scholarly journals Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios

2019 ◽  
Author(s):  
Marc J Williams ◽  
Luiz Zapata ◽  
Benjamin Werner ◽  
Chris Barnes ◽  
Andrea Sottoriva ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
Quantitative Model ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
Synonymous Mutations ◽  
Fitness Effects ◽  
Somatic Evolution ◽  
Normal Oesophagus

AbstractThe distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells, however the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics that yields the selective coefficients from individual driver mutations from dN/dS estimates, and then measure the DFE for somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 mutants (proliferative bias 1-5%). Accurate measurement of the per-gene DFE in cancer evolution is precluded by the quality of currently available sequencing data. This study provides the theoretical link between dN/dS values and selective coefficients in somatic evolution, and reveals the DFE for mutations in human tissues.

scholarly journals Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Marc J Williams ◽  
Luis Zapata ◽  
Benjamin Werner ◽  
Chris P Barnes ◽  
Andrea Sottoriva ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
Quantitative Model ◽  
Driver Mutations ◽  
Broad Distribution ◽  
Synonymous Mutations ◽  
Fitness Effects ◽  
Somatic Evolution ◽  
Normal Oesophagus ◽  
Somatic Mutant ◽  
New Mutations

The distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells. However the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics that determines the selective coefficients of individual driver mutations from dN/dS estimates. We then measure the DFE for somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 mutants (proliferative bias 1–5%). This study provides the theoretical link between dN/dS values and selective coefficients in somatic evolution, and measures the DFE of mutations in human tissues.

Opposing Evolutionary Pressures Drive Clonal Evolution and Health Outcomes in the Aging Blood System

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Kimberly Skead ◽  
Armande Ang Houle ◽  
Sagi Abelson ◽  
Marie-Julie Fave ◽  
Boxi Lin ◽  
...  
Keyword(s):  
Gene Disruption ◽  
Large Scale ◽  
Evolutionary Dynamics ◽  
Clonal Evolution ◽  
Neutral Evolution ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
High Coverage ◽  
Passenger Mutations

The age-associated accumulation of somatic mutations and large-scale structural variants (SVs) in the early hematopoietic hierarchy have been linked to premalignant stages for cancer and cardiovascular disease (CVD). However, only a small proportion of individuals harboring these mutations progress to disease, and mechanisms driving the transformation to malignancy remains unclear. Hematopoietic evolution, and cancer evolution more broadly, has largely been studied through a lens of adaptive evolution and the contribution of functionally neutral or mildly damaging mutations to early disease-associated clonal expansions has not been well characterised despite comprising the majority of the mutational burden in healthy or tumoural tissues. Through combining deep learning with population genetics, we interrogate the hematopoietic system to capture signatures of selection acting in healthy and pre-cancerous blood populations. Here, we leverage high-coverage sequencing data from healthy and pre-cancerous individuals from the European Prospective Investigation into Cancer and Nutrition Study (n=477) and dense genotyping from the Canadian Partnership for Tomorrow's Health (n=5,000) to show that blood rejects the paradigm of strictly adaptive or neutral evolution and is subject to pervasive negative selection. We observe clear age associations across hematopoietic populations and the dominant class of selection driving evolutionary dynamics acting at an individual level. We find that both the location and ratio of passenger to driver mutations are critical in determining if positive selection acting on driver mutations is able to overwhelm regulated hematopoiesis and allow clones harbouring disease-predisposing mutations to rise to dominance. Certain genes are enriched for passenger mutations in healthy individuals fitting purifying models of evolution, suggesting that the presence of passenger mutations in a subset of genes might confer a protective role against disease-predisposing clonal expansions. Finally, we find that the density of gene disruption events with known pathogenic associations in somatic SVs impacts the frequency at which the SV segregates in the population with variants displaying higher gene disruption density segregating at lower frequencies. Understanding how blood evolves towards malignancy will allow us to capture cancer in its earliest stages and identify events initiating departures from healthy blood evolution. Further, as the majority of mutations are passengers, studying their contribution to tumorigenesis, will unveil novel therapeutic targets thus enabling us to better understand patterns of clonal evolution in order to diagnose and treat disease in its infancy. Disclosures Dick: Bristol-Myers Squibb/Celgene: Research Funding.

scholarly journals Creating Standards for Evaluating Tumour Subclonal Reconstruction

2018 ◽  
Author(s):  
Adriana Salcedo ◽  
Maxime Tarabichi ◽  
Shadrielle Melijah G. Espiritu ◽  
Amit G. Deshwar ◽  
Matei David ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
Read Depth ◽  
Response To Therapy ◽  
Systematic Evaluation ◽  
Computational Techniques ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
Somatic Variant ◽  
Quantitative Metrics ◽  
Algorithmic Problems

AbstractTumours evolve through time and space. Computational techniques have been developed to infer their evolutionary dynamics from DNA sequencing data. A growing number of studies have used these approaches to link molecular cancer evolution to clinical progression and response to therapy. There has not yet been a systematic evaluation of methods for reconstructing tumour subclonality, in part due to the underlying mathematical and biological complexity and to difficulties in creating gold-standards. To fill this gap, we systematically elucidated the key algorithmic problems in subclonal reconstruction and developed mathematically valid quantitative metrics for evaluating them. We then created approaches to simulate realistic tumour genomes, harbouring all known mutation types and processes both clonally and subclonally. We then simulated 580 tumour genomes for reconstruction, varying tumour read-depth and benchmarking somatic variant detection and subclonal reconstruction strategies. The inference of tumour phylogenies is rapidly becoming standard practice in cancer genome analysis; this study creates a baseline for its evaluation.

scholarly journals The fitness landscape of the codon space across environments

2018 ◽  
Author(s):  
Inès Fragata ◽  
Sebastian Matuszewski ◽  
Mark A. Schmitz ◽  
Thomas Bataillon ◽  
Jeffrey D. Jensen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Fitness Landscapes ◽  
Synonymous Mutations ◽  
Landscape Studies ◽  
Fitness Effects ◽  
Bayesian Monte Carlo ◽  
The Relationship

AbstractFitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and reestimate selection coefficients of all possible codon mutations across 9 amino-acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino-acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies.

scholarly journals Interpreting dN/dS under different selective regimes in cancer evolution

2021 ◽  
Author(s):  
Andrés Pérez-Figueroa ◽  
David Posada
Keyword(s):  
Negative Selection ◽  
Mutation Detection ◽  
Cancer Genomics ◽  
Detection Threshold ◽  
Cancer Genes ◽  
Selection Coefficient ◽  
Cancer Evolution ◽  
Synonymous Mutations ◽  
Somatic Evolution ◽  
The Relationship

The standard relationship between the dN/dS statistic and the selection coefficient is contingent upon the computation of the rate of fixation of non-synonymous and synonymous mutations among divergent lineages (substitutions). In cancer genomics, however, dN/dS is typically calculated by including mutations that are still segregating in the cell population. The interpretation of dN/dS within sexual populations has been shown to be problematic. Here we used a simple model of somatic evolution to study the relationship between dN/dS and the selection coefficient in the presence of deleterious, neutral, and beneficial mutations in cancer. We found that dN/dS can be used to distinguish cancer genes under positive or negative selection, but it is not always informative about the magnitude of the selection coefficient. In particular, under the asexual scenario simulated, dN/dS is insensitive to negative selection strength. Furthermore, the relationship between dN/dS and the positive selection coefficient depends on the mutation detection threshold, and, in particular scenarios, it can become non-linear. Our results warn about the necessary caution when interpreting the results drawn from dN/dS estimates in cancer.

scholarly journals Evolutionary dynamics of neoantigens in growing tumours

2019 ◽  
Author(s):  
Eszter Lakatos ◽  
Marc J. Williams ◽  
Ryan O. Schenck ◽  
William C. H. Cross ◽  
Jacob Househam ◽  
...  
Keyword(s):  
Negative Selection ◽  
Evolutionary Dynamics ◽  
Immune Escape ◽  
Patient Specific ◽  
Mathematical Framework ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
Clone Size ◽  
Strong Negative Selection ◽  
Immune Escape Mechanisms

ABSTRACTCancer evolution is driven by the acquisition of somatic mutations that provide cells with a beneficial phenotype in a changing microenvironment. However, mutations that give rise to neoantigens, novel cancer–specific peptides that elicit an immune response, are likely to be disadvantageous. Here we show how the clonal structure and immunogenotype of growing tumours is shaped by negative selection in response to neoantigenic mutations. We construct a mathematical model of neoantigen evolution in a growing tumour, and verify the model using genomic sequencing data. The model predicts that, in the absence of active immune escape mechanisms, tumours either evolve clonal neoantigens (antigen– ‘hot’), or have no clonally– expanded neoantigens at all (antigen– ‘cold’), whereas antigen– ‘warm’ tumours (with high frequency subclonal neoantigens) form only following the evolution of immune evasion. Counterintuitively, strong negative selection for neoantigens during tumour formation leads to an increased number of antigen– warm or – hot tumours, as a consequence of selective pressure for immune escape. Further, we show that the clone size distribution under negative selection is effectively– neutral, and moreover, that stronger negative selection paradoxically leads to more neutral– like dynamics. Analysis of antigen clone sizes and immune escape in colorectal cancer exome sequencing data confirms these results. Overall, we provide and verify a mathematical framework to understand the evolutionary dynamics and clonality of neoantigens in human cancers that may inform patient– specific immunotherapy decision– making.

scholarly journals Evolution of the Wx genotype combination in hybrid rice

2019 ◽  
Author(s):  
bingran Zhao ◽  
Ye Shao ◽  
Yan Peng ◽  
Bigang Mao ◽  
Qiming Lv ◽  
...  
Keyword(s):  
Hybrid Rice ◽  
Allelic Variation ◽  
Amylose Content ◽  
Major Gene ◽  
Eating Quality ◽  
Sequencing Data ◽  
Genotype Combination ◽  
Synonymous Mutations ◽  
Allelic Variations

Abstract Background: With increased interest in the quality characteristics of hybrid rice, its quality traits have received a certain extent of improvement. However, comparisons to high-quality conventional rice, especially its eating quality, have revealed that more work is still required. Amylose content is a key determinant of the eating quality of rice, and Wx , the major gene controlling amylose content, has many allelic variants. A complete understanding of the Wx allelic variations in cultivated rice and the evolution process of the Wx genotype in hybrid rice are the premises for the rational utilization of rich genetic resources in the quality breeding of hybrid rice. Based on the 3K RGP re-sequencing data, we sought to analyse the allelic variation at the Wx locus and develop a set of Kompetitive Allele-Specific PCR markers. Furthermore, we used the markers to analyse the evolution of a combination of the Wx genotype in hybrid rice.Results: Eight known alleles existing globally were identified, and their evident regional preferences and Indica - japonica background differences were revealed. An additional five non-synonymous mutations were identified in the coding region of the Wx gene for the first time, including a new functional site located in the active centre of OsGBSS1. By genotyping the basic hybrid parents obtained from 1976 to 2018, we found that only three Wx allelic variations existed. Wx lv was widely used in the female parents of the three-line hybrid rice, and Wx a was used in the female parents of early two-line hybrid rice; however, they were gradually replaced by Wx b .Conclusions: In this study, the Wx lv allele was found to be the cause of the poor eating quality of early hybrid rice. With the elimination of the Wx lv allele and introduction of Wx b in both parents, the eating quality of hybrid rice was generally improved. Only three allelic variations were present in the previous hybrid rice. For further eating quality improvement of hybrid rice, more Wx alleles should be introduced.

scholarly journals Normal tissue architecture determines the evolutionary course of cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jeffrey West ◽  
Ryan O. Schenck ◽  
Chandler Gatenbee ◽  
Mark Robertson-Tessi ◽  
Alexander R. A. Anderson
Keyword(s):  
Evolutionary Dynamics ◽  
Neutral Evolution ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Tissue Architecture ◽  
Spatial Constraints ◽  
Fitness Effects ◽  
Two Factors ◽  
Mixing Rates ◽  
Precancerous Stage

AbstractCancer growth can be described as a caricature of the renewal process of the tissue of origin, where the tissue architecture has a strong influence on the evolutionary dynamics within the tumor. Using a classic, well-studied model of tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how tissue structure influences functional (driver) mutations and genetic heterogeneity over time. This approach explores a key mechanism behind both inter-patient and intratumoral tumor heterogeneity: competition for space. Time-varying competition leads to an emergent transition from Darwinian premalignant growth to subsequent invasive neutral tumor growth. Initial spatial constraints determine the emergent mode of evolution (Darwinian to neutral) without a change in cell-specific mutation rate or fitness effects. Driver acquisition during the Darwinian precancerous stage may be modulated en route to neutral evolution by the combination of two factors: spatial constraints and limited cellular mixing. These two factors occur naturally in ductal carcinomas, where the branching topology of the ductal network dictates spatial constraints and mixing rates.

scholarly journals A generalized theory of somatic evolution

2018 ◽  
Author(s):  
Andrii Rozhok ◽  
James DeGregori
Keyword(s):  
Stem Cell ◽  
Current Knowledge ◽  
Age Distribution ◽  
Experimental Studies ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Theoretical Idea ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Multi Stage

AbstractThe modern Multi-Stage Model of Carcinogenesis (MMC) was developed in the 1950s through the ‘70s and postulated carcinogenesis as a process of rounds of Darwinian selection favoring progressively more malignant cell phenotypes. Through this period, almost nothing was known about driver mutations in cancers. Also, stem cells and cellular tissue organization were poorly characterized. The general multi-stage process was later confirmed by experimental studies, and cancer risk and incidence has been explained as primarily a function of mutation occurrence. However, the MMC has never been formally tested for its ability to account for current knowledge about cancer evolution. In particular, different numbers of cancer drivers required for different cancers and vast discrepancies in the organization of stem cell compartments for different tissues appear inconsistent with the very similar age distribution of the vast majority of cancers. In this regard, the initial theoretical idea underlying MMC is often over-interpreted with little connection to modern evidence, and a general theory of somatic evolution still does not exist. In this study, we applied Monte Carlo modeling and demonstrated the effect of various parameters, such as mutation rate, mutation effects and cell division, on the MMC performance. Our modeling demonstrates that the MMC requires considerable modification in order to describe cancer incidence. We elucidate the required conditions for how somatic cell selection should operate within the MMC in order to explain modern data on stem cell clonality and cancer, and propose a generalized theory of somatic evolution based on these results.

Service Quality Of Industrial Parks In The View Of Foreign Direct Investment Firms

2019 ◽  
Vol 118 (11) ◽  
pp. 552-562
Author(s):  
Nguyen Thi Ngan ◽  
Bui Huy Khoi
Keyword(s):  
Foreign Direct Investment ◽  
Service Quality ◽  
Direct Investment ◽  
Reliability And Validity ◽  
Quantitative Model ◽  
Industrial Park ◽  
Industrial Parks ◽  
Average Variance ◽  
Composite Reliability

This research aims to assess the service quality of industrial parks (IP) in the view of FDI (foreign direct investment) firms in Vietnam. Data was collected from 270 FDI firms in Vietnam - Singapore Industrial Parks (VSIP) in Vietnam. The proposed research model was based on researches on service quality. Cronbach's Alpha Average Variance Extracted (Pvc),rho (ρA), and Composite Reliability (Pc) tested the reliability and validity of the scale. The analysis results showed that four factors were affecting the servicequality of industrial park in Vietnam being tangibleof VSIP, reliability of VSIP, the empathyof FDI investors, and their assurance. The responsivenessof VSIP did not affect the servicequality of the industrial park. Contents of the article focus on two main issues: the analysis framework of the quantitative model and implicating results todevelop the industrial park services. The limitation of the research was only in VSIP in Vietnam.

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