scholarly journals The Dynamics of Adaptive Genetic Diversity During the Early Stages of Clonal Evolution

2017 ◽  
Author(s):  
Jamie R. Blundell ◽  
Katja Schwartz ◽  
Danielle Francois ◽  
Daniel S. Fisher ◽  
Gavin Sherlock ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Mathematical Modelling ◽  
Experimental Evolution ◽  
General Feature ◽  
Clonal Evolution ◽  
Cell Populations ◽  
Fitness Effects ◽  
Microbial Infections ◽  
Adaptive Genetic Diversity ◽  
Lineage Tracking

The dynamics of genetic diversity in large clonally-evolving cell populations are poorly understood, despite having implications for the treatment of cancer and microbial infections. Here, we combine barcode lineage tracking, sequencing of adaptive clones, and mathematical modelling of mutational dynamics to understand diversity changes during experimental evolution. We find that, despite differences in beneficial mutational mechanisms and fitness effects between two environments, early adaptive genetic diversity increases predictably, driven by the expansion of many single-mutant lineages. However, a crash in diversity follows, caused by highly-fit double-mutants fed from exponentially growing single-mutants, a process closely related to the classic Luria-Delbruck experiment. The diversity crash is likely to be a general feature of clonal evolution, however its timing and magnitude is stochastic and depends on the population size, the distribution of beneficial fitness effects, and patterns of epistasis.

scholarly journals Predicting mutational routes to new adaptive phenotypes

2018 ◽  
Author(s):  
Peter A. Lind ◽  
Eric Libby ◽  
Jenny Herzog ◽  
Paul B. Rainey
Keyword(s):  
Mathematical Modelling ◽  
Adaptive Evolution ◽  
Experimental Evolution ◽  
Additional Data ◽  
Mutation Rates ◽  
Mechanistic Models ◽  
Short Term ◽  
Regulatory Pathways ◽  
Fitness Effects ◽  
Mutational Hotspots

AbstractPredicting evolutionary change poses numerous challenges. Here we take advantage of the model bacterium Pseudomonas fluorescens in which the genotype-to-phenotype map determining evolution of the adaptive “wrinkly spreader” (WS) type is known. We present mathematical descriptions of three necessary regulatory pathways and use these to predict both the rate at which each mutational route is used and the expected mutational targets. To test predictions, mutation rates and targets were determined for each pathway. Unanticipated mutational hotspots caused experimental observations to depart from predictions but additional data led to refined models. A mismatch was observed between the spectra of WS-causing mutations obtained with and without selection due to low fitness of previously undetected WS-causing mutations. Our findings contribute toward the development of mechanistic models for forecasting evolution, highlight current limitations, and draw attention to challenges in predicting locus-specific mutational biases and fitness effects.Impact statementA combination of genetics, experimental evolution and mathematical modelling defines information necessary to predict the outcome of short-term adaptive evolution.

scholarly journals The dynamics of adaptive genetic diversity during the early stages of clonal evolution

2018 ◽  
Vol 3 (2) ◽  
pp. 293-301 ◽  
Author(s):  
Jamie R. Blundell ◽  
Katja Schwartz ◽  
Danielle Francois ◽  
Daniel S. Fisher ◽  
Gavin Sherlock ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Clonal Evolution ◽  
Early Stages ◽  
Adaptive Genetic Diversity

scholarly journals Partial selfing eliminates inbreeding depression while maintaining genetic diversity

2017 ◽  
Author(s):  
Ivo M. Chelo ◽  
Bruno Afonso ◽  
Sara Carvalho ◽  
Ioannis Theologidis ◽  
Christine Goy ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Inbreeding Depression ◽  
Experimental Evolution ◽  
Natural Populations ◽  
Ancestral Population ◽  
Origin And Evolution ◽  
C Elegans ◽  
Genome Wide ◽  
Adaptive Genetic Diversity

AbstractClassical theory on the origin and evolution of selfing and outcrossing relies on the role of inbreeding depression created by unlinked partially-deleterious recessive alleles to predict that individuals from natural populations predominantly self or outcross. Comparative data indicates, however, that maintenance of partial selfing and outcrossing at intermediate frequencies is common in nature. In part to explain the presence of mixed reproductive modes within populations, several hypotheses regarding the evolution of inbreeding depression have been put forward based on the complex interaction of linkage and identity disequilibrium among fitness loci, together with Hill-Robertson effects. We here ask what is the genetic basis of inbreeding depression so that populations with intermediate selfing rates can eliminate it while maintain potentially adaptive genetic diversity. For this, we use experimental evolution in the nematode C. elegans under partial selfing and compare it to the experimental evolution of populations evolved under exclusive selfing and predominant outcrossing. We find that the ancestral risk of extinction upon enforced inbreeding by selfing is maintained when populations evolve under predominant outcrossing, but reduced when populations evolve under partial or exclusive selfing. Analysis of genome-wide single-nucleotide polymorphism (SNP) during experimental evolution and after enforced inbreeding suggests that, under partial selfing, populations were purged of unlinked deleterious recessive alleles that segregate in the ancestral population, which in turn allowed the expression of unlinked overdominant fitness loci. Taken together, these observations indicate that populations evolving under partial selfing gain the short-term benefits of selfing, in purging deleterious recessive alleles, but also the long-term benefits of outcrossing, in maintaining genetic diversity that may important for future adaptation.

scholarly journals Overexpression of Extradomain-B Fibronectin is Associated with Invasion of Breast Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1826
Author(s):  
Amita Vaidya ◽  
Helen Wang ◽  
Victoria Qian ◽  
Hannah Gilmore ◽  
Zheng-Rong Lu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Clonal Evolution ◽  
Clinical Samples ◽  
Cell Populations ◽  
Akt Inhibitor ◽  
Poor Overall Survival ◽  
Critical Function ◽  
Invasive Cell

Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the expression profile of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN) in invasive breast cancer. Analyses of TCGA/GTEx databases and immunostaining of clinical samples found a significant overexpression of EDB-FN in breast tumors, which correlated with poor overall survival. Significant upregulation of EDB-FN was observed in invasive cell populations generated from relatively less invasive MCF7 and MDA-MB-468 cells by long-term TGF-β treatment and acquired chemoresistance. Treatment of the invasive cell populations with an AKT inhibitor (MK2206-HCl) reduced their invasive potential, with a concomitant decrease in their EDB-FN expression, partly through the phosphoAKT-SRp55 pathway. EDB-FN downregulation, with direct RNAi of EDB-FN or indirectly through RNAi of SRp55, also resulted in reduced motility of the invasive cell populations, validating the correlation between EDB-FN expression and invasion of breast cancer cells. These data establish EDB-FN as a promising molecular marker for non-invasive therapeutic surveillance of aggressive breast cancer.

Capturing neutral and adaptive genetic diversity for conservation in a highly structured tree species

2016 ◽  
Vol 26 (7) ◽  
pp. 2254-2266 ◽  
Author(s):  
Isabel Rodríguez-Quilón ◽  
Luis Santos-del-Blanco ◽  
María Jesús Serra-Varela ◽  
Jarkko Koskela ◽  
Santiago C. González-Martínez ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Tree Species ◽  
Adaptive Genetic Diversity

Patterns of neutral and adaptive genetic diversity across the natural range of sugar pine (Pinus lambertiana Dougl.)

2016 ◽  
Vol 12 (3) ◽  
Author(s):  
Carl Vangestel ◽  
Alejandra Vázquez-Lobo ◽  
Pedro J. Martínez-García ◽  
Irina Calic ◽  
Jill L. Wegrzyn ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Pinus Lambertiana ◽  
Sugar Pine ◽  
Natural Range ◽  
Adaptive Genetic Diversity

scholarly journals Evolutionary dynamics of Tomato spotted wilt virus within and between alternate plant hosts and thrips

2020 ◽  
Author(s):  
Casey L. Ruark-Seward ◽  
Brian Bonville ◽  
George Kennedy ◽  
David A. Rasmussen
Keyword(s):  
Genetic Diversity ◽  
Tomato Spotted Wilt Virus ◽  
Frankliniella Occidentalis ◽  
Evolutionary Dynamics ◽  
Western Flower Thrips ◽  
Datura Stramonium ◽  
Multiple Time ◽  
Fitness Effects ◽  
Tomato Spotted Wilt ◽  
Wilt Virus

AbstractTomato spotted wilt virus (TSWV) is a generalist pathogen with one of the broadest known host ranges among RNA viruses. To understand how TSWV adapts to different hosts, we experimentally passaged viral populations between two alternate hosts, Emilia sochifolia and Datura stramonium, and an obligate vector in which it also replicates, western flower thrips (Frankliniella occidentalis). Deep sequencing viral populations at multiple time points allowed us to track the evolutionary dynamics of viral populations within and between hosts. High levels of viral genetic diversity were maintained in both plants and thrips between transmission events. Rapid fluctuations in the frequency of amino acid variants indicated strong host-specific selection pressures on proteins involved in viral movement (NSm) and replication (RdRp). While several genetic variants showed opposing fitness effects in different hosts, fitness effects were generally positively correlated between hosts indicating that positive rather than antagonistic pleiotropy is pervasive. These results suggest that high levels of genetic diversity together with the positive pleiotropic effects of mutations have allowed TSWV to rapidly adapt to new hosts and expand its host range.

scholarly journals Vast population genetic diversity underlies the treatment dynamics ofETV6-RUNX1acute lymphoblastic leukemia

2017 ◽  
Author(s):  
Veronica Gonzalez-Pena ◽  
Matthew MacKay ◽  
Iwijn De Vlaminck ◽  
John Easton ◽  
Charles Gawad
Keyword(s):  
Genetic Diversity ◽  
Single Cell ◽  
Population Genetic ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Genetic Alterations ◽  
Dependent Manner ◽  
Acute Leukemias ◽  
Population Genetic Diversity

AbstractEnsemble-averaged genome profiling of diagnostic samples suggests that acute leukemias harbor few somatic genetic alterations. We used single-cell exome and error-corrected sequencing to survey the genetic diversity underlyingETV6-RUNX1acute lymphoblastic leukemia (ALL) at high resolution. The survey uncovered a vast range of low-frequency genetic variants that were undetected in conventional bulk assays, including additional clone-specific “driver” RAS mutations. Single-cell exome sequencing revealed APOBEC mutagenesis to be important in disease initiation but not in progression and identified many more mutations per cell than previously found. Using this data, we created a branching model ofETV6-RUNX1ALL development that recapitulates the genetic features of patients. Exposure of leukemic populations to chemotherapy selected for specific clones in a dose-dependent manner. Together, these data have important implications for understanding the development and treatment response of childhood leukemia, and they provide a framework for using population genetics to deeply interrogate cancer clonal evolution.One-Sentence SummaryAPOBEC and replication-associated mutagenesis contribute to the development of ETV6-RUNX1 ALL, creating massive leukemic population genetic diversity that results in clonal differences in susceptibilities to chemotherapy.

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