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1
Wikberg, Sofie. "Fitness in Clonal Plants." Oikos 72, no. 2 (March 1995): 293. http://dx.doi.org/10.2307/3546232.
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Watson, Caroline J., A. L. Papula, Gladys Y. P. Poon, Wing H. Wong, Andrew L. Young, Todd E. Druley, Daniel S. Fisher, and Jamie R. Blundell. "The evolutionary dynamics and fitness landscape of clonal hematopoiesis." Science 367, no. 6485 (March 26, 2020): 1449–54. http://dx.doi.org/10.1126/science.aay9333.
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Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.
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Burns, Thomas P. "Fitness in Clonal Organisms: A Special Case of Extensive Fitness." Oikos 65, no. 3 (December 1992): 535. http://dx.doi.org/10.2307/3545572.
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Pan, Jean J., and Jason S. Price. "Fitness and evolution in clonal plants: the impact of clonal growth." Evolutionary Ecology 15, no. 4-6 (July 2001): 583–600. http://dx.doi.org/10.1023/a:1016065705539.
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Barrett, Spencer C. H. "Influences of clonality on plant sexual reproduction." Proceedings of the National Academy of Sciences 112, no. 29 (July 20, 2015): 8859–66. http://dx.doi.org/10.1073/pnas.1501712112.
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Flowering plants possess an unrivaled diversity of mechanisms for achieving sexual and asexual reproduction, often simultaneously. The commonest type of asexual reproduction is clonal growth (vegetative propagation) in which parental genotypes (genets) produce vegetative modules (ramets) that are capable of independent growth, reproduction, and often dispersal. Clonal growth leads to an expansion in the size of genets and increased fitness because large floral displays increase fertility and opportunities for outcrossing. Moreover, the clonal dispersal of vegetative propagules can assist “mate finding,” particularly in aquatic plants. However, there are ecological circumstances in which functional antagonism between sexual and asexual reproductive modes can negatively affect the fitness of clonal plants. Populations of heterostylous and dioecious species have a small number of mating groups (two or three), which should occur at equal frequency in equilibrium populations. Extensive clonal growth and vegetative dispersal can disrupt the functioning of these sexual polymorphisms, resulting in biased morph ratios and populations with a single mating group, with consequences for fertility and mating. In populations in which clonal propagation predominates, mutations reducing fertility may lead to sexual dysfunction and even the loss of sex. Recent evidence suggests that somatic mutations can play a significant role in influencing fitness in clonal plants and may also help explain the occurrence of genetic diversity in sterile clonal populations. Highly polymorphic genetic markers offer outstanding opportunities for gaining novel insights into functional interactions between sexual and clonal reproduction in flowering plants.
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Avagyan, S., J. E. Henninger, W. P. Mannherz, M. Mistry, J. Yoon, S. Yang, M. C. Weber, J. L. Moore, and L. I. Zon. "Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis." Science 374, no. 6568 (November 5, 2021): 768–72. http://dx.doi.org/10.1126/science.aba9304.
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Colorful clones in the blood Stem cells in regenerating tissues such as the blood can acquire mutations that enable a growth advantage, increasing the chance of developing cancer. It is unclear how such diverse mutations promote clonal fitness. Avagyan et al . generated a platform in zebrafish to label clones with unique hues while inducing mutations in genes implicated in human blood disorders. Mutations in some genes caused clones to expand over time, resulting in clonal dominance. Progenitors in the dominant clone expressed anti-inflammatory factors to resist the inflammatory environment produced by their own mature progeny, leading to a self-perpetuating cycle promoting clonal fitness. Targeting these resistance pathways may be used to abate clonal hematopoiesis and prevent its associated pathology. —BAP
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Skums, Pavel, Viachaslau Tsyvina, and Alex Zelikovsky. "Inference of clonal selection in cancer populations using single-cell sequencing data." Bioinformatics 35, no. 14 (July 2019): i398—i407. http://dx.doi.org/10.1093/bioinformatics/btz392.
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Abstract Summary Intra-tumor heterogeneity is one of the major factors influencing cancer progression and treatment outcome. However, evolutionary dynamics of cancer clone populations remain poorly understood. Quantification of clonal selection and inference of fitness landscapes of tumors is a key step to understanding evolutionary mechanisms driving cancer. These problems could be addressed using single-cell sequencing (scSeq), which provides an unprecedented insight into intra-tumor heterogeneity allowing to study and quantify selective advantages of individual clones. Here, we present Single Cell Inference of FItness Landscape (SCIFIL), a computational tool for inference of fitness landscapes of heterogeneous cancer clone populations from scSeq data. SCIFIL allows to estimate maximum likelihood fitnesses of clone variants, measure their selective advantages and order of appearance by fitting an evolutionary model into the tumor phylogeny. We demonstrate the accuracy our approach, and show how it could be applied to experimental tumor data to study clonal selection and infer evolutionary history. SCIFIL can be used to provide new insight into the evolutionary dynamics of cancer. Availability and implementation Its source code is available at https://github.com/compbel/SCIFIL.
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Derbal, Youcef. "Cell Adaptive Fitness and Cancer Evolutionary Dynamics." Cancer Informatics 22 (January 2023): 117693512311546. http://dx.doi.org/10.1177/11769351231154679.
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Genome instability of cancer cells translates into increased entropy and lower information processing capacity, leading to metabolic reprograming toward higher energy states, presumed to be aligned with a cancer growth imperative. Dubbed as the cell adaptive fitness, the proposition postulates that the coupling between cell signaling and metabolism constrains cancer evolutionary dynamics along trajectories privileged by the maintenance of metabolic sufficiency for survival. In particular, the conjecture postulates that clonal expansion becomes restricted when genetic alterations induce a sufficiently high level of disorder, that is, high entropy, in the regulatory signaling network, abrogating as a result the ability of cancer cells to successfully replicate, leading to a stage of clonal stagnation. The proposition is analyzed in the context of an in-silico model of tumor evolutionary dynamics to illustrate how cell-inherent adaptive fitness may predictably constrain clonal evolution of tumors, which would have significant implications for the design of adaptive cancer therapies.
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Fuzi, Miklos, and Evgeni Sokurenko. "Commensal Fitness Advantage May Contribute to the Global Dissemination of Multidrug-Resistant Lineages of Bacteria—The Case of Uropathogenic E. coli." Pathogens 12, no. 9 (September 10, 2023): 1150. http://dx.doi.org/10.3390/pathogens12091150.
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It is widely accepted that favorable fitness in commensal colonization is one of the prime facilitators of clonal dissemination in bacteria. The question arises as to what kind of fitness advantage may be wielded by uropathogenic strains of the two predominant fluoroquinolone- and multidrug-resistant clonal groups of E. coli—ST131-H30 and ST1193, which has permitted their unprecedented pandemic-like global expansion in the last few decades. The colonization-associated genes’ content, carriage of low-cost plasmids, and integrons with weak promoters could certainly contribute to the fitness of the pandemic groups, although those genetic factors are common among other clonal groups as well. Also, ST131-H30 and ST1193 strains harbor fluoroquinolone-resistance conferring mutations targeting serine residues in DNA gyrase (GyrA-S83) and topoisomerase IV (ParC-S80) that, in those clonal backgrounds, might result in a commensal fitness benefit, i.e., beyond the antibiotic resistance per se. This fitness gain might have contributed not only to the widespread dissemination of these major clones in the healthcare setting but also to their long-term colonization of healthy individuals and, thus, circulation in the community, even in a low or no fluoroquinolone use environment. This evolutionary shift affecting commensal E. coli, initiated by mutations co-favorable in both antibiotics-treated patients and healthy individuals warrants more in-depth studies to monitor further changes in the epidemiological situation and develop effective measures to reduce the antibiotic resistance spread.
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Gordo, Isabel, and Paulo R. A. Campos. "Evolution of clonal populations approaching a fitness peak." Biology Letters 9, no. 1 (February 23, 2013): 20120239. http://dx.doi.org/10.1098/rsbl.2012.0239.
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Populations facing novel environments are expected to evolve through the accumulation of adaptive substitutions. The dynamics of adaptation depend on the fitness landscape and possibly on the genetic background on which new mutations arise. Here, we model the dynamics of adaptive evolution at the phenotypic and genotypic levels, focusing on a Fisherian landscape characterized by a single peak. We find that Fisher's geometrical model of adaptation, extended to allow for small random environmental variations, is able to explain several features made recently in experimentally evolved populations. Consistent with data on populations evolving under controlled conditions, the model predicts that mean population fitness increases rapidly when populations face novel environments and then achieves a dynamic plateau, the rate of molecular evolution is remarkably constant over long periods of evolution, mutators are expected to invade and patterns of epistasis vary along the adaptive walk. Negative epistasis is expected in the initial steps of adaptation but not at later steps, a prediction that remains to be tested. Furthermore, populations are expected to exhibit high levels of phenotypic diversity at all times during their evolution. This implies that populations are possibly able to adapt rapidly to novel abiotic environments.
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Dorken, Marcel E., and Wendy E. Van Drunen. "Sex allocation in clonal plants: might clonal expansion enhance fitness gains through male function?" Evolutionary Ecology 24, no. 6 (May 25, 2010): 1463–74. http://dx.doi.org/10.1007/s10682-010-9393-2.
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Demetrio, Guilherme Ramos, Dalton Serafim, and Flávia de Freitas Coelho. "Is Clonal Integration a Buffer for the Stress of Resource Acquisition Depletion in Eichhornia crassipes (Pontederiaceae) Ramets?" Stresses 4, no. 4 (November 2, 2024): 734–43. http://dx.doi.org/10.3390/stresses4040047.
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Natural selection favors the allocation of finite resources to different functions maximizing fitness. In this sense, some functions may decrease whereas others increase when resources are limited in a process called a trade-off. However, a great variety of situations may obscure trade-off detection in clonal plants, such as the ability to generate offspring by clonal growth that represents opportunities for resource uptake. The aim of this work was to evaluate if clonal integration and resource availability mediate biomass allocation patterns in E. crassipes through a greenhouse experiment. We set ramets in clonal and isolated conditions, and with and without leaf blades, and compared the relationship of biomass proportion allocated to each vegetative organ. We found that biomass allocation to vegetative structures in E. crassipes is primarily shaped by resource pools and is enhanced by clonal integration as attached ramets invest more in growth and vegetative structures. In this sense, regarding trade-off patterns in biomass allocation among vegetative organs and under resource depletion, clonal integration may represent a way to stabilize biomass allocation patterns and may decrease trade-off importance. We discuss trade-offs and clonal integration as evolutionary strategies that allow plant persistence and improve plants fitness. These findings may support aquatic plant management and control efforts while highlighting the evolutionary significance of clonal integration for plant life strategies.
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Traulsen, Arne, Tom Lenaerts, Jorge M. Pacheco, and David Dingli. "On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population." Journal of The Royal Society Interface 10, no. 79 (February 6, 2013): 20120810. http://dx.doi.org/10.1098/rsif.2012.0810.
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The theory of the clonal origin of cancer states that a tumour arises from one cell that acquires mutation(s) leading to the malignant phenotype. It is the current belief that many of these mutations give a fitness advantage to the mutant population allowing it to expand, eventually leading to disease. However, mutations that lead to such a clonal expansion need not give a fitness advantage and may in fact be neutral—or almost neutral—with respect to fitness. Such mutant clones can be eliminated or expand stochastically, leading to a malignant phenotype (disease). Mutations in haematopoietic stem cells give rise to diseases such as chronic myeloid leukaemia (CML) and paroxysmal nocturnal haemoglobinuria (PNH). Although neutral drift often leads to clonal extinction, disease is still possible, and in this case, it has important implications both for the incidence of disease and for therapy, as it may be more difficult to eliminate neutral mutations with therapy. We illustrate the consequences of such dynamics, using CML and PNH as examples. These considerations have implications for many other tumours as well.
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Van Drunen, Wendy E., Mark van Kleunen, and Marcel E. Dorken. "Consequences of clonality for sexual fitness: Clonal expansion enhances fitness under spatially restricted dispersal." Proceedings of the National Academy of Sciences 112, no. 29 (July 20, 2015): 8929–36. http://dx.doi.org/10.1073/pnas.1501720112.
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Clonality is a pervasive feature of sessile organisms, but this form of asexual reproduction is thought to interfere with sexual fitness via the movement of gametes among the modules that comprise the clone. This within-clone movement of gametes is expected to reduce sexual fitness via mate limitation of male reproductive success and, in some cases, via the production of highly inbred (i.e., self-fertilized) offspring. However, clonality also results in the spatial expansion of the genetic individual (i.e., genet), and this should decrease distances gametes and sexually produced offspring must travel to avoid competing with other gametes and offspring from the same clone. The extent to which any negative effects of clonality on mating success might be offset by the positive effects of spatial expansion is poorly understood. Here, we develop spatially explicit models in which fitness was determined by the success of genets through their male and female sex functions. Our results indicate that clonality serves to increase sexual fitness when it is associated with the outward expansion of the genet. Our models further reveal that the main fitness benefit of clonal expansion might occur through the dispersal of offspring over a wider area compared with nonclonal phenotypes. We conclude that, instead of interfering with sexual reproduction, clonal expansion should often serve to enhance sexual fitness.
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Bingham, Brian L., James L. Dimond, and Gisèle Muller-Parker. "Symbiotic state influences life-history strategy of a clonal cnidarian." Proceedings of the Royal Society B: Biological Sciences 281, no. 1789 (August 22, 2014): 20140548. http://dx.doi.org/10.1098/rspb.2014.0548.
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Along the North American Pacific coast, the common intertidal sea anemone Anthopleura elegantissima engages in facultative, flexible symbioses with Symbiodinium muscatinei (a dinoflagellate) and Elliptochloris marina (a chlorophyte). Determining how symbiotic state affects host fitness is essential to understanding the ecological significance of engaging in such flexible relationships with diverse symbionts. Fitness consequences of hosting S. muscatinei , E. marina or negligible numbers of either symbiont (aposymbiosis) were investigated by measuring growth, cloning by fission and gonad development after 8.5–11 months of sustained exposure to high, moderate or low irradiance under seasonal environmental conditions. Both symbiotic state and irradiance affected host fitness, leading to divergent life-history strategies. Moderate and high irradiances led to a greater level of gonad development in individuals hosting E. marina , while high irradiance and high summer temperature promoted cloning in individuals hosting S. muscatinei and reduced fitness of aposymbiotic anemones. Associating with S. muscatinei may contribute to the success of A. elegantissima as a spatial competitor on the high shore: (i) by offsetting the costs of living under high temperature and irradiance conditions, and (ii) by promoting a high fission rate and clonal expansion. Our results suggest that basic life-history characteristics of a clonal cnidarian can be affected by the identity of the endosymbionts it hosts.
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MURRAY, J. L. S., and PETER A. JUMARS. "Clonal Fitness of Attached Bacteria Predicted by Analog Modeling." BioScience 52, no. 4 (2002): 343. http://dx.doi.org/10.1641/0006-3568(2002)052[0343:cfoabp]2.0.co;2.
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Bolton, Kelly L., Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Daniel Kelly, Minal Patel, et al. "Cancer therapy shapes the fitness landscape of clonal hematopoiesis." Nature Genetics 52, no. 11 (October 26, 2020): 1219–26. http://dx.doi.org/10.1038/s41588-020-00710-0.
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Pedersen, Bård, Juha Tuomi, and Bard Pedersen. "Hierarchical Selection and Fitness in Modular and Clonal Organisms." Oikos 73, no. 2 (June 1995): 167. http://dx.doi.org/10.2307/3545905.
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Hodgson, D. J. "Monoclonal aphid colonies and the measurement of clonal fitness." Ecological Entomology 26, no. 4 (August 2001): 444–48. http://dx.doi.org/10.1046/j.1365-2311.2001.00327.x.
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Frede, Julia, David J. Adams, and Philip H. Jones. "Mutation, clonal fitness and field change in epithelial carcinogenesis." Journal of Pathology 234, no. 3 (October 10, 2014): 296–301. http://dx.doi.org/10.1002/path.4409.
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Avagyan, Serine, Jonathan E. Henninger, William P. Mannherz, Meeta Mistry, Song Yang, Margaret C. Weber, Jessica Moore, and Leonard I. Zon. "Loss of nr4a1 abrogates Fitness of asxl1-mutant Hematopoietic Clones." Blood 138, Supplement 1 (November 5, 2021): 3272. http://dx.doi.org/10.1182/blood-2021-149731.
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Abstract Clonal fitness of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH), a state of clonal expansion associated with increased risk of blood malignancies and cardiovascular disease. Mechanisms by which acquired mutations lead to clonal fitness are not known. We used a zebrafish model to study the effect of acquired asxl1 mutations on HSPC clonality with TWISTR (Tissue editing With Inducible Stem cell Tagging via Recombination) that combined mosaic CRISPR-Cas9 mutagenesis with color labeling of HSPC clones. TWISTR asxl1 mutants showed clonal dominant states with the expansion of single-colored clones contributing to over 30% of myelopoiesis. These zebrafish had normal hematopoietic output and no major lineage skewing. Single-cell RNA sequencing analysis of TWISTR mutant marrow cells harboring asxl1 mutations showed >10-fold upregulation of inflammatory cytokines in mutant mature myeloid cells and >30-fold upregulation of anti-inflammatory modulators in immature progenitors. Increased inflammation has been widely documented in persons with CH with acquired mutations in DNMT3A, TET2, ASXL1 and other genes. Moreover, chronic inflammation due to infection was shown to promote relative clonal fitness in Dnmt3a mutant mice. Based on our results, we proposed the hypothesis that upregulation of the anti-inflammatory genes, including nr4a1, served as a mechanism of resistance to chronic inflammation created by the mutant HSPC progeny, resulting in a self-perpetuating cycle of clonal fitness in that environment. To test this, we used TWISTR to generate mosaic mutants of asxl1 and nr4a1 by injecting zebrafish with guide RNAs targeting exon 12 of asxl1 and exon 3 of nr4a1 together. Our model would predict that abrogation of nr4a1 expression in asxl1-mutant clones would weaken their fitness relative to clones that maintained nr4a1 expression. We sorted over 300 clones of various sizes from this cohort of zebrafish and sequenced the two targeted genes. We found that clones with frameshift mutations in asxl1 with either no nr4a1 mutations or heterozygous nr4a1 mutations had a clone size of 20%±14% or 19.7%±15% in myeloid cells, respectively. Asxl1-mutant clones with biallelic frameshift mutations in nr4a1 were significantly smaller with a clone size of 13.8±11.5% (p < 0.015). Clones with intact asxl1 did not differ in their clone size independent of nr4a1 genetic status (11.9% wildtype nr4a1 vs 11.5% homozygous nr4a1 mutant). Chemical inhibition of nr4a1 over 3 months resulted in reduced change of edited clones in asxl1-mutant zebrafish compared to vehicle-treated zebrafish, with median change in allelic fraction of 3%±4.8% vs 5.3%±7.5%, respectively. This suggested that upregulation of nr4a1 in asxl1-mutant clones maintains their fitness in inflammatory conditions, potentially by limiting HSPC exhaustion. We successfully used TWISTR to study asxl1 induced CH in zebrafish and identified nr4a1 upregulation as a critical pathway engaged for establishing clonal fitness. Disclosures Zon: Fate Therapeutics: Current equity holder in publicly-traded company, Other: Founder; CAMP4 Therapeutics: Current holder of individual stocks in a privately-held company, Other: Founder; Amagma Therapeutics: Current holder of individual stocks in a privately-held company, Other: Founder; Scholar Rock: Current equity holder in publicly-traded company, Other: Founder; Branch Biosciences: Current holder of individual stocks in a privately-held company, Other: Founder; Celularity: Consultancy; Cellarity: Consultancy.
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Viny, Aaron D. "DNMT3A-Mutant Leukemia Cells Primed to “Fork It Over” under DNA Damage." Clinical Cancer Research 28, no. 4 (December 7, 2021): 573–75. http://dx.doi.org/10.1158/1078-0432.ccr-21-3949.
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Summary Mutations in the gene DNMT3A have been identified in various hematopoietic conditions, including clonal hematopoiesis, myelodysplastic syndrome, and acute myeloid leukemia. The clinical significance of this early mutation and the resultant enhanced clonal fitness have been a focus for therapeutic intervention. See related article by Venugopal et al., p. 756
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Kato, Masayasu, Eduardo S. Mizubuti, Stephen B. Goodwin, and William E. Fry. "Sensitivity to Protectant Fungicides and Pathogenic Fitness of Clonal Lineages of Phytophthora infestans in the United States." Phytopathology® 87, no. 9 (September 1997): 973–78. http://dx.doi.org/10.1094/phyto.1997.87.9.973.
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Since 1991, dramatic changes have occurred in the genetic composition of populations of Phytophthora infestans in the United States. Clonal lineages recently introduced into the United States (US-7 and US-8) are more common now than the previously dominant lineage (US-1). To help determine why these changes occurred, four clonal lineages of P. in-festans common during the early 1990s in the United States and Canada were evaluated for sensitivity to the protectant fungicides mancozeb and chlorothalonil using amended agar assays for isolates collected from 1990 to 1994. No isolate or lineage was resistant to either mancozeb or chlorothalonil. There were significant differences among isolates for degree of sensitivity to one fungicide individually, but there were no significant (P = 0.05) differences among the US-1, US-6, US-7, and US-8 clonal lineages for degree of sensitivity to both fungicides. Therefore, resistance to protectant fungicides cannot explain the rapid increase in frequency of the US-7 and US-8 clonal lineages. Three components of pathogenic fitness (latent period, lesion area, and sporulation after 96 h) were tested for the three clonal lineages that were detected most commonly during 1994 (US-1, US-7, and US-8). All but one of the isolates in this analysis were collected during 1994 and evaluated within 10 months of collection by inoculating detached leaflets of the susceptible potato cultivar Norchip. There were significant differences between the US-1 and US-8 clonal lineages for lesion area and sporulation, and between US-1 and US-7 for latent period. The US-6 clonal lineage was excluded from the pathogenic fitness experiments, because no isolates of this lineage were collected during 1994. Compared with US-7 and US-8, US-1 had the longest latent period and the smallest lesions with the least sporulation. Incorporation of the differences between US-1 and US-8 in computer simulation experiments revealed that significantly more protectant fungicide (e.g., 25%) would be required to suppress epidemics caused by the US-8 clonal lineage compared with US-1. These differences in pathogenic fitness components probably contribute to the general predominance of the “new” clonal lineages (especially US-8) relative to the “old” US-1 lineage.
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Fam, D. F., S. P. Koh, Tiong Sieh Kiong, and K. H. Chong. "Comparative Analysis of Selective Clonal Mutation with Conventional GA Operators in Solar Tracking Environment." Advanced Materials Research 341-342 (September 2011): 456–61. http://dx.doi.org/10.4028/www.scientific.net/amr.341-342.456.
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Genetic Algorithm (GA) belongs to elementary stochastic optimization algorithms inspired by evolution.It points out the ability of simple representations using bit strings to encode complicated structures and the power of simple transformations to reach the desired solution. Research shows that a new operator namely Selective Clonal Mutation (SCM) for better genetic solutions has been successfully developed so that faster convergence to the best desired solution could be obtained. This operator has produced the best fitness value as compared to the conventional genetic algorithm result within 50 generation, Selective Clonal Mutation (SCM) is able to produce the best fitness value at 0.01731 with optimum voltage 10.05V in solar tracking environment.
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Link, Daniel C. "Clonal Evolution During Stress Hematopoiesis." Blood 130, Suppl_1 (December 7, 2017): SCI—38—SCI—38. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-38.sci-38.
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Hematopoietic stem and progenitor cells (HSPCs) acquire somatic mutations with age resulting in a heterogeneous cell population, with each HSPC possessing its own unique set of private mutations. HSPCs that acquire somatic mutations that confer a competitive fitness advantage relative to their normal counterparts may clonally expand. Indeed, several groups have documented the presence of clonal hematopoiesis in healthy individuals. Although originally thought to be limited to older individuals, a recent study using an ultra-sensitive sequencing technique showed that expanded hematopoietic clones are detectable in the majority of healthy 50-60-year-old individuals. With some notable exceptions, the same genes that are commonly mutated in clonal hematopoiesis also are somatically mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, only a small fraction of individuals with clonal hematopoiesis subsequently develop a myeloid malignancy and the size of the mutant clone in clonal hematopoiesis can remain stable for years without disease progression. These observations raise several questions that will be addressed in this presentation. What drives expansion of hematopoietic clones? What role do external hematopoietic stressors, such as exposure to chemotherapy, play in the development of clonal hematopoiesis? Why do so few people with clonal hematopoiesis develop a myeloid malignancy, and are there certain mutations that confer a higher risk of transformation? Disclosures No relevant conflicts of interest to declare.
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Miller, Peter G., Christopher J. Gibson, Arnav Mehta, Adam S. Sperling, Dennie T. Frederick, Michael P. Manos, Benchun Miao, et al. "Fitness Landscape of Clonal Hematopoiesis Under Selective Pressure of Immune Checkpoint Blockade." JCO Precision Oncology, no. 4 (September 2020): 1027–33. http://dx.doi.org/10.1200/po.20.00186.
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PURPOSE Conventional cytotoxic therapies increase the risk of clonal hematopoiesis and select for TP53-mutant clones, which carry a high risk for transformation to therapy-related myelodysplastic neoplasms. In contrast, the effect of immune checkpoint blockade (ICB) on clonal hematopoiesis is unknown. METHODS Paired peripheral-blood samples taken before and after treatment with ICB were obtained for 91 patients with either cutaneous melanoma or basal cell carcinoma. Error-corrected sequencing of a targeted panel of genes recurrently mutated in clonal hematopoiesis was performed on peripheral-blood genomic DNA. RESULTS The average interval between acquisition of the paired samples was 180 days. Forty-one percent of the patients had clonal hematopoiesis at a variant allele frequency (VAF) > 0.01 in the pretreatment sample. There was near-complete agreement in the distribution and burden of clonal hematopoiesis mutations in the paired blood samples, with 87 of 88 mutations identified across the cohort present in paired samples, regardless of the duration between sample collection. The VAF in the paired samples also showed a high correlation, with an R2 = 0.95 ( P < .0001). In contrast to cytotoxic therapy, exposure to ICB did not lead to selection of TP53- or PPM1D-mutant clones. However, consistent with the known effects of DNA-damaging therapy, we identified one patient who had eight unique TP53 mutations in the posttreatment blood sample after receiving two courses of radiation therapy. CONCLUSION There was no expansion of hematopoietic clones or selection for clones at high risk for malignant transformation in patients who received ICB, observations that warrant further validation in larger cohorts. These findings highlight an important difference between ICB and conventional cytotoxic therapies and their respective impacts on premalignant genetic lesions.
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Ho, I.-Lin, Chieh-Yuan Li, Fuchenchu Wang, Li Zhao, Jingjing Liu, Er-Yen Yen, Charles A. Dyke, et al. "Abstract 1494: Clonal dominance defines metastatic dissemination in pancreatic cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1494. http://dx.doi.org/10.1158/1538-7445.am2024-1494.
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Abstract Tumors represent ecosystems where subclones compete during tumor growth. While extensively investigated, a comprehensive picture of the interplay of clonal lineages during dissemination is still lacking. Using patient-derived pancreatic cancer cells, we created orthotopically-implanted clonal replica tumors to trace clonal dynamics of unperturbed tumor expansion and dissemination. This model revealed the multifaceted nature of tumor growth, with rapid changes in clonal fitness leading to continuous reshuffling of tumor architecture and alternating clonal dominance as a distinct feature of cancer growth. Regarding dissemination, a large fraction of tumor lineages could be found at secondary sites each having distinctive organ growth patterns as well as numerous undescribed behaviors such as abortive colonization. Paired analysis of primary and secondary sites revealed fitness as major contributor to dissemination. From the analysis of pro- and non-metastatic isogenic subclones, we identified a transcriptomic signature able to identify metastatic cells in human tumors and predict patients’ survival. Citation Format: I-Lin Ho, Chieh-Yuan Li, Fuchenchu Wang, Li Zhao, Jingjing Liu, Er-Yen Yen, Charles A. Dyke, Rutvi Shah, Zhaoliang Liu, Ali Osman Çetin, Francesca Citron, Sergio Attanasio, Virgina Giuliani, Tim Heffernan, Kim-Anh Do, Gaetano Gargiulo, Giulio Draetta, Alessandro Carugo, Ruitao Lin, Andrea Viale. Clonal dominance defines metastatic dissemination in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1494.
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Seidl Johnson, Anna C., Kenneth E. Frost, Douglas I. Rouse, and Amanda J. Gevens. "Effect of Temperature on Growth and Sporulation of US-22, US-23, and US-24 Clonal Lineages of Phytophthora infestans and Implications for Late Blight Epidemiology." Phytopathology® 105, no. 4 (April 2015): 449–59. http://dx.doi.org/10.1094/phyto-03-14-0064-r.
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Epidemics of late blight, caused by Phytophthora infestans (Mont.) de Bary, have been studied by plant pathologists and regarded with great concern by potato and tomato growers since the Irish potato famine in the 1840s. P. infestans populations have continued to evolve, with unique clonal lineages arising which differ in pathogen fitness and pathogenicity, potentially impacting epidemiology. In 2012 and 2013, the US-23 clonal lineage predominated late blight epidemics in most U.S. potato and tomato production regions, including Wisconsin. This lineage was unknown prior to 2009. For isolates of three recently identified clonal lineages of P. infestans (US-22, US-23, and US-24), sporulation rates were experimentally determined on potato and tomato foliage and the effect of temperature on lesion growth rate on tomato was investigated. The US-22 and US-23 isolates had greater lesion growth rates on tomato than US-24 isolates. Sporulation rates for all isolates were greater on potato than tomato, and the US-23 isolates had greater sporulation rates on both tomato and potato than the US-22 and US-24 isolates. Experimentally determined correlates of fitness were input to the LATEBLIGHT model and epidemics were simulated using archived Wisconsin weather data from four growing seasons (2009 to 2012) to investigate the effect of isolates of these new lineages on late blight epidemiology. The fast lesion growth rates of US-22 and US-23 isolates resulted in severe epidemics in all years tested, particularly in 2011. The greater sporulation rates of P. infestans on potato resulted in simulated epidemics that progressed faster than epidemics simulated for tomato; the high sporulation rates of US-23 isolates resulted in simulated epidemics more severe than simulated epidemics of isolates of the US-22 and US-24 isolates and EC-1 clonal lineages on potato and tomato. Additionally, US-23 isolates consistently caused severe simulated epidemics when lesion growth rate and sporulation were input into the model singly or together. Sporangial size of the US-23 isolates was significantly smaller than that of US-22 and US-24 isolates, which may result in more efficient release of sporangia from the tomato or potato canopy. Our experimentally determined correlates of fitness and the simulated epidemics resulting from their incorporation into the LATEBLIGHT model suggest that US-23 isolates of P. infestans may have the greatest fitness among currently prevalent lineages and may be the most likely lineage to persist in the P. infestans population. The US-23 clonal lineage has been documented as the most prevalent lineage in recent years, indicating its overall fitness. In our work, US-23 had the highest epidemic potential among current genotypes. Given that epidemic potential is a component of fitness, this may, in part, explain the current predominance of the US-23 lineage.
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Wong, Terrence Neal, Jeffery M. Klco, Ryan Demeter, Christopher A. Miller, Allegra Petti, Nichole Havey, Robert Fulton, et al. "Non-Malignant Oligoclonal Hematopoiesis Commonly Follows Cytoreductive Chemotherapy in Adult De Novo AML Patients." Blood 126, no. 23 (December 3, 2015): 686. http://dx.doi.org/10.1182/blood.v126.23.686.686.
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Abstract Our group (Welch, Cell 2012) previously showed that hematopoietic stem and progenitor cells (HSPCs) acquire somatic mutations with age. This produces a genetically heterogeneous HSPC population with each HSPC possessing its own unique set of mutations. Later work from our group (Xie, Nature Medicine 2014) and others (Genovese, Jaiswal, NEJM 2014) demonstrated that some these mutations may provide HSPCs with a fitness advantage, allowing them to clonally expand over time in healthy individuals. We recently published data (Wong, Nature 2015) suggesting that cytotoxic therapy can select for HSPC clones with TP53 mutations, resulting in their clonal expansion and contributing to the subsequent development of therapy-related AML/MDS. From these data, we hypothesized that the intensive cytoreductive chemotherapy used to treat AML poses a significant selection pressure on a patient's non-malignant HSPC population, favoring HSPCs with specific somatic mutations and potentially resulting in oligoclonal hematopoiesis even after elimination of the founding AML clone. To test this hypothesis, we performed enhanced exome sequencing on cryopreserved bone marrow cells from 25 adult de novo AML patients (who received a "7+3" regimen for induction of remission) at time of their initial diagnosis, at first morphologic remission (~day 30), and at long-term follow up (at first relapse or during a prolonged first remission) (Klco, JAMA, in press). In 15 patients, we observed genetic clearance of the AML founding clone at the time of first morphologic remission (defined as all AML founding clone mutations declining to a variant allele frequency (VAF) < 2.5%). Surprisingly, in 5 of the 15 patients exhibiting clearance of their AML founding clone, we observed a concomitant expansion of a non-malignant clonal population during cytoreductive therapy, resulting in long-lived clonal hematopoiesis. Somatic mutations harbored by these expanding hematopoietic clones were validated with a high-coverage PCR-based sequencing approach. In contrast to the studies highlighting clonal hematopoiesis in individuals unexposed to chemotherapy, patients with evidence of persistent clonal hematopoiesis after cytoreductive therapy (median age = 52.2 years) were similar in age to patients without such evidence (median age = 54.1 years). The majority of these "rising clones" harbored somatic mutations in genes frequently mutated in AML such as DNMT3A, TET2 and TP53. Using next-generation sequencing and droplet digital PCR, we determined that in all of the patients with an expanding non-malignant clone, the clone was, in fact, present in the initial AML diagnosis sample at very low VAFs (0.007-0.75%). These populations rapidly expanded with chemotherapy, comprising 13-57% of the total hematopoietic population upon its completion. In all 4 of cases with sample availability, these clones remained at an expanded level a year or more after initial chemotherapy exposure. These results suggest that certain non-malignant HSPCs, having previously acquired specific aging-related somatic mutations, may gain a competitive fitness advantage after cytoreductive therapy, expand, and persist long after the completion of chemotherapy. Two of the five patients with clonal non-leukemic hematopoiesis post-chemotherapy relapsed. In both patients, the relapsed AML clone evolved from the original AML founding clone and did not involve the non-malignant clonal population, which also persisted at relapse. Both patients re-achieved morphologic remission with salvage therapy. A post-salvage therapy bone marrow sample was available in one of the cases. Interestingly, it showed that the patient's non-malignant clonal population expanded even further with salvage therapy, eventually comprising almost 80% of the total bone marrow cells. These results show that non-malignant oligoclonal hematopoiesis is common in AML patients after cytoreductive chemotherapy, with non-malignant HSPCs carrying certain somatic mutations often gaining a fitness advantage and expanding. The long-term clinical consequences of oligoclonal hematopoiesis after cytoreductive chemotherapy are unknown but are likely to be different from oligoclonal hematopoiesis developing in healthy elderly individuals. Additional studies will be required to define the mechanisms by which certain HSPCs gain a fitness advantage after cytoreductive chemotherapy. Disclosures No relevant conflicts of interest to declare.
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Huber, Meret, Saskia Gablenz, and Martin Höfer. "Transgenerational non-genetic inheritance has fitness costs and benefits under recurring stress in the clonal duckweed Spirodela polyrhiza." Proceedings of the Royal Society B: Biological Sciences 288, no. 1955 (July 21, 2021): 20211269. http://dx.doi.org/10.1098/rspb.2021.1269.
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Although non-genetic inheritance is thought to play an important role in plant ecology and evolution, evidence for adaptive transgenerational plasticity is scarce. Here, we investigated the consequences of copper excess on offspring defences and fitness under recurring stress in the duckweed Spirodela polyrhiza across multiple asexual generations . Growing large monoclonal populations (greater than 10 000 individuals) for 30 generations under copper excess had negative fitness effects after short and no fitness effect after prolonged growth under recurring stress. These time-dependent growth rates were likely influenced by environment-induced transgenerational responses, as propagating plants as single descendants for 2 to 10 generations under copper excess had positive, negative or neutral effects on offspring fitness depending on the interval between initial and recurring stress (5 to 15 generations). Fitness benefits under recurring stress were independent of flavonoid accumulations, which in turn were associated with altered plant copper concentrations. Copper excess modified offspring fitness under recurring stress in a genotype-specific manner, and increasing the interval between initial and recurring stress reversed these genotype-specific fitness effects. Taken together, these data demonstrate time- and genotype-dependent adaptive and non-adaptive transgenerational responses under recurring stress, which suggests that non-genetic inheritance alters the evolutionary trajectory of clonal plant lineages in fluctuating environments.
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Weaver, Scott C., Aaron C. Brault, Wenli Kang, and John J. Holland. "Genetic and Fitness Changes Accompanying Adaptation of an Arbovirus to Vertebrate and Invertebrate Cells." Journal of Virology 73, no. 5 (May 1, 1999): 4316–26. http://dx.doi.org/10.1128/jvi.73.5.4316-4326.1999.
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ABSTRACT The alternating host cycle and persistent vector infection may constrain the evolution of arboviruses. To test this hypothesis, eastern equine encephalitis virus was passaged in BHK or mosquito cells, as well as in alternating (both) host cell passages. High and low multiplicities were used to examine the effect of defective interfering particles. Clonal BHK and persistent mosquito cell infections were also evaluated. Fitness was measured with one-step growth curves and competition assays, and mutations were evaluated by nucleotide sequencing and RNA fingerprinting. All passages and assays were done at 32°C to eliminate temperature as a selection factor. Viruses passaged in either cell type alone exhibited fitness declines in the bypassed cells, while high-multiplicity and clonal passages caused fitness declines in both types of cells. Bypassed cell fitness losses were mosquito and vertebrate specific and were not restricted to individual cell lines. Fitness increases occurred in the cell line used for single-host-adaptation passages and in both cells for alternately passaged viruses. Surprisingly, single-host-cell passage increased fitness in that cell type no more than alternating passages. However, single-host-cell adaptation resulted in more mutations than alternating cell passages. Mosquito cell adaptation invariably resulted in replacement of the stop codon in nsP3 with arginine or cysteine. In one case, BHK cell adaptation resulted in a 238-nucleotide deletion in the 3′ untranslated region. Many nonsynonymous substitutions were shared among more than one BHK or mosquito cell passage series, suggesting positive Darwinian selection. Our results suggest that alternating host transmission cycles constrain the evolutionary rates of arboviruses but not their fitness for either host alone.
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Vorburger, C., and N. Ramsauer. "Genetic variation and covariation of aphid life-history traits across unrelated host plants." Bulletin of Entomological Research 98, no. 6 (July 1, 2008): 543–53. http://dx.doi.org/10.1017/s0007485308005853.
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AbstractA central paradigm of life-history theory is the existence of resource mediated trade-offs among different traits that contribute to fitness, yet observations inconsistent with this tenet are not uncommon. We previously found a clonal population of the aphid Myzus persicae to exhibit positive genetic correlations among major components of fitness, resulting in strong heritable fitness differences on a common host. This raises the question of how this genetic variation is maintained. One hypothesis states that variation for resource acquisition on different hosts may override variation for allocation, predicting strong fitness differences within hosts as a rule, but changes in fitness hierarchies across hosts due to trade-offs. Therefore, we carried out a life-table experiment with 17 clones of M. persicae, reared on three unrelated host plants: radish, common lambsquarters and black nightshade. We estimated the broad-sense heritabilities of six life-history traits on each host, the genetic correlations among traits within hosts, and the genetic correlations among traits on different hosts (cross-environment genetic correlations). The three plants represented radically different environments with strong effects on performance of M. persicae, yet we detected little evidence for trade-offs. Fitness components were positively correlated within hosts but also between the two more benign hosts (radish and lambsquarters), as well as between those and another host tested earlier. The comparison with the most stressful host, nightshade, was hampered by low survival. Survival on nightshade also exhibited genetic variation but was unrelated to fitness on other hosts. Acknowledging that the number of environments was necessarily limited in a quantitative genetic experiment, we suggest that the rather consistent fitness hierarchies across very different plants provided little evidence to support the idea that the clonal variation for life-history traits and their covariance structure are maintained by strong genotype×environment interactions with respect to hosts. Alternative explanations are discussed.
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Jaiswal, Siddhartha, and Benjamin L. Ebert. "Clonal hematopoiesis in human aging and disease." Science 366, no. 6465 (October 31, 2019): eaan4673. http://dx.doi.org/10.1126/science.aan4673.
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As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called “clonal hematopoiesis,” is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.
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Fennell, Katie A., Dane Vassiliadis, Enid Y. N. Lam, Luciano G. Martelotto, Jesse J. Balic, Sebastian Hollizeck, Tom S. Weber, et al. "Non-genetic determinants of malignant clonal fitness at single-cell resolution." Nature 601, no. 7891 (December 8, 2021): 125–31. http://dx.doi.org/10.1038/s41586-021-04206-7.
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Hughes, D. J. "Genotype-Environment Interactions and Relative Clonal Fitness in a Marine Bryozoan." Journal of Animal Ecology 61, no. 2 (June 1992): 291. http://dx.doi.org/10.2307/5322.
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Frick, Peter L., Bishal B. Paudel, Darren R. Tyson, and Vito Quaranta. "Quantifying heterogeneity and dynamics of clonal fitness in response to perturbation." Journal of Cellular Physiology 230, no. 7 (March 27, 2015): 1403–12. http://dx.doi.org/10.1002/jcp.24888.
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Watson, Caroline J., Sophia Apostolidou, Usha Menon, and Jamie R. Blundell. "Tracing the Evolution of Clonal Hematopoiesis to AML Using Longitudinal Pre-Diagnosis Blood Samples." Blood 138, Supplement 1 (November 5, 2021): 599. http://dx.doi.org/10.1182/blood-2021-147503.
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Abstract The acquisition of somatic mutations in hematopoietic stem and progenitor cells (HSPCs) is increasingly common with age (`clonal hematopoiesis'). If sequential acquisition and clonal expansion of mutations occurs, progression to Acute Myeloid Leukemia (AML) can occur. While the mutational landscape of clonal hematopoiesis antecedent to AML development has been well-defined (Abelson et al. 2018, Desai et al. 2018), the timing of acquisition and growth dynamics of these high-risk mutations remain largely unknown. At what age are these mutations acquired? Are the fitness effects (growth rates) conferred by specific mutations predictable from person-to-person and how do fitness effects change with additive mutations? Are the clonal dynamics that precede AML development characterised by strong competition between clones (clonal interference)? To answer these questions, we identified 220 women from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) who were cancer-free at enrolment but subsequently developed AML during the >12 years follow-up. 50 of these women had annual blood samples collected at multiple time-points pre-AML diagnosis (mean: 5 time-points, range: 2-11). Deep error-corrected duplex sequencing, with a variant allele frequency (VAF) detection limit of 0.1%, was performed on peripheral blood DNA from these women, as well as from age- and timepoint-matched controls who remained blood cancer free. A custom designed next-generation sequencing (NGS) panel was used to enable detection of mutations in 34 clonal hematopoiesis/AML-associated genes, genome-wide mosaic chromosomal alterations (mCAs) and AML-associated translocations. Having samples from multiple timepoints enabled the fitness effects (growth rates) of mutations to be calculated, as well as the additive effect of further mutations. These growth rates, in combination with insights from evolutionary theory, allowed the acquisition time of many mutations to be estimated, with initiating driver mutations often arising in the first 2 decades of life in the pre-AML cases. Growth trajectory dynamics of co-occurring mutations enabled the clonal composition to be inferred in many instances and revealed linear evolution of successive mutations in some pre-AML cases, but a branching pattern with clear evidence of clonal interference in others. Specific variants, which we have previously identified as 'highly fit' in clonal hematopoiesis (Watson et al. 2020), were significantly enriched in pre-AML cases compared to controls and were often detectable at VAFs >10% more than 5 years pre-diagnosis. NPM1 mutations, which characteristically occur `late' in AML development, could be detected as early as 2 years pre-diagnosis, highlighting the benefit afforded by error-corrected low VAF variant calling, particularly in high-risk individuals. Our findings, exploiting longitudinal blood samples collected pre-AML combined with an integrated assessment of multiple types of genetic changes, reveal key insights into the evolutionary dynamics of mutations in the years preceding AML development. Understanding which features distinguish pre-malignant from benign clonal evolution is key for risk stratification of individuals with clonal hematopoiesis to allow rational monitoring and identification of individuals that may benefit from early intervention studies. Figure 1 Figure 1. Disclosures Watson: Johnson & Johnson: Consultancy; Inivata: Consultancy. Menon: Abcodia Ltd: Current holder of individual stocks in a privately-held company. Blundell: Johnson & Johnson: Consultancy; Inivata: Consultancy.
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Petrone, Giulia, Isik Turker, Pradeep Natarajan, and Kelly L. Bolton. "Clinical and Therapeutic Implications of Clonal Hematopoiesis." Annual Review of Genomics and Human Genetics 25, no. 1 (August 27, 2024): 329–51. http://dx.doi.org/10.1146/annurev-genom-120722-100409.
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Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic stem and progenitor cells (HSPCs) acquire mutations that lead to a proliferative advantage and clonal expansion. The most commonly mutated genes are epigenetic regulators, DNA damage response genes, and splicing factors, which are essential to maintain functional HSPCs and are frequently involved in the development of hematologic malignancies. Established risk factors for CH, including age, prior cytotoxic therapy, and smoking, increase the risk of acquiring CH and/or may increase CH fitness. CH has emerged as a novel risk factor in many age-related diseases, such as hematologic malignancies, cardiovascular disease, diabetes, and autoimmune disorders, among others. Future characterization of the mechanisms driving CH evolution will be critical to develop preventative and therapeutic approaches.
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Elena, Santiago F., Fernando González-Candelas, Isabel S. Novella, Elizabeth A. Duarte, David K. Clarke, Esteban Domingo, John J. Holland, and Andrés Moya. "Evolution of Fitness in Experimental Populations of Vesicular Stomatitis Virus." Genetics 142, no. 3 (March 1, 1996): 673–79. http://dx.doi.org/10.1093/genetics/142.3.673.
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Abstract The evolution of fitness in experimental clonal populations of vesicular stomatitis virus (VSV) has been compared under different genetic (fitness of initial clone) and demographic (population dynamics) regimes. In spite of the high genetic heterogeneity among replicates within experiments, there is a clear effect of population dynamics on the evolution of fitness. Those populations that went through strong periodic bottlenecks showed a decreased fitness in competition experiments with wild type. Conversely, mutant populations that were transferred under the dynamics of continuous population expansions increased their fitness when compared with the same wild type. The magnitude of the observed effect depended on the fitness of the original viral clone. Thus, high fitness clones showed a larger reduction in fitness than low fitness clones under dynamics with included periodic bottleneck. In contrast, the gain in fitness was larger the lower the initial fitness of the viral clone. The quantitative genetic analysis of the trait “fitness” in the resulting populations shows that genetic variation for the trait is positively correlated with the magnitude of the change in the same trait. The results are interpreted in terms of the operation of Muller's ratchet and genetic drift as opposed to the appearance of beneficial mutations.
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Willi, Yvonne, and Josh Van Buskirk. "Genomic compatibility occurs over a wide range of parental genetic similarity in an outcrossing plant." Proceedings of the Royal Society B: Biological Sciences 272, no. 1570 (June 15, 2005): 1333–38. http://dx.doi.org/10.1098/rspb.2005.3077.
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The theory of inbreeding and outbreeding suggests that there is a hump-shaped relationship between the genetic similarity of sexually reproducing parents and the performance of their offspring. Inbreeding depression occurs when genetic similarity is high, whereas hybrid breakdown is expected when genetic similarity is low. Between these extremes, the effect of genetic similarity on fitness is unclear. We studied the shape of this relationship by crossing 65 target genotypes of the clonal, self-incompatible Ranunculus reptans with partner genotypes spanning a broad scale of genetic similarity, ranging from crosses within populations to between-population crosses and hybridisation with a closely related species. Offspring were raised in outdoor tubs. Results revealed a quadratic relationship between parental genetic distance and offspring performance, with the clonal component of fitness more strongly hump-shaped than the sexual component. Optimal genetic similarity encompassed a broad range of within-population and between-population crosses. This pattern of genomic compatibility has important implications for the evolution of mating systems and mate choice.
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Laruelle, Annick, Claudia Manini, José I. López, and André Rocha. "Early Evolution in Cancer: A Mathematical Support for Pathological and Genomic Evidence in Clear Cell Renal Cell Carcinoma." Cancers 15, no. 24 (December 18, 2023): 5897. http://dx.doi.org/10.3390/cancers15245897.
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Clear cell renal cell carcinoma (CCRCC) is an aggressive form of cancer and a paradigmatic example of intratumor heterogeneity (ITH). The hawk-dove game is a mathematical tool designed to analyze competition in biological systems. Using this game, the study reported here analyzes the early phase of CCRCC development, comparing clonal fitness in homogeneous (linear evolutionary) and highly heterogeneous (branching evolutionary) models. Fitness in the analysis is a measure of tumor aggressiveness. The results show that the fittest clone in a heterogeneous environment is fitter than the clone in a homogeneous context in the early phases of tumor evolution. Early and late periods of tumor evolution in CCRCC are also compared. The study shows the convergence of mathematical, histological, and genomics studies with respect to clonal aggressiveness in different periods of the natural history of CCRCC. Such convergence highlights the importance of multidisciplinary approaches for obtaining a better understanding of the intricacies of cancer.
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Naddaf, Lamis, Marco De Dominici, Xiaowen Chen, Parveen Kumar, James S. Chavez, Travis Roeder, Shilpita Karmakar, et al. "Title: In Vivo Clonal Tracing of Hematopoietic Stem and Progenitor Cells Reveals Increased Clonal Heterogeneity during Aging, Alongside Critical Changes in Selection Patterns." Blood 144, Supplement 1 (November 5, 2024): 2671. https://doi.org/10.1182/blood-2024-202289.
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Aging impacts the bone marrow microenvironment by inducing inflammation. We hypothesize that aging increases heritable epigenetic heterogeneity, leading to transcriptome heterogeneity within hematopoietic stem and progenitor cells (HSPC). This resulting heterogenous state, combined with the aged microenvironment-driven selection, shifts the functional capacity of the hematopoietic system, contributing to the functional decline of the hematopoietic system as well as the evolution of diseases such as myelodysplastic syndrome and leukemias. Our research aims to investigate clonal heterogeneity in both young and old mice and highlight the phenotypic patterns selected in each case. We employed CellTag indexing and single-cell RNA sequencing to track HSPC, identify the selected clones in young and old mice BM, and characterize their molecular signatures. We generated 10x Genomics single-cell RNA-seq for tagged HSPC after 15-day culturing (in vitro) and two months post-transplantation into mice (in vivo). Tracing the expansion of HSPC clones in young and old BM revealed critical changes in HSPC heterogeneity and selection in older mice. We observed an increase in transcriptional heterogeneity of old HSPC as compared to young samples (P<0.01, Wilcox test). Genes with higher gene expression variability in older mice coincide with pathways pivotal for HSPC fitness, e.g., ribosome synthesis, inflammation response mechanisms (JAK-STAT), hematopoietic cell lineage, AML, and cancer pathways (FDR<0.1, GSEA). At the clonal composition level, young HSPCs exhibited more oligoclonal reconstitution than old HSPC, indicated by lower Shannon entropy in young HSPCs compared to old (P<0.05 Wilcox test). This result suggests stricter clonal quality control in the young microenvironment, potentially leading to increased purifying selection that removes clones with significant transcriptional profile alterations and reduced fitness. Moreover, comparing the transcriptional profiles of clones showing robust expansion after transplantation (selected or “winner” clones) with negatively selected clones revealed several common pathways shared between young and old selected clones after expansion (FDR<0.1, GSEA), including cell cycle activity, stress response, WNT signaling, and metabolism - identifying candidate mediators of HSPC fitness in vivo. However, major differences between old and young selected clones were evident before expansion. In young, selected clones, signatures related to inflammatory response were observed.Strikingly, we observed a significant positive expression correlation (P<0.0001, Wilcox test) among the selected clones only in young mice, not in old mice. The high transcriptomic similarity among selected clones is consistent with strict clonal quality control in the young BM microenvironment. Notably, we traced the selected clones back among the tagged HSPCs in vitro (scRNA-seq) and observed higher transcriptomic similarity among selected clones from young vs. old donor mice even before transplantation (P<0.0001, Wilcox test). Collectively, these results underscore the selective nature of the young BM, contrasting with the decline of HSPC quality control in old BM, contributing to functional hematopoietic decline and fueling pre-malignant evolution. These studies reveal striking differences in clonal dynamics and quality control among HSPC in young and old mice. Clonal tracing of hematopoietic clones provides insight into how clonal competition and microenvironmental selection can contribute to hematopoietic decline and malignant evolution. Better understanding of the pathways that contribute to HSPC fitness and functional decline with aging could lead to approaches to track and perhaps even counter these aging-associated changes, which is expected to contribute to improved hematopoietic function and reduced risk of malignancy in the elderly.
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Samadzadegan, Farhad, Shahin Rahmatollahi Namin, and Mohammad Ali Rajabi. "Evaluating the Potential of Clonal Selection Optimization Algorithm to Hyperspectral Image Feature Selection." Key Engineering Materials 500 (January 2012): 799–805. http://dx.doi.org/10.4028/www.scientific.net/kem.500.799.
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The great number of captured near spectral bands in hyperspectral images causes the curse of dimensionality problem and results in low classification accuracy. The feature selection algorithms try to overcome this problem by limiting the input space dimensions of classification for hyperspectral images. In this paper, immune clonal selection optimization algorithm is used for feature selection. Also one of the fastest Artificial Immune classification algorithms is used to compute fitness function of the feature selection. The comparison of the feature selection results with genetic algorithm shows the clonal selection’s higher performance to solve selection of features.
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Salehi, Sohrab, Farhia Kabeer, Nicholas Ceglia, Mirela Andronescu, Marc J. Williams, Kieran R. Campbell, Tehmina Masud, et al. "Clonal fitness inferred from time-series modelling of single-cell cancer genomes." Nature 595, no. 7868 (June 23, 2021): 585–90. http://dx.doi.org/10.1038/s41586-021-03648-3.
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Reusch, T. B. H. "Fitness-consequences of geitonogamous selfing in a clonal marine angiosperm (Zostera marina)." Journal of Evolutionary Biology 14, no. 1 (January 8, 2001): 129–38. http://dx.doi.org/10.1046/j.1420-9101.2001.00257.x.
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Zhang, Yunchun, Xiaojun Du, Qiaoying Zhang, Xianming Gao, and Zhixian Su. "Fitness analysis of seed and vegetative reproduction of clonal tree Symplocos laurina." Frontiers of Forestry in China 1, no. 2 (June 2006): 142–49. http://dx.doi.org/10.1007/s11461-006-0014-8.
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Zhu, Min, Tianshi Lu, Yuemeng Jia, Xin Luo, Purva Gopal, Lin Li, Mobolaji Odewole, et al. "Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease." Cell 177, no. 3 (April 2019): 608–21. http://dx.doi.org/10.1016/j.cell.2019.03.026.
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Wikberg, Sofie, Brita M. Svensson, Bengt Å. Carlsson, and Bengt A. Carlsson. "Fitness, Population Growth Rate and Flowering in Carex bigelowii, a Clonal Sedge." Oikos 70, no. 1 (May 1994): 57. http://dx.doi.org/10.2307/3545699.
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Mi, Xiaoli, Dennis Yuan, Rebecca Murray, Jani Huuhtanen, Beatrice Zhang, Jean Quentin, Olga Shestova, et al. "Molecular Attributes of CAR T Cell Fitness in Patients with Chronic Lymphocytic Leukemia." Blood 142, Supplement 1 (November 28, 2023): 3452. http://dx.doi.org/10.1182/blood-2023-187956.
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Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of hematologic malignancies, leading to FDA approval in B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma. While many patients with previously untreatable disease have achieved excellent responses and long-term remissions, a substantial number do not respond or relapse after months to years. Most prior studies of CAR T cell-intrinsic determinants of response and resistance have focused on infusion products. Functional expansion and persistence of CAR T cells in patients constitute an important feature of treatment success, yet the trajectories of CAR T cells and their molecular underpinnings remain poorly understood due to technical challenges. Here we performed single-cell multiomics with T-cell receptor (TCR) lineage tracing to study the molecular attributes of CAR T cell fitness, which we define as the ability to expand and/or persist to at least 12 months after infusion. We recently published long-term follow-up from a prospective single-center phase 2 clinical trial in which CD19-directed CAR T cells with 4-1BB co-stimulation were administered to patients with relapsed or refractory chronic lymphocytic leukemia (CLL) not in complete remission despite at least 6 months of ibrutinib. In this trial, we found high rates of deep and durable remissions with prolonged persistence of functional CAR T cells determined by flow cytometric detection of CAR T cells with concomitant B-cell aplasia. We obtained CAR T cell infusion products and peripheral blood at day 10 and month 12 from five patients with durable remissions. We then performed single-cell multiomics sequencing to measure gene expression, TCRs, surface proteins, and chromatin accessibility to define the multidimensional phenotypes and clonal trajectories of CAR T cells over time ( Figure). We first evaluated CAR T cell dynamics from infusion product to day 10 and identified clones that expanded using TCR as a molecular barcode. While ~90% of CAR T cells in the infusion product are CD4 +, peak expansion at day 10 is driven by effector CD8 + CAR T cells. Clonally expanded CAR T cells at day 10, compared to non-expanded CAR T cells, showed higher expression of multiple cytotoxicity genes ( GZMH, GZMB, GNLY, PRF1) and co-inhibitory receptors ( LAG3, PDCD1, and KLRB1) and lower expression of memory genes ( SELL, LTB, TCF7). Using TCR lineage tracing and a machine learning classifier, we identified similar markers predictive of clonal expansion from the infusion product, e.g. CD8A, GNLY, KLRG1, KLRK1 among the top positive markers and CD4 and SELL among the top negative markers. Along with clonal expansion, we found that CD8 + CAR T cells undergo significant evolution in their chromatin accessibility landscape from infusion product to day 10. Genomic regions that are more open at infusion are enriched for Fos/Jun (AP-1) and Batf family of transcription factor (TF) motifs, consistent with their function in promoting effector T cell differentiation and proliferation. Genomic regions that are more open at day 10 are enriched for Eomes, T-bet, and other T-box TF motifs, consistent with their roles in regulating T cell cytolytic function, memory formation, and exhaustion. These data provide insights into the regulatory mechanisms of rapid CAR T cell expansion post-infusion in patients which have not yet been reported. We found that most clonally expanded CAR T cells at day 10 contracted or disappeared by month 12. However, a subset of CD8 + CAR T cells in 2 patients that did not undergo early expansion surprisingly demonstrated late clonal expansion and persistence at month 12, coinciding with hyper-expansion (>200 cells per clone) of their TCR clonotypes with or without CAR expression. We then investigated the specificity of TCRs using publicly available databases and found late expansions of clones predicted to bind viral peptides. This observation suggests that the TCR antigen specificity may contribute to the long-term persistence or fitness of CAR T cell clones, in contrast to recent studies of long-lived CAR T cells in a limited number of patients which argue that persistence is driven by specific phenotypes rather than clonotype-specific features. Further validation of this finding is ongoing through flow enrichment of rare persistent CAR T cells for deeper single-cell sequencing and in vitro cellular immunology assays.
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Vail, Daniel J., Dongxu Jiang, Kunho Chung, Yahan Zhang, Sophia Martinez, Luca Guarnera, Yvonne Parker, et al. "Age-Related Cellular Factors Facilitate TET2 Mutant Clonal Hematopoiesis." Blood 144, Supplement 1 (November 5, 2024): 1278. https://doi.org/10.1182/blood-2024-211683.
Full textAbstract:
Background and Significance: Besides chemotherapy and inherited or acquired bone marrow failure, aging is one of the most important risk factors for the development of clonal hematopoiesis (CH), and both intrinsic and chronological factors may play a role. While initially asymptomatic and referred as to clonal hematopoiesis of indeterminate potential (CHIP), CH frequently leads to adverse clinical consequences with increased risk of cardiovascular disease, certain pulmonary disorders, and other diseases. CHIP carriers experience increased risk of progression to myeloid neoplasia (MN). The process of clonal expansion may be protracted, and its penetrance is difficult to assess due to competing mortalities. While various genetic lesions have been described as common to CHIP, loss of function TET2 mutation (TET2MT) is very common. The prevalence of TET2MT CH increases with age; for instance, our earlier research demonstrates that most cases of myelodysplastic syndrome in patients over age 70 are likely from TET2MT CHIP. TET2MT are prototypic CH lesions, being both weakly leukemogenic in the context of healthy, young hematopoiesis and increasingly strong initiators of leukemogenic cascades in aging populations. In the current study, we investigate whether the progression of CH is not only linked to cell intrinsic properties of TET2MT clones, but also to other extrinsic age-related changes in bone marrow niche, including inflammation, loss of hematopoietic stem cell (HSC) fitness, and quantitative contraction of the HSC compartment. These factors are particularly important for TET2MT CHIP because they may, perhaps in addition to TET2 deficient clones, be subjects of therapeutic or preventive interventions. Methods and Results: We developed novel murine models of Tet2 mutant (Tet2+/- and Tet2-/-) inB6CD45.2, B6TomatoRedmTmG and CD45.1 JaxBoy, and utilized young (8-16 weeks) and old (>16 months) WT mice to dissect the role of cell intrinsic and extrinsic aging factors in CHIP evolution. We utilized various surface markers along with cell intrinsic fluorophores to monitor different hematopoietic compartments. Data analyses were performed in FlowJo™ and statistical analyses were performed using Dunnett's test (sample size n<8) or one-way ANOVA for multiple comparisons. Our models enabled precise monitoring of CH using phenotypic markers. We performed an in vivo marrow competitive bone marrow repopulation assay, where grafts from either young or old WT donors from CD45.2 mice (90%) competed with Tet2-/- B6TomatoRedmTmG (10%) in congenic CD45.1 JaxBoy recipient mice irradiated with 9.2 gray ionizing radiation. The Tet2-/- fractions traced by tdTomato fluorescence and the WT donor fraction traced as tdTomato negative and CD45.2 positive were monitored until sacrifice at 52 weeks. 5 months post-transplant, we observed that the expansion rate of Tet2-/- clone was accelerated (>2-fold, n=5, p =0.006, t-test) when the competitor graft was from old donors compared to young donors. Marrow cells derived from young donors restricted the expansion of Tet2-/- HSC due to better fitness, reducing the proportion of Tet2-/- cells from 80.47% in the transplants from old WT donors to 33.80% in those from young donors (n=5, p=0.0002, t-test) 52 weeks post-transplant at the end of the experiment. In a further analysis, we observed that aging effects on hematopoiesis varied across compartments, notably contracting the T-cell compartment from 49.25% (young WT donors) to 25.08% (old WT donors) (n=5, p=0.0339) consistent with immune cell deficit with aging. Using these models, we have identified that aging HSCs feature a lack of fitness that may contribute to the emergence and expansion of CH. Our data suggest that the age-associated attrition of normal HSCs allows the expansion of TET2MT CHIP. Therefore, enhancing the fitness of a polyclonal, normal HSC compartment by targeting the factors that created such attrition, may restrict or delay clonal evolution and prevent associated morbidities.