genome-wide linkage in cancer prevents most deleterious mutations from being removed due to Hill-Robertson interference3 (‘inefficient selection’). The weak selection model argues that most genes are only important for multicellular function and that selection acts only on a subset of essential genes. In contrast, the inefficient selection model predicts that only cancers with low mutational burdens, where linkage effects are minimal, will exhibit strong signals of negative selection against deleterious passengers and positive selection for beneficial drivers. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, are present in clonal and subclonal mutations, and persist in Copy Number Alterations. A consequence of this inability to remove deleterious passengers is that tumors with elevated mutational burdens, which are expected to harbor substantial protein folding stress, upregulate heat shock pathways. Finally, using evolutionary modeling, we find that Hill-Robertson interference alone can reproduce the patterns of attenuated selection observed in both drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost). Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage.

scholarly journals Selection bias in mutation accumulation

2021 ◽  
Author(s):  
Lindi M Wahl ◽  
Deepa Agashe
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
De Novo ◽  
Mutation Accumulation ◽  
Microbial Populations ◽  
Single Individual ◽  
Deleterious Mutations ◽  
De Novo Mutations ◽  
Fitness Effects ◽  
Wide Range

Mutation accumulation (MA) experiments, in which de novo mutations are sampled and subsequently characterized, are an essential tool in understanding the processes underlying evolution. In microbial populations, MA protocols typically involve a period of population growth between severe bottlenecks, such that a single individual can form a visible colony. While it has long been appreciated that the action of positive selection during this growth phase cannot be eliminated, it is typically assumed to be negligible. Here, we quantify the effect of both positive and negative selection in MA studies, demonstrating that selective effects can substantially bias the distribution of fitness effects (DFE) and mutation rates estimated from typical MA protocols in microbes. We then present a simple correction for this bias which applies to both beneficial and deleterious mutations, and can be used to correct the observed DFE in multiple environments. Finally, we use simulated MA experiments to illustrate the extent to which the MA-inferred DFE differs from the underlying true DFE, and demonstrate that the proposed correction accurately reconstructs the true DFE over a wide range of scenarios. These results highlight that positive selection during microbial MA experiments is in fact not negligible, but can be corrected to gain a more accurate understanding of fundamental evolutionary parameters.

scholarly journals Hadrurid Scorpion Toxins: Evolutionary Conservation and Selective Pressures

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 637 ◽  
Author(s):  
Carlos E. Santibáñez-López ◽  
Matthew R. Graham ◽  
Prashant P. Sharma ◽  
Ernesto Ortiz ◽  
Lourival D. Possani
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Evolutionary Dynamics ◽  
Housekeeping Genes ◽  
Evolutionary Conservation ◽  
Gene Duplications ◽  
Scorpion Toxins ◽  
Selective Pressures ◽  
Phylogenetic Inertia ◽  
The Family

Scorpion toxins are thought to have originated from ancestral housekeeping genes that underwent diversification and neofunctionalization, as a result of positive selection. Our understanding of the evolutionary origin of these peptides is hindered by the patchiness of existing taxonomic sampling. While recent studies have shown phylogenetic inertia in some scorpion toxins at higher systematic levels, evolutionary dynamics of toxins among closely related taxa remain unexplored. In this study, we used new and previously published transcriptomic resources to assess evolutionary relationships of closely related scorpions from the family Hadruridae and their toxins. In addition, we surveyed the incidence of scorpine-like peptides (SLP, a type of potassium channel toxin), which were previously known from 21 scorpion species. We demonstrate that scorpine-like peptides exhibit gene duplications. Our molecular analyses demonstrate that only eight sites of two SLP copies found in scorpions are evolving under positive selection, with more sites evolving under negative selection, in contrast to previous findings. These results show evolutionary conservation in toxin diversity at shallow taxonomic scale.

scholarly journals Evolution of Selective RNA Processing and Stabilization operons in cellulosome-harboring Clostridium spp.

2021 ◽  
Author(s):  
Yogendra Bhaskar ◽  
Mohammadhadi Heidari B. ◽  
Chenggang Xu ◽  
Jian Xu
Keyword(s):  
Positive Selection ◽  
Rna Processing ◽  
Similar Pattern ◽  
Glycoside Hydrolase ◽  
Negative Selection ◽  
Gene Variation ◽  
Genome Wide ◽  
Operon Evolution ◽  
Clostridium Spp ◽  
Selection Of

In selective RNA processing and stabilization (SRPS) operons, the stoichiometry of encoded proteins is determined by their respective 3'-end stem-loops (SLs), yet the evolution of this mechanism remains elusive. In cellulosomal operons of Clostridium spp., we show that the SLs and their associated genes form a monogamy companionship during the operon evolution. Based on ∆G of such SLs, we propose CoSLOE (Composite SL-based Operon Evolution) model with evolutionary ratio (ER) >1 or <1 for positive or negative selection of SRPS operons. In the composite SL-∆G-based tree (CoSL-tree) of cellulosomal operons, when traversing from leafs to the root nodes, ERs reveal diversifying/positive selection towards a less efficient cellulosomal system, consistent with glycoside-hydrolase gene variation both in-operon and genome-wide. A similar pattern is followed by the ATPase operon and the majority of orthologous SRPS operons genome-wide, suggesting conservation among operons in such selection. Thus SRPS operons via their transcript-stabilizing non-coding elements are highlighting a link between operon stoichiometry and operon evolution.

scholarly journals The Advantages of Segregation and the Evolution of Sex

Genetics ◽  
2003 ◽  
Vol 164 (3) ◽  
pp. 1099-1118 ◽  
Author(s):  
Sarah P Otto
Keyword(s):  
Sexual Reproduction ◽  
Asexual Reproduction ◽  
Deleterious Mutations ◽  
Evolution Of Sex ◽  
Beneficial Mutations ◽  
Selection Regime ◽  
Strong Selection ◽  
Genome Wide ◽  
Low Levels

AbstractIn diploids, sexual reproduction promotes both the segregation of alleles at the same locus and the recombination of alleles at different loci. This article is the first to investigate the possibility that sex might have evolved and been maintained to promote segregation, using a model that incorporates both a general selection regime and modifier alleles that alter an individual’s allocation to sexual vs. asexual reproduction. The fate of different modifier alleles was found to depend strongly on the strength of selection at fitness loci and on the presence of inbreeding among individuals undergoing sexual reproduction. When selection is weak and mating occurs randomly among sexually produced gametes, reductions in the occurrence of sex are favored, but the genome-wide strength of selection is extremely small. In contrast, when selection is weak and some inbreeding occurs among gametes, increased allocation to sexual reproduction is expected as long as deleterious mutations are partially recessive and/or beneficial mutations are partially dominant. Under strong selection, the conditions under which increased allocation to sex evolves are reversed. Because deleterious mutations are typically considered to be partially recessive and weakly selected and because most populations exhibit some degree of inbreeding, this model predicts that higher frequencies of sex would evolve and be maintained as a consequence of the effects of segregation. Even with low levels of inbreeding, selection is stronger on a modifier that promotes segregation than on a modifier that promotes recombination, suggesting that the benefits of segregation are more likely than the benefits of recombination to have driven the evolution of sexual reproduction in diploids.

The Role of Behavioral Frictions in Health Insurance Marketplace Enrollment and Risk: Evidence from a Field Experiment

2021 ◽  
Vol 111 (5) ◽  
pp. 1549-1574
Author(s):  
Richard Domurat ◽  
Isaac Menashe ◽  
Wesley Yin
Keyword(s):  
Health Insurance ◽  
Field Experiment ◽  
Positive Selection ◽  
Adverse Selection ◽  
Low Income ◽  
Market Risk ◽  
Selection Model ◽  
Heterogeneous Effects ◽  
Low Income Consumers

We experimentally varied information mailed to 87,000 households in California’s health insurance marketplace to study the role of frictions in insurance take-up. Reminders about the enrollment deadline raised enrollment by 1.3 pp (16 percent) in this typically low take-up population. Heterogeneous effects of personalized subsidy information indicate misperceptions about program benefits. Consistent with an adverse selection model with frictional enrollment costs, the intervention lowered average spending risk by 5.1 percent, implying that marginal respondents were 37 percent less costly than inframarginal consumers. We observe the largest positive selection among low income consumers, who exhibit the largest frictions in enrollment. Finally, we estimate the implied value of the letter intervention to be $25 to $53 per month in subsidy dollars. These results suggest that frictions may partially explain low take-up for marketplace insurance, and that interventions reducing them can improve enrollment and market risk in exchanges. (JEL C93, G22, G52, H75, I13)

scholarly journals Genome-wide scans for the identification of Plasmodium vivax genes under positive selection

2017 ◽  
Vol 16 (1) ◽  
Author(s):  
Hai-Mo Shen ◽  
Shen-Bo Chen ◽  
Yue Wang ◽  
Bin Xu ◽  
Eniola Michael Abe ◽  
...  
Keyword(s):  
Positive Selection ◽  
Plasmodium Vivax ◽  
Genome Wide

scholarly journals Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Peter Tsvetkov ◽  
Marc L Mendillo ◽  
Jinghui Zhao ◽  
Jan E Carette ◽  
Parker H Merrill ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cellular Protein ◽  
Fitness Cost ◽  
Survival Advantage ◽  
Protein Homeostasis ◽  
Proteotoxic Stress ◽  
Genome Wide ◽  
Regulatory Complex ◽  
Modest Reduction ◽  
Specific Inhibitors

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.

scholarly journals Dietary adaptation of FADS genes in Europe varied across time and geography

2017 ◽  
Author(s):  
Kaixiong Ye ◽  
Feng Gao ◽  
David Wang ◽  
Ofer Bar-Yosef ◽  
Alon Keinan
Keyword(s):  
Positive Selection ◽  
Association Studies ◽  
Fatty Acid Desaturase ◽  
Genome Wide Association Studies ◽  
Omega 3 ◽  
Dietary Adaptation ◽  
Genome Wide ◽  
Before And After ◽  
Omega 6 ◽  
Rate Limiting

AbstractFatty acid desaturase (FADS) genes encode rate-limiting enzymes for the biosynthesis of omega-6 and omega-3 long chain polyunsaturated fatty acids (LCPUFAs). This biosynthesis is essential for individuals subsisting on LCPUFAs-poor, plant-based diets. Positive selection on FADS genes has been reported in multiple populations, but its presence and pattern in Europeans remain elusive. Here, with analyses of ancient and modern DNA, we demonstrated that positive selection acted on the same FADS variants both before and after the advent of farming in Europe, but on opposite alleles. Selection in recent farmers also varied geographically, with the strongest signal in Southern Europe. These varying selection patterns concur with anthropological evidence of differences in diets, and with the association of recently-adaptive alleles with higher FADS1 expression and enhanced LCPUFAs biosynthesis. Genome-wide association studies revealed associations of recently-adaptive alleles with not only LCPUFAs, but also other lipids and decreased risk of several inflammation-related diseases.

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