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.

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 The evolutionary impacts of synonymous mutations

2021 ◽  
Author(s):  
Deepa Agashe
Keyword(s):  
Synonymous Codon ◽  
Analytical Framework ◽  
Synonymous Mutations ◽  
Fitness Effects ◽  
Distinct Category ◽  
Dramatic Shift ◽  
Evolutionary Consequences ◽  
New Mutations

During the 50 years since the genetic code was cracked, our understanding of the evolutionary consequences of synonymous mutations has undergone a dramatic shift. Synonymous codon changes were initially considered selectively neutral, and as such, exemplars of evolution via genetic drift. However, the pervasive and non-negligible fitness impacts of synonymous mutations are now clear across organisms. Despite the accumulated evidence, it remains challenging to incorporate the effects of synonymous changes in studies of selection, because the existing analytical framework was built with a focus on the fitness effects of nonsynonymous mutations. In this chapter, I trace the development of this topic and discuss the evidence that gradually transformed our thinking about the role of synonymous mutations in evolution. I suggest that our evolutionary framework should encompass the impacts of all mutations on various forms of information transmission. Folding synonymous mutations into a common distribution – rather than setting them apart as a distinct category – will allow a more complete and cohesive picture of the evolutionary consequences of new mutations.

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 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 Functional alterations caused by mutations reflect evolutionary trends of SARS-CoV-2

2021 ◽  
Author(s):  
Liang Cheng ◽  
Xudong Han ◽  
Zijun Zhu ◽  
Changlu Qi ◽  
Ping Wang ◽  
...  
Keyword(s):  
Reference Genome ◽  
Sequence Data ◽  
Purifying Selection ◽  
Virus Genome ◽  
Receptor Binding Domain ◽  
Evolutionary Trends ◽  
Synonymous Mutations ◽  
Almost All ◽  
Virus Strains ◽  
New Mutations

Abstract Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the COVID-19 pandemic has spread rapidly worldwide. Due to the limited virus strains, few key mutations that would be very important with the evolutionary trends of virus genome were observed in early studies. Here, we downloaded 1809 sequence data of SARS-CoV-2 strains from GISAID before April 2020 to identify mutations and functional alterations caused by these mutations. Totally, we identified 1017 nonsynonymous and 512 synonymous mutations with alignment to reference genome NC_045512, none of which were observed in the receptor-binding domain (RBD) of the spike protein. On average, each of the strains could have about 1.75 new mutations each month. The current mutations may have few impacts on antibodies. Although it shows the purifying selection in whole-genome, ORF3a, ORF8 and ORF10 were under positive selection. Only 36 mutations occurred in 1% and more virus strains were further analyzed to reveal linkage disequilibrium (LD) variants and dominant mutations. As a result, we observed five dominant mutations involving three nonsynonymous mutations C28144T, C14408T and A23403G and two synonymous mutations T8782C, and C3037T. These five mutations occurred in almost all strains in April 2020. Besides, we also observed two potential dominant nonsynonymous mutations C1059T and G25563T, which occurred in most of the strains in April 2020. Further functional analysis shows that these mutations decreased protein stability largely, which could lead to a significant reduction of virus virulence. In addition, the A23403G mutation increases the spike-ACE2 interaction and finally leads to the enhancement of its infectivity. All of these proved that the evolution of SARS-CoV-2 is toward the enhancement of infectivity and reduction of virulence.

scholarly journals Stochastic fluctuations drive non-genetic evolution of proliferation in clonal cancer cell populations

2021 ◽  
Author(s):  
Carmen Ortega-Sabater ◽  
Gabriel Fernandez-Calvo ◽  
Víctor M Pérez-García
Keyword(s):  
Evolutionary Dynamics ◽  
Growth Dynamics ◽  
Driver Mutations ◽  
Organizational Changes ◽  
Tumour Heterogeneity ◽  
Stochastic Fluctuations ◽  
Oncological Patients ◽  
Single Genotype ◽  
History Of ◽  
Broad Variety

Evolutionary dynamics allows to understand many changes happening in a broad variety of biological systems, ranging from individuals to complete ecosystems. It is also behind a number of remarkable organizational changes that happen during the natural history of cancers. These reflect tumour heterogeneity, which is present at all cellular levels, including the genome, proteome and phenome, shaping its development and interrelation with its environment. An intriguing observation in different cohorts of oncological patients is that tumours exhibit an increased proliferation as the disease progresses, while the timescales involved are apparently too short for the fixation of sufficient driver mutations to promote an explosive growth. In this paper we discuss how phenotypic plasticity, emerging from a single genotype, may play a key role and provide a ground for a continuous acceleration of the proliferation rate of clonal populations with time. Here we address this question by means of stochastic and deterministic mathematical models that capture proliferation trait heterogeneity in clonal populations and elucidate the contribution of phenotypic transitions on tumour growth dynamics.

scholarly journals The distribution of mutational effects on fitness in Caenorhabditis elegans inferred from standing genetic variation

2020 ◽  
Author(s):  
Kimberly J. Gilbert ◽  
Stefan Zdraljevic ◽  
Daniel E. Cook ◽  
Asher D. Cutter ◽  
Erik C. Andersen ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Caenorhabditis Elegans ◽  
Population Size ◽  
Genomic Structure ◽  
Random Mating ◽  
Population Substructure ◽  
C Elegans ◽  
Fitness Effects ◽  
Self Fertilization ◽  
New Mutations

ABSTRACTThe distribution of fitness effects for new mutations is one of the most theoretically important but difficult to estimate properties in population genetics. A crucial challenge to inferring the distribution of fitness effects (DFE) from natural genetic variation is the sensitivity of the site frequency spectrum to factors like population size change, population substructure, and non-random mating. Although inference methods aim to control for population size changes, the influence of non-random mating remains incompletely understood, despite being a common feature of many species. We report the distribution of fitness effects estimated from 326 genomes of Caenorhabditis elegans, a nematode roundworm with a high rate of self-fertilization. We evaluate the robustness of DFE inferences using simulated data that mimics the genomic structure and reproductive life history of C. elegans. Our observations demonstrate how the combined influence of self-fertilization, genome structure, and natural selection can conspire to compromise estimates of the DFE from extant polymorphisms. These factors together tend to bias inferences towards weakly deleterious mutations, making it challenging to have full confidence in the inferred DFE of new mutations as deduced from standing genetic variation in species like C. elegans. Improved methods for inferring the distribution of fitness effects are needed to appropriately handle strong linked selection and selfing. These results highlight the importance of understanding the combined effects of processes that can bias our interpretations of evolution in natural populations.

scholarly journals Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3623-3623
Author(s):  
Lierni Fernández-Ibarrondo ◽  
Joan Gibert ◽  
Concepción Fernández-Rodríguez ◽  
Laura Camacho ◽  
Anna Angona ◽  
...  
Keyword(s):  
Dna Repair ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Evolutionary Dynamics ◽  
Driver Mutations ◽  
Molecular Response ◽  
Increased Risk ◽  
Cytoreductive Treatment ◽  
Allelic Burden

Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p<0.001), and displayed higher leukocyte count (p<0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.

scholarly journals Somatic evolution in non-neoplastic IBD-affected colon

2019 ◽  
Author(s):  
Sigurgeir Olafsson ◽  
Rebecca E. McIntyre ◽  
Tim Coorens ◽  
Timothy Butler ◽  
Hyunchul Jung ◽  
...  
Keyword(s):  
Chronic Inflammatory Disease ◽  
Interleukin 17 ◽  
Normal Colon ◽  
Synonymous Mutations ◽  
Somatic Evolution ◽  
Colonic Crypts ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Selection Mechanisms ◽  
Mutational Processes

Summary paragraphInflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. Here, we whole-genome sequenced 447 colonic crypts from 46 IBD patients, and compared these to 412 crypts from 41 non-IBD controls. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.

scholarly journals Sequence diversity and evolution of an iflavirus family associated with ticks

2020 ◽  
Author(s):  
Romain Daveu ◽  
Caroline Hervet ◽  
Louane Sigrist ◽  
Davide Sassera ◽  
Aaron Jex ◽  
...  
Keyword(s):  
Cell Line ◽  
Complete Genome ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Rna Viruses ◽  
Ixodes Scapularis ◽  
Fine Scale ◽  
Rna Seq ◽  
Strong Positive Selection ◽  
Synonymous Mutations

AbstractWe studied a family of iflaviruses, a group of RNA viruses frequently found in arthropods, focusing on viruses associated with ticks. Our aim was to bring insight on the evolutionary dynamics of this group of viruses, which may interact with the biology of ticks. We explored systematically de novo RNA-Seq assemblies available for species of ticks which allowed to identify nine new genomes of iflaviruses. The phylogeny of virus sequences was not congruent with that of the tick hosts, suggesting recurrent host changes across tick genera along evolution. We identified five different variants with a complete or near-complete genome in Ixodes ricinus. These sequences were closely related, which allowed a fine-scale estimation of patterns of substitutions: we detected a strong excess of synonymous mutations suggesting evolution under strong positive selection. ISIV, a sequence found in the ISE6 cell line of Ixodes scapularis, was unexpectedly nearidentical with I. ricinus variants, suggesting a contamination of this cell line by I. ricinus material. Overall, our work constitutes a step in the understanding of the interactions between this family of viruses and ticks.

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