Natural Inspired Intelligent Visual Computing and Its Application to Viticulture.

PubMed

Ang, Li Minn; Seng, Kah Phooi; Ge, Feng Lu

2017-05-23

This paper presents an investigation of natural inspired intelligent computing and its corresponding application towards visual information processing systems for viticulture. The paper has three contributions: (1) a review of visual information processing applications for viticulture; (2) the development of natural inspired computing algorithms based on artificial immune system (AIS) techniques for grape berry detection; and (3) the application of the developed algorithms towards real-world grape berry images captured in natural conditions from vineyards in Australia. The AIS algorithms in (2) were developed based on a nature-inspired clonal selection algorithm (CSA) which is able to detect the arcs in the berry images with precision, based on a fitness model. The arcs detected are then extended to perform the multiple arcs and ring detectors information processing for the berry detection application. The performance of the developed algorithms were compared with traditional image processing algorithms like the circular Hough transform (CHT) and other well-known circle detection methods. The proposed AIS approach gave a Fscore of 0.71 compared with Fscores of 0.28 and 0.30 for the CHT and a parameter-free circle detection technique (RPCD) respectively.

Kin Recognition in a Clonal Fish, Poecilia formosa

PubMed Central

Makowicz, Amber M.; Tiedemann, Ralph; Schlupp, Ingo

2016-01-01

Relatedness strongly influences social behaviors in a wide variety of species. For most species, the highest typical degree of relatedness is between full siblings with 50% shared genes. However, this is poorly understood in species with unusually high relatedness between individuals: clonal organisms. Although there has been some investigation into clonal invertebrates and yeast, nothing is known about kin selection in clonal vertebrates. We show that a clonal fish, the Amazon molly (Poecilia formosa), can distinguish between different clonal lineages, associating with genetically identical, sister clones, and use multiple sensory modalities. Also, they scale their aggressive behaviors according to the relatedness to other females: they are more aggressive to non-related clones. Our results demonstrate that even in species with very small genetic differences between individuals, kin recognition can be adaptive. Their discriminatory abilities and regulation of costly behaviors provides a powerful example of natural selection in species with limited genetic diversity. PMID:27483372

Modeling of genetic gain for single traits from marker-assisted seedling selection in clonally propagated crops

PubMed Central

Ru, Sushan; Hardner, Craig; Carter, Patrick A; Evans, Kate; Main, Dorrie; Peace, Cameron

2016-01-01

Seedling selection identifies superior seedlings as candidate cultivars based on predicted genetic potential for traits of interest. Traditionally, genetic potential is determined by phenotypic evaluation. With the availability of DNA tests for some agronomically important traits, breeders have the opportunity to include DNA information in their seedling selection operations—known as marker-assisted seedling selection. A major challenge in deploying marker-assisted seedling selection in clonally propagated crops is a lack of knowledge in genetic gain achievable from alternative strategies. Existing models based on additive effects considering seed-propagated crops are not directly relevant for seedling selection of clonally propagated crops, as clonal propagation captures all genetic effects, not just additive. This study modeled genetic gain from traditional and various marker-based seedling selection strategies on a single trait basis through analytical derivation and stochastic simulation, based on a generalized seedling selection scheme of clonally propagated crops. Various trait-test scenarios with a range of broad-sense heritability and proportion of genotypic variance explained by DNA markers were simulated for two populations with different segregation patterns. Both derived and simulated results indicated that marker-based strategies tended to achieve higher genetic gain than phenotypic seedling selection for a trait where the proportion of genotypic variance explained by marker information was greater than the broad-sense heritability. Results from this study provides guidance in optimizing genetic gain from seedling selection for single traits where DNA tests providing marker information are available. PMID:27148453

Reconstruction of cartilage with clonal mesenchymal stem cell-acellular dermal matrix in cartilage defect model in nonhuman primates.

PubMed

Ma, Anlun; Jiang, Li; Song, Lijun; Hu, Yanxin; Dun, Hao; Daloze, Pierre; Yu, Yonglin; Jiang, Jianyuan; Zafarullah, Muhammad; Chen, Huifang

2013-07-01

Articular cartilage defects are commonly associated with trauma, inflammation and osteoarthritis. Mesenchymal stem cell (MSC)-based therapy is a promising novel approach for repairing articular cartilage. Direct intra-articular injection of uncommitted MSCs does not regenerate high-quality cartilage. This study explored utilization of a new three-dimensional, selected chondrogenic clonal MSC-loaded monkey acellular dermal matrix (MSC-ADM) scaffold to repair damaged cartilage in an experimental model of knee joint cartilage defect in Cynomolgus monkeys. MSCs were characterized for cell size, cell yield, phenotypes, proliferation and chondrogenic differentiation capacity. Chondrogenic differentiation assays were performed at different MSC passages by sulfated glycosaminoglycans (sGAG), collagen, and fluorescence activated cell sorter (FACS) analysis. Selected chondrogenic clonal MSCs were seeded onto ADM scaffold with the sandwich model and MSC-loaded ADM grafts were analyzed by confocal microscopy and scanning electron microscopy. Cartilage defects were treated with normal saline, clonal MSCs and clonal MSC-ADM grafts, respectively. The clinical parameters, and histological and immunohistochemical examinations were evaluated at weeks 8, 16, 24 post-treatment, respectively. Polyclonal and clonal MSCs could differentiate into the chondrogenic lineage after stimulation with suitable chondrogenic factors. They expressed mesenchymal markers and were negative for hematopoietic markers. Articular cartilage defects were considerably improved and repaired by selected chondrogenic clonal MSC-based treatment, particularly, in MSC-ADM-treated group. The histological scores in MSC-ADM-treated group were consistently higher than those of other groups. Our results suggest that selected chondrogenic clonal MSC-loaded ADM grafts could improve the cartilage lesions in Cynomolgus monkey model, which may be applicable for repairing similar human cartilage defects. Copyright © 2013 Elsevier B.V. All rights reserved.

The maintenance of sex: Ronald Fisher meets the Red Queen.

PubMed

Green, David; Mason, Chris

2013-08-21

Sex in higher diploids carries a two-fold cost of males that should reduce its fitness relative to cloning, and result in its extinction. Instead, sex is widespread and clonal species face early obsolescence. One possible reason is that sex is an adaptation that allows organisms to respond more effectively to endless changes in their environment. The purpose of this study was to model mutation and selection in a diploid organism in an evolving environment and ascertain their support for sex. We used a computational approach to model finite populations where a haploid environment subjects a diploid host to endlessly evolving change. Evolution in both populations is primarily through adoption of novel advantageous mutations within a large allele space. Sex outcompetes cloning by two complementary mechanisms. First, sexual diploids adopt advantageous homozygous mutations more rapidly than clonal ones under conditions of lag load (the gap between the actual adaptation of the diploid population and its theoretical optimum). This rate advantage can offset the higher fecundity of cloning. Second, a relative advantage to sex emerges where populations are significantly polymorphic, because clonal polymorphism runs the risk of clonal interference caused by selection on numerous lines of similar adaptation. This interference extends allele lifetime and reduces the rate of adaptation. Sex abolishes the interference, making selection faster and elevating population fitness. Differences in adaptation between sexual and clonal populations increase markedly with the number of loci under selection, the rate of mutation in the host, and a rapidly evolving environment. Clonal interference in these circumstances leads to conditions where the greater fecundity of clones is unable to offset their poor adaptation. Sexual and clonal populations then either co-exist, or sex emerges as the more stable evolutionary strategy. Sex can out-compete clones in a rapidly evolving environment, such as that characterized by pathogens, where clonal interference reduces the adaptation of clonal populations and clones adopt advantageous mutations more slowly. Since all organisms carry parasitic loads, the model is of potentially general applicability.

Bambus 2: scaffolding metagenomes.

PubMed

Koren, Sergey; Treangen, Todd J; Pop, Mihai

2011-11-01

Sequencing projects increasingly target samples from non-clonal sources. In particular, metagenomics has enabled scientists to begin to characterize the structure of microbial communities. The software tools developed for assembling and analyzing sequencing data for clonal organisms are, however, unable to adequately process data derived from non-clonal sources. We present a new scaffolder, Bambus 2, to address some of the challenges encountered when analyzing metagenomes. Our approach relies on a combination of a novel method for detecting genomic repeats and algorithms that analyze assembly graphs to identify biologically meaningful genomic variants. We compare our software to current assemblers using simulated and real data. We demonstrate that the repeat detection algorithms have higher sensitivity than current approaches without sacrificing specificity. In metagenomic datasets, the scaffolder avoids false joins between distantly related organisms while obtaining long-range contiguity. Bambus 2 represents a first step toward automated metagenomic assembly. Bambus 2 is open source and available from http://amos.sf.net. mpop@umiacs.umd.edu. Supplementary data are available at Bioinformatics online.

Bambus 2: scaffolding metagenomes

PubMed Central

Koren, Sergey; Treangen, Todd J.; Pop, Mihai

2011-01-01

Motivation: Sequencing projects increasingly target samples from non-clonal sources. In particular, metagenomics has enabled scientists to begin to characterize the structure of microbial communities. The software tools developed for assembling and analyzing sequencing data for clonal organisms are, however, unable to adequately process data derived from non-clonal sources. Results: We present a new scaffolder, Bambus 2, to address some of the challenges encountered when analyzing metagenomes. Our approach relies on a combination of a novel method for detecting genomic repeats and algorithms that analyze assembly graphs to identify biologically meaningful genomic variants. We compare our software to current assemblers using simulated and real data. We demonstrate that the repeat detection algorithms have higher sensitivity than current approaches without sacrificing specificity. In metagenomic datasets, the scaffolder avoids false joins between distantly related organisms while obtaining long-range contiguity. Bambus 2 represents a first step toward automated metagenomic assembly. Availability: Bambus 2 is open source and available from http://amos.sf.net. Contact: mpop@umiacs.umd.edu Supplementary Information: Supplementary data are available at Bioinformatics online. PMID:21926123

Bacterial clonal diagnostics as a tool for evidence-based empiric antibiotic selection

PubMed Central

Tchesnokova, Veronika; Avagyan, Hovhannes; Rechkina, Elena; Chan, Diana; Muradova, Mariya; Haile, Helen Ghirmai; Radey, Matthew; Weissman, Scott; Riddell, Kim; Scholes, Delia; Johnson, James R.

2017-01-01

Despite the known clonal distribution of antibiotic resistance in many bacteria, empiric (pre-culture) antibiotic selection still relies heavily on species-level cumulative antibiograms, resulting in overuse of broad-spectrum agents and excessive antibiotic/pathogen mismatch. Urinary tract infections (UTIs), which account for a large share of antibiotic use, are caused predominantly by Escherichia coli, a highly clonal pathogen. In an observational clinical cohort study of urgent care patients with suspected UTI, we assessed the potential for E. coli clonal-level antibiograms to improve empiric antibiotic selection. A novel PCR-based clonotyping assay was applied to fresh urine samples to rapidly detect E. coli and the urine strain's clonotype. Based on a database of clonotype-specific antibiograms, the acceptability of various antibiotics for empiric therapy was inferred using a 20%, 10%, and 30% allowed resistance threshold. The test's performance characteristics and possible effects on prescribing were assessed. The rapid test identified E. coli clonotypes directly in patients’ urine within 25–35 minutes, with high specificity and sensitivity compared to culture. Antibiotic selection based on a clonotype-specific antibiogram could reduce the relative likelihood of antibiotic/pathogen mismatch by ≥ 60%. Compared to observed prescribing patterns, clonal diagnostics-guided antibiotic selection could safely double the use of trimethoprim/sulfamethoxazole and minimize fluoroquinolone use. In summary, a rapid clonotyping test showed promise for improving empiric antibiotic prescribing for E. coli UTI, including reversing preferential use of fluoroquinolones over trimethoprim/sulfamethoxazole. The clonal diagnostics approach merges epidemiologic surveillance, antimicrobial stewardship, and molecular diagnostics to bring evidence-based medicine directly to the point of care. PMID:28350870

Bacterial clonal diagnostics as a tool for evidence-based empiric antibiotic selection.

PubMed

Tchesnokova, Veronika; Avagyan, Hovhannes; Rechkina, Elena; Chan, Diana; Muradova, Mariya; Haile, Helen Ghirmai; Radey, Matthew; Weissman, Scott; Riddell, Kim; Scholes, Delia; Johnson, James R; Sokurenko, Evgeni V

2017-01-01

Despite the known clonal distribution of antibiotic resistance in many bacteria, empiric (pre-culture) antibiotic selection still relies heavily on species-level cumulative antibiograms, resulting in overuse of broad-spectrum agents and excessive antibiotic/pathogen mismatch. Urinary tract infections (UTIs), which account for a large share of antibiotic use, are caused predominantly by Escherichia coli, a highly clonal pathogen. In an observational clinical cohort study of urgent care patients with suspected UTI, we assessed the potential for E. coli clonal-level antibiograms to improve empiric antibiotic selection. A novel PCR-based clonotyping assay was applied to fresh urine samples to rapidly detect E. coli and the urine strain's clonotype. Based on a database of clonotype-specific antibiograms, the acceptability of various antibiotics for empiric therapy was inferred using a 20%, 10%, and 30% allowed resistance threshold. The test's performance characteristics and possible effects on prescribing were assessed. The rapid test identified E. coli clonotypes directly in patients' urine within 25-35 minutes, with high specificity and sensitivity compared to culture. Antibiotic selection based on a clonotype-specific antibiogram could reduce the relative likelihood of antibiotic/pathogen mismatch by ≥ 60%. Compared to observed prescribing patterns, clonal diagnostics-guided antibiotic selection could safely double the use of trimethoprim/sulfamethoxazole and minimize fluoroquinolone use. In summary, a rapid clonotyping test showed promise for improving empiric antibiotic prescribing for E. coli UTI, including reversing preferential use of fluoroquinolones over trimethoprim/sulfamethoxazole. The clonal diagnostics approach merges epidemiologic surveillance, antimicrobial stewardship, and molecular diagnostics to bring evidence-based medicine directly to the point of care.

CLImAT-HET: detecting subclonal copy number alterations and loss of heterozygosity in heterogeneous tumor samples from whole-genome sequencing data.

PubMed

Yu, Zhenhua; Li, Ao; Wang, Minghui

2017-03-15

Copy number alterations (CNA) and loss of heterozygosity (LOH) represent a large proportion of genetic structural variations of cancer genomes. These aberrations are continuously accumulated during the procedure of clonal evolution and patterned by phylogenetic branching. This invariably results in the emergence of multiple cell populations with distinct complement of mutational landscapes in tumor sample. With the advent of next-generation sequencing technology, inference of subclonal populations has become one of the focused interests in cancer-associated studies, and is usually based on the assessment of combinations of somatic single-nucleotide variations (SNV), CNA and LOH. However, cancer samples often have several inherent issues, such as contamination of normal stroma, tumor aneuploidy and intra-tumor heterogeneity. Addressing these critical issues is imperative for accurate profiling of clonal architecture. We present CLImAT-HET, a computational method designed for capturing clonal diversity in the CNA/LOH dimensions by taking into account the intra-tumor heterogeneity issue, in the case where a reference or matched normal sample is absent. The algorithm quantitatively represents the clonal identification problem using a factorial hidden Markov model, and takes an integrated analysis of read counts and allele frequency data. It is able to infer subclonal CNA and LOH events as well as the fraction of cells harboring each event. The results on simulated datasets indicate that CLImAT-HET has high power to identify CNA/LOH segments, it achieves an average accuracy of 0.87. It can also accurately infer proportion of each clonal population with an overall Pearson correlation coefficient of 0.99 and a mean absolute error of 0.02. CLImAT-HET shows significant advantages when compared with other existing methods. Application of CLImAT-HET to 5 primary triple negative breast cancer samples demonstrates its ability to capture clonal diversity in the CAN/LOH dimensions. It detects two clonal populations in one sample, and three clonal populations in one other sample. CLImAT-HET, a novel algorithm is introduced to infer CNA/LOH segments from heterogeneous tumor samples. We demonstrate CLImAT-HET's ability to accurately recover clonal compositions using tumor WGS data without a match normal sample.

Clonal propagation of eucalyptus in Brazilian nurseries

Treesearch

Ken McNabb; Natal Goncalves; Jose Goncalves

2002-01-01

Brazil has established extensive Eucalyptus plantations to support a growing forest products industry. During the past 25 years, the country has been a pioneer in developing clonal propagation systems to regenerate these highly productive plantations. Original clonal selections optimized disease resistance, coppicing ability, and volume growth, while recent priorities...

Natural and Chemotherapy-Induced Clonal Evolution of Tumors.

PubMed

Ibragimova, M K; Tsyganov, M M; Litviakov, N V

2017-04-01

Evolution and natural selection of tumoral clones in the process of transformation and the following carcinogenesis can be called natural clonal evolution. Its main driving factors are internal: genetic instability initiated by driver mutations and microenvironment, which enables selective pressure while forming the environment for cell transformation and their survival. We present our overview of contemporary research dealing with mechanisms of carcinogenesis in different localizations from precancerous pathologies to metastasis and relapse. It shows that natural clonal evolution establishes intratumoral heterogeneity and enables tumor progression. Tumors of monoclonal origin are of low-level intratumoral heterogeneity in the initial stages, and this increases with the size of the tumor. Tumors of polyclonal origin are of extremely high-level intratumoral heterogeneity in the initial stages and become more homogeneous when larger due to clonal expansion. In cases of chemotherapy-induced clonal evolution of a tumor, chemotherapy becomes the leading factor in treatment. The latest research shows that the impact of chemotherapy can radically increase the speed of clonal evolution and lead to new malignant and resistant clones that cause tumor metastasis. Another option of chemotherapy-induced clonal evolution is formation of a new dominant clone from a clone that was minor in the initial tumor and obtained free space due to elimination of sensitive clones by chemotherapy. As a result, in ~20% of cases, chemotherapy can stimulate metastasis and relapse of tumors due to clonal evolution. The conclusion of the overview formulates approaches to tumor treatment based on clonal evolution: in particular, precision therapy, prediction of metastasis stimulation in patients treated with chemotherapy, methods of genetic evaluation of chemotherapy efficiency and clonal-oriented treatment, and approaches to manipulating the clonal evolution of tumors are presented.

Deep sequencing is an appropriate tool for the selection of unique Hepatitis C virus (HCV) variants after single genomic amplification.

PubMed

Guinoiseau, Thibault; Moreau, Alain; Hohnadel, Guillaume; Ngo-Giang-Huong, Nicole; Brulard, Celine; Vourc'h, Patrick; Goudeau, Alain; Gaudy-Graffin, Catherine

2017-01-01

Hepatitis C virus (HCV) evolves rapidly in a single host and circulates as a quasispecies wich is a complex mixture of genetically distinct virus's but closely related namely variants. To identify intra-individual diversity and investigate their functional properties in vitro, it is necessary to define their quasispecies composition and isolate the HCV variants. This is possible using single genome amplification (SGA). This technique, based on serially diluted cDNA to amplify a single cDNA molecule (clonal amplicon), has already been used to determine individual HCV diversity. In these studies, positive PCR reactions from SGA were directly sequenced using Sanger technology. The detection of non-clonal amplicons is necessary for excluding them to facilitate further functional analysis. Here, we compared Next Generation Sequencing (NGS) with De Novo assembly and Sanger sequencing for their ability to distinguish clonal and non-clonal amplicons after SGA on one plasma specimen. All amplicons (n = 42) classified as clonal by NGS were also classified as clonal by Sanger sequencing. No double peaks were seen on electropherograms for non-clonal amplicons with position-specific nucleotide variation below 15% by NGS. Altogether, NGS circumvented many of the difficulties encountered when using Sanger sequencing after SGA and is an appropriate tool to reliability select clonal amplicons for further functional studies.

Deep sequencing is an appropriate tool for the selection of unique Hepatitis C virus (HCV) variants after single genomic amplification

PubMed Central

Guinoiseau, Thibault; Moreau, Alain; Hohnadel, Guillaume; Ngo-Giang-Huong, Nicole; Brulard, Celine; Vourc’h, Patrick; Goudeau, Alain; Gaudy-Graffin, Catherine

2017-01-01

Hepatitis C virus (HCV) evolves rapidly in a single host and circulates as a quasispecies wich is a complex mixture of genetically distinct virus’s but closely related namely variants. To identify intra-individual diversity and investigate their functional properties in vitro, it is necessary to define their quasispecies composition and isolate the HCV variants. This is possible using single genome amplification (SGA). This technique, based on serially diluted cDNA to amplify a single cDNA molecule (clonal amplicon), has already been used to determine individual HCV diversity. In these studies, positive PCR reactions from SGA were directly sequenced using Sanger technology. The detection of non-clonal amplicons is necessary for excluding them to facilitate further functional analysis. Here, we compared Next Generation Sequencing (NGS) with De Novo assembly and Sanger sequencing for their ability to distinguish clonal and non-clonal amplicons after SGA on one plasma specimen. All amplicons (n = 42) classified as clonal by NGS were also classified as clonal by Sanger sequencing. No double peaks were seen on electropherograms for non-clonal amplicons with position-specific nucleotide variation below 15% by NGS. Altogether, NGS circumvented many of the difficulties encountered when using Sanger sequencing after SGA and is an appropriate tool to reliability select clonal amplicons for further functional studies. PMID:28362878

Invasive alien plants benefit more from clonal integration in heterogeneous environments than natives.

PubMed

Wang, Yong-Jian; Müller-Schärer, Heinz; van Kleunen, Mark; Cai, Ai-Ming; Zhang, Ping; Yan, Rong; Dong, Bi-Cheng; Yu, Fei-Hai

2017-12-01

What confers invasive alien plants a competitive advantage over native plants remains open to debate. Many of the world's worst invasive alien plants are clonal and able to share resources within clones (clonal integration), particularly in heterogeneous environments. Here, we tested the hypothesis that clonal integration benefits invasive clonal plants more than natives and thus confers invasives a competitive advantage. We selected five congeneric and naturally co-occurring pairs of invasive alien and native clonal plants in China, and grew pairs of connected and disconnected ramets under heterogeneous light, soil nutrient and water conditions that are commonly encountered by alien plants during their invasion into new areas. Clonal integration increased biomass of all plants in all three heterogeneous resource environments. However, invasive plants benefited more from clonal integration than natives. Consequently, invasive plants produced more biomass than natives. Our results indicate that clonal integration may confer invasive alien clonal plants a competitive advantage over natives. Therefore, differences in the ability of clonal integration could potentially explain, at least partly, the invasion success of alien clonal plants in areas where resources are heterogeneously distributed. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Ecological Consequences of Clonal Integration in Plants

PubMed Central

Liu, Fenghong; Liu, Jian; Dong, Ming

2016-01-01

Clonal plants are widespread throughout the plant kingdom and dominate in diverse habitats. Spatiotemporal heterogeneity of environment is pervasive at multiple scales, even at scales relevant to individual plants. Clonal integration refers to resource translocation and information communication among the ramets of clonal plants. Due to clonal integration, clonal plant species possess a series of peculiar attributes: plasticity in response to local and non-local conditions, labor division with organ specialization for acquiring locally abundant resources, foraging behavior by selective placement of ramets in resource-rich microhabitats, and avoidance of intraclonal competition. Clonal integration has very profound ecological consequences for clonal plants. It allows them to efficiently cope with environmental heterogeneity, by alleviating local resource shortages, buffering environmental stresses and disturbances, influencing competitive ability, increasing invasiveness, and altering species composition and invasibility at the community level. In this paper, we present a comprehensive review of research on the ecological consequences of plant clonal integration based on a large body of literature. We also attempt to propose perspectives for future research. PMID:27446093

Disruptive chemicals, senescence and immortality

PubMed Central

Carnero, Amancio; Blanco-Aparicio, Carmen; Kondoh, Hiroshi; Lleonart, Matilde E.; Martinez-Leal, Juan Fernando; Mondello, Chiara; Ivana Scovassi, A.; Bisson, William H.; Amedei, Amedeo; Roy, Rabindra; Woodrick, Jordan; Colacci, Annamaria; Vaccari, Monica; Raju, Jayadev; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Salem, Hosni K.; Memeo, Lorenzo; Forte, Stefano; Singh, Neetu; Hamid, Roslida A.; Ryan, Elizabeth P.; Brown, Dustin G.; Wise, John Pierce; Wise, Sandra S.; Yasaei, Hemad

2015-01-01

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated ‘selection and succession’ of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of ‘driver mutations’ enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes. PMID:26106138

Artificial immune system algorithm in VLSI circuit configuration

NASA Astrophysics Data System (ADS)

Mansor, Mohd. Asyraf; Sathasivam, Saratha; Kasihmuddin, Mohd Shareduwan Mohd

2017-08-01

In artificial intelligence, the artificial immune system is a robust bio-inspired heuristic method, extensively used in solving many constraint optimization problems, anomaly detection, and pattern recognition. This paper discusses the implementation and performance of artificial immune system (AIS) algorithm integrated with Hopfield neural networks for VLSI circuit configuration based on 3-Satisfiability problems. Specifically, we emphasized on the clonal selection technique in our binary artificial immune system algorithm. We restrict our logic construction to 3-Satisfiability (3-SAT) clauses in order to outfit with the transistor configuration in VLSI circuit. The core impetus of this research is to find an ideal hybrid model to assist in the VLSI circuit configuration. In this paper, we compared the artificial immune system (AIS) algorithm (HNN-3SATAIS) with the brute force algorithm incorporated with Hopfield neural network (HNN-3SATBF). Microsoft Visual C++ 2013 was used as a platform for training, simulating and validating the performances of the proposed network. The results depict that the HNN-3SATAIS outperformed HNN-3SATBF in terms of circuit accuracy and CPU time. Thus, HNN-3SATAIS can be used to detect an early error in the VLSI circuit design.

Marker-based estimates reveal significant non-additive effects in clonally propagated cassava (Manihot esculenta): implications for the prediction of total genetic value and the selection of varieties

USDA-ARS?s Scientific Manuscript database

In clonally propagated crops, non-additive genetic effects can be effectively exploited by the identification of superior genetic individuals as varieties. Cassava (Manihot esculenta Crantz) is a clonally propagated staple food crop that feeds hundreds of millions. We quantified the amount and natur...

QML-AiNet: An immune network approach to learning qualitative differential equation models

PubMed Central

Pang, Wei; Coghill, George M.

2015-01-01

In this paper, we explore the application of Opt-AiNet, an immune network approach for search and optimisation problems, to learning qualitative models in the form of qualitative differential equations. The Opt-AiNet algorithm is adapted to qualitative model learning problems, resulting in the proposed system QML-AiNet. The potential of QML-AiNet to address the scalability and multimodal search space issues of qualitative model learning has been investigated. More importantly, to further improve the efficiency of QML-AiNet, we also modify the mutation operator according to the features of discrete qualitative model space. Experimental results show that the performance of QML-AiNet is comparable to QML-CLONALG, a QML system using the clonal selection algorithm (CLONALG). More importantly, QML-AiNet with the modified mutation operator can significantly improve the scalability of QML and is much more efficient than QML-CLONALG. PMID:25648212

QML-AiNet: An immune network approach to learning qualitative differential equation models.

PubMed

Pang, Wei; Coghill, George M

2015-02-01

In this paper, we explore the application of Opt-AiNet, an immune network approach for search and optimisation problems, to learning qualitative models in the form of qualitative differential equations. The Opt-AiNet algorithm is adapted to qualitative model learning problems, resulting in the proposed system QML-AiNet. The potential of QML-AiNet to address the scalability and multimodal search space issues of qualitative model learning has been investigated. More importantly, to further improve the efficiency of QML-AiNet, we also modify the mutation operator according to the features of discrete qualitative model space. Experimental results show that the performance of QML-AiNet is comparable to QML-CLONALG, a QML system using the clonal selection algorithm (CLONALG). More importantly, QML-AiNet with the modified mutation operator can significantly improve the scalability of QML and is much more efficient than QML-CLONALG.

Clonality, genetic diversity and support for the diversifying selection hypothesis in natural populations of a flower-living yeast.

PubMed

Herrera, C M; Pozo, M I; Bazaga, P

2011-11-01

Vast amounts of effort have been devoted to investigate patterns of genetic diversity and structuring in plants and animals, but similar information is scarce for organisms of other kingdoms. The study of the genetic structure of natural populations of wild yeasts can provide insights into the ecological and genetic correlates of clonality, and into the generality of recent hypotheses postulating that microbial populations lack the potential for genetic divergence and allopatric speciation. Ninety-one isolates of the flower-living yeast Metschnikowia gruessii from southeastern Spain were DNA fingerprinted using amplified fragment length polymorphism (AFLP) markers. Genetic diversity and structuring was investigated with band-based methods and model- and nonmodel-based clustering. Linkage disequilibrium tests were used to assess reproduction mode. Microsite-dependent, diversifying selection was tested by comparing genetic characteristics of isolates from bumble bee vectors and different floral microsites. AFLP polymorphism (91%) and genotypic diversity were very high. Genetic diversity was spatially structured, as shown by amova (Φ(st)  = 0.155) and clustering. The null hypothesis of random mating was rejected, clonality seeming the prevailing reproductive mode in the populations studied. Genetic diversity of isolates declined from bumble bee mouthparts to floral microsites, and frequency of five AFLP markers varied significantly across floral microsites, thus supporting the hypothesis of diversifying selection on clonal lineages. Wild populations of clonal fungal microbes can exhibit levels of genetic diversity and spatial structuring that are not singularly different from those shown by sexually reproducing plants or animals. Microsite-dependent, divergent selection can maintain high local and regional genetic diversity in microbial populations despite extensive clonality. © 2011 Blackwell Publishing Ltd.

Disruptive chemicals, senescence and immortality.

PubMed

Carnero, Amancio; Blanco-Aparicio, Carmen; Kondoh, Hiroshi; Lleonart, Matilde E; Martinez-Leal, Juan Fernando; Mondello, Chiara; Scovassi, A Ivana; Bisson, William H; Amedei, Amedeo; Roy, Rabindra; Woodrick, Jordan; Colacci, Annamaria; Vaccari, Monica; Raju, Jayadev; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Salem, Hosni K; Memeo, Lorenzo; Forte, Stefano; Singh, Neetu; Hamid, Roslida A; Ryan, Elizabeth P; Brown, Dustin G; Wise, John Pierce; Wise, Sandra S; Yasaei, Hemad

2015-06-01

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Inferring a Population Structure for Staphylococcus epidermidis from Multilocus Sequence Typing Data▿

PubMed Central

Miragaia, M.; Thomas, J. C.; Couto, I.; Enright, M. C.; de Lencastre, H.

2007-01-01

Despite its importance as a human pathogen, information on population structure and global epidemiology of Staphylococcus epidermidis is scarce and the relative importance of the mechanisms contributing to clonal diversification is unknown. In this study, we addressed these issues by analyzing a representative collection of S. epidermidis isolates from diverse geographic and clinical origins using multilocus sequence typing (MLST). Additionally, we characterized the mobile element (SCCmec) carrying the genetic determinant of methicillin resistance. The 217 S. epidermidis isolates from our collection were split by MLST into 74 types, suggesting a high level of genetic diversity. Analysis of MLST data using the eBURST algorithm revealed the existence of nine epidemic clonal lineages that were disseminated worldwide. One single clonal lineage (clonal complex 2) comprised 74% of the isolates, whereas the remaining isolates were clustered into 8 minor clonal lineages and 13 singletons. According to our evolutionary model, SCCmec was acquired at least 56 times by S. epidermidis. Although geographic dissemination of S. epidermidis strains and the value of the index of association between the alleles, 0.2898 (P < 0.05), support the clonality of S. epidermidis species, examination of the sequence changes at MLST loci during clonal diversification showed that recombination gives rise to new alleles approximately twice as frequently as point mutations. We suggest that S. epidermidis has a population with an epidemic structure, in which nine clones have emerged upon a recombining background and evolved quickly through frequent transfer of genetic mobile elements, including SCCmec. PMID:17220222

Aging, clonal hematopoiesis and preleukemia: not just bad luck?

PubMed

Shlush, Liran I; Zandi, Sasan; Itzkovitz, Shalev; Schuh, Andre C

2015-11-01

Chronological human aging is associated with a number of changes in the hematopoietic system, occurring at many levels from stem to mature cells, and the marrow microenvironment as well. This review will focus mainly on the aging of hematopoietic stem and progenitor cells (HSPCs), and on the associated increases in the incidence of hematological malignancies. HSPCs manifest reduced function and acquire molecular changes with chronological aging. Furthermore, while for many years it has been known that the human hematopoietic system becomes increasingly clonal with chronological aging (clonal hematopoiesis), only in the last few years has it become clear that clonal hematopoiesis may result from the accumulation of preleukemic mutations in HSPCs. Such mutations confer a selective advantage that leads to clonal hematopoiesis, and that may occasionally result in the development of leukemia, and define the existence of both preleukemic stem cells, and of 'preleukemia' as a clinical entity. While it is well appreciated that clonal hematopoiesis is very common in the elderly, several questions remain unanswered: why and how does clonal hematopoiesis develop? How is clonal hematopoiesis related to the age-related changes observed in the hematopoietic system? And why do only some individuals with clonal hematopoiesis develop leukemia?

Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles.

PubMed

Ostrovnaya, Irina; Seshan, Venkatraman E; Olshen, Adam B; Begg, Colin B

2011-06-15

If a cancer patient develops multiple tumors, it is sometimes impossible to determine whether these tumors are independent or clonal based solely on pathological characteristics. Investigators have studied how to improve this diagnostic challenge by comparing the presence of loss of heterozygosity (LOH) at selected genetic locations of tumor samples, or by comparing genomewide copy number array profiles. We have previously developed statistical methodology to compare such genomic profiles for an evidence of clonality. We assembled the software for these tests in a new R package called 'Clonality'. For LOH profiles, the package contains significance tests. The analysis of copy number profiles includes a likelihood ratio statistic and reference distribution, as well as an option to produce various plots that summarize the results. Bioconductor (http://bioconductor.org/packages/release/bioc/html/Clonality.html) and http://www.mskcc.org/mskcc/html/13287.cfm.

Predicting distant failure in early stage NSCLC treated with SBRT using clinical parameters.

PubMed

Zhou, Zhiguo; Folkert, Michael; Cannon, Nathan; Iyengar, Puneeth; Westover, Kenneth; Zhang, Yuanyuan; Choy, Hak; Timmerman, Robert; Yan, Jingsheng; Xie, Xian-J; Jiang, Steve; Wang, Jing

2016-06-01

The aim of this study is to predict early distant failure in early stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) using clinical parameters by machine learning algorithms. The dataset used in this work includes 81 early stage NSCLC patients with at least 6months of follow-up who underwent SBRT between 2006 and 2012 at a single institution. The clinical parameters (n=18) for each patient include demographic parameters, tumor characteristics, treatment fraction schemes, and pretreatment medications. Three predictive models were constructed based on different machine learning algorithms: (1) artificial neural network (ANN), (2) logistic regression (LR) and (3) support vector machine (SVM). Furthermore, to select an optimal clinical parameter set for the model construction, three strategies were adopted: (1) clonal selection algorithm (CSA) based selection strategy; (2) sequential forward selection (SFS) method; and (3) statistical analysis (SA) based strategy. 5-cross-validation is used to validate the performance of each predictive model. The accuracy was assessed by area under the receiver operating characteristic (ROC) curve (AUC), sensitivity and specificity of the system was also evaluated. The AUCs for ANN, LR and SVM were 0.75, 0.73, and 0.80, respectively. The sensitivity values for ANN, LR and SVM were 71.2%, 72.9% and 83.1%, while the specificity values for ANN, LR and SVM were 59.1%, 63.6% and 63.6%, respectively. Meanwhile, the CSA based strategy outperformed SFS and SA in terms of AUC, sensitivity and specificity. Based on clinical parameters, the SVM with the CSA optimal parameter set selection strategy achieves better performance than other strategies for predicting distant failure in lung SBRT patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Complete and Draft Genome Sequences of Nine Lactobacillus sakei Strains Selected from the Three Known Phylogenetic Lineages and Their Main Clonal Complexes.

PubMed

Loux, Valentin; Coeuret, Gwendoline; Zagorec, Monique; Champomier Vergès, Marie-Christine; Chaillou, Stéphane

2018-04-19

We present here the complete and draft genome sequences of nine Lactobacillus sakei strains, selected from the entire range of clonal complexes from the three known lineages of the species. The strains were chosen to provide a wide view of pangenomic and plasmidic diversity for this important foodborne species. Copyright © 2018 Loux et al.

Clonal tests of new cottonwood selections from the southeast

Treesearch

Jonathan Paul Jeffreys; Samuel B. Land; Emily B. Schultz; Andrew J. Londo

2006-01-01

One hundred “new” clones and 20 “check” clones were established with unrooted cuttings during March-April 2003 in a second-stage clonal trial in Missouri and Georgia. The new clones had been selected for 2-year superiority in Melampsora leaf rust resistance, height growth, and diameter growth during first-stage rooted cutting trials. All 120 clones were vegetatively...

Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla

PubMed Central

McCaughtry, Tom M.; Baldwin, Troy A.; Wilken, Matthew S.; Hogquist, Kristin A.

2008-01-01

The thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the cortex. Cortical epithelial cells are vital for positive selection, but whether such cells can also promote negative selection is controversial. We used the HYcd4 model, where T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the thymic cortex. However, the kinetics in vivo indicated that apoptosis was activated asynchronously relative to TCR activation. We found that radioresistant antigen-presenting cells and, specifically, cortical epithelial cells do not efficiently induce apoptosis, although they do cause TCR activation. Rather, thymocytes undergoing clonal deletion were preferentially associated with rare CD11c+ cortical dendritic cells, and elimination of such cells impaired deletion. PMID:18936237

Flower-deficient mice have reduced susceptibility to skin papilloma formation

PubMed Central

Petrova, Evgeniya; López-Gay, Jesús M.; Rhiner, Christa; Moreno, Eduardo

2012-01-01

SUMMARY Skin papillomas arise as a result of clonal expansion of mutant cells. It has been proposed that the expansion of pretumoral cell clones is propelled not only by the increased proliferation capacity of mutant cells, but also by active cell selection. Previous studies in Drosophila describe a clonal selection process mediated by the Flower (Fwe) protein, whereby cells that express certain Fwe isoforms are recognized and forced to undergo apoptosis. It was further shown that knock down of fwe expression in Drosophila can prevent the clonal expansion of dMyc-overexpressing pretumoral cells. Here, we study the function of the single predicted mouse homolog of Drosophila Fwe, referred to as mFwe, by clonal overexpression of mFwe isoforms in Drosophila and by analyzing mFwe knock-out mice. We show that clonal overexpression of certain mFwe isoforms in Drosophila also triggers non-autonomous cell death, suggesting that Fwe function is evolutionarily conserved. Although mFwe-deficient mice display a normal phenotype, they develop a significantly lower number of skin papillomas upon exposure to DMBA/TPA two-stage skin carcinogenesis than do treated wild-type and mFwe heterozygous mice. Furthermore, mFwe expression is higher in papillomas and the papilloma-surrounding skin of treated wild-type mice compared with the skin of untreated wild-type mice. Thus, we propose that skin papilloma cells take advantage of mFwe activity to facilitate their clonal expansion. PMID:22362363

Beating the odds: The poisson distribution of all input cells during limiting dilution grossly underestimates whether a cell line is clonally-derived or not.

PubMed

Zhou, Yizhou; Shaw, David; Lam, Cynthia; Tsukuda, Joni; Yim, Mandy; Tang, Danming; Louie, Salina; Laird, Michael W; Snedecor, Brad; Misaghi, Shahram

2017-09-23

Establishing that a cell line was derived from a single cell progenitor and defined as clonally-derived for the production of clinical and commercial therapeutic protein drugs has been the subject of increased emphasis in cell line development (CLD). Several regulatory agencies have expressed that the prospective probability of clonality for CHO cell lines is assumed to follow the Poisson distribution based on the input cell count. The probability of obtaining monoclonal progenitors based on the Poisson distribution of all cells suggests that one round of limiting dilution may not be sufficient to assure the resulting cell lines are clonally-derived. We experimentally analyzed clonal derivatives originating from single cell cloning (SCC) via one round of limiting dilution, following our standard legacy cell line development practice. Two cell populations with stably integrated DNA spacers were mixed and subjected to SCC via limiting dilution. Cells were cultured in the presence of selection agent, screened, and ranked based on product titer. Post-SCC, the growing cell lines were screened by PCR analysis for the presence of identifying spacers. We observed that the percentage of nonclonal populations was below 9%, which is considerably lower than the determined probability based on the Poisson distribution of all cells. These results were further confirmed using fluorescence imaging of clonal derivatives originating from SCC via limiting dilution of mixed cell populations expressing GFP or RFP. Our results demonstrate that in the presence of selection agent, the Poisson distribution of all cells clearly underestimates the probability of obtaining clonally-derived cell lines. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 2017. © 2017 American Institute of Chemical Engineers.

Clonality and serotypes of Streptococcus mutans among children by multilocus sequence typing

PubMed Central

Momeni, Stephanie S.; Whiddon, Jennifer; Cheon, Kyounga; Moser, Stephen A.; Childers, Noel K.

2015-01-01

Studies using multilocus sequence typing (MLST) have demonstrated that Streptococcus mutans isolates are genetically diverse. Our laboratory previously demonstrated clonality of S. mutans using MLST but could not discount the possibility of sampling bias. In this study, the clonality of randomly selected S. mutans plaque isolates from African American children was examined using MLST. Serotype and presence of collagen-binding proteins (CBP) cnm/cbm were also assessed. One hundred S. mutans isolates were randomly selected for MLST analysis. Sequence analysis was performed and phylogenetic trees were generated using START2 and MEGA. Thirty-four sequence types (ST) were identified of which 27 were unique to this population. Seventy-five percent of the isolates clustered into 16 clonal groups. Serotypes observed were c (n=84), e (n=3), and k (n=11). The prevalence of S. mutans isolates serotype k was notably high at 17.5%. All isolates were cnm/cbm negative. The clonality of S. mutans demonstrated in this study illustrates the importance of localized populations studies and are consistent with transmission. The prevalence of serotype k, a recently proposed systemic pathogen, observed in this study is higher than reported in most populations and is the first report of S. mutans serotype k in a US population. PMID:26443288

Restricted T cell receptor repertoire in CLL-like monoclonal B cell lymphocytosis and early stage CLL.

PubMed

Blanco, Gonzalo; Vardi, Anna; Puiggros, Anna; Gómez-Llonín, Andrea; Muro, Manuel; Rodríguez-Rivera, María; Stalika, Evangelia; Abella, Eugenia; Gimeno, Eva; López-Sánchez, Manuela; Senín, Alicia; Calvo, Xavier; Abrisqueta, Pau; Bosch, Francesc; Ferrer, Ana; Stamatopoulos, Kostas; Espinet, Blanca

2018-01-01

Analysis of the T cell receptor (TR) repertoire of chronic lymphocytic leukemia-like monoclonal B cell lymphocytosis (CLL-like MBL) and early stage CLL is relevant for understanding the dynamic interaction of expanded B cell clones with bystander T cells. Here we profiled the T cell receptor β chain (TRB) repertoire of the CD4 + and CD8 + T cell fractions from 16 CLL-like MBL and 13 untreated, Binet stage A/Rai stage 0 CLL patients using subcloning analysis followed by Sanger sequencing. The T cell subpopulations of both MBL and early stage CLL harbored restricted TRB gene repertoire, with CD4 + T cell clonal expansions whose frequency followed the numerical increase of clonal B cells. Longitudinal analysis in MBL cases revealed clonal persistence, alluding to persistent antigen stimulation. In addition, the identification of shared clonotypes among different MBL/early stage CLL cases pointed towards selection of the T cell clones by common antigenic elements. T cell clonotypes previously described in viral infections and immune disorders were also detected. Altogether, our findings evidence that antigen-mediated TR restriction occurs early in clonal evolution leading to CLL and may further increase together with B cell clonal expansion, possibly suggesting that the T cell selecting antigens are tumor-related.

Panmictic and Clonal Evolution on a Single Patchy Resource Produces Polymorphic Foraging Guilds

PubMed Central

Getz, Wayne M.; Salter, Richard; Lyons, Andrew J.; Sippl-Swezey, Nicolas

2015-01-01

We develop a stochastic, agent-based model to study how genetic traits and experiential changes in the state of agents and available resources influence individuals’ foraging and movement behaviors. These behaviors are manifest as decisions on when to stay and exploit a current resource patch or move to a particular neighboring patch, based on information of the resource qualities of the patches and the anticipated level of intraspecific competition within patches. We use a genetic algorithm approach and an individual’s biomass as a fitness surrogate to explore the foraging strategy diversity of evolving guilds under clonal versus hermaphroditic sexual reproduction. We first present the resource exploitation processes, movement on cellular arrays, and genetic algorithm components of the model. We then discuss their implementation on the Nova software platform. This platform seamlessly combines the dynamical systems modeling of consumer-resource interactions with agent-based modeling of individuals moving over a landscapes, using an architecture that lays transparent the following four hierarchical simulation levels: 1.) within-patch consumer-resource dynamics, 2.) within-generation movement and competition mitigation processes, 3.) across-generation evolutionary processes, and 4.) multiple runs to generate the statistics needed for comparative analyses. The focus of our analysis is on the question of how the biomass production efficiency and the diversity of guilds of foraging strategy types, exploiting resources over a patchy landscape, evolve under clonal versus random hermaphroditic sexual reproduction. Our results indicate greater biomass production efficiency under clonal reproduction only at higher population densities, and demonstrate that polymorphisms evolve and are maintained under random mating systems. The latter result questions the notion that some type of associative mating structure is needed to maintain genetic polymorphisms among individuals exploiting a common patchy resource on an otherwise spatially homogeneous landscape. PMID:26274613

Prospects for Genomic Selection in Cassava Breeding.

PubMed

Wolfe, Marnin D; Del Carpio, Dunia Pino; Alabi, Olumide; Ezenwaka, Lydia C; Ikeogu, Ugochukwu N; Kayondo, Ismail S; Lozano, Roberto; Okeke, Uche G; Ozimati, Alfred A; Williams, Esuma; Egesi, Chiedozie; Kawuki, Robert S; Kulakow, Peter; Rabbi, Ismail Y; Jannink, Jean-Luc

2017-11-01

Cassava ( Crantz) is a clonally propagated staple food crop in the tropics. Genomic selection (GS) has been implemented at three breeding institutions in Africa to reduce cycle times. Initial studies provided promising estimates of predictive abilities. Here, we expand on previous analyses by assessing the accuracy of seven prediction models for seven traits in three prediction scenarios: cross-validation within populations, cross-population prediction and cross-generation prediction. We also evaluated the impact of increasing the training population (TP) size by phenotyping progenies selected either at random or with a genetic algorithm. Cross-validation results were mostly consistent across programs, with nonadditive models predicting of 10% better on average. Cross-population accuracy was generally low (mean = 0.18) but prediction of cassava mosaic disease increased up to 57% in one Nigerian population when data from another related population were combined. Accuracy across generations was poorer than within-generation accuracy, as expected, but accuracy for dry matter content and mosaic disease severity should be sufficient for rapid-cycling GS. Selection of a prediction model made some difference across generations, but increasing TP size was more important. With a genetic algorithm, selection of one-third of progeny could achieve an accuracy equivalent to phenotyping all progeny. We are in the early stages of GS for this crop but the results are promising for some traits. General guidelines that are emerging are that TPs need to continue to grow but phenotyping can be done on a cleverly selected subset of individuals, reducing the overall phenotyping burden. Copyright © 2017 Crop Science Society of America.

An atlas of B-cell clonal distribution in the human body.

PubMed

Meng, Wenzhao; Zhang, Bochao; Schwartz, Gregory W; Rosenfeld, Aaron M; Ren, Daqiu; Thome, Joseph J C; Carpenter, Dustin J; Matsuoka, Nobuhide; Lerner, Harvey; Friedman, Amy L; Granot, Tomer; Farber, Donna L; Shlomchik, Mark J; Hershberg, Uri; Luning Prak, Eline T

2017-09-01

B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks-one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.

Clonal evolution of chemotherapy-resistant urothelial carcinoma.

PubMed

Faltas, Bishoy M; Prandi, Davide; Tagawa, Scott T; Molina, Ana M; Nanus, David M; Sternberg, Cora; Rosenberg, Jonathan; Mosquera, Juan Miguel; Robinson, Brian; Elemento, Olivier; Sboner, Andrea; Beltran, Himisha; Demichelis, Francesca; Rubin, Mark A

2016-12-01

Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.

Clonal Evolution of Chemotherapy-resistant Urothelial Carcinoma

PubMed Central

Faltas, Bishoy M.; Prandi, Davide; Tagawa, Scott T.; Molina, Ana M.; Nanus, David M.; Sternberg, Cora; Rosenberg, Jonathan; Mosquera, Juan Miguel; Robinson, Brian; Elemento, Olivier; Sboner, Andrea; Beltran, Himisha; Demichelis, Francesca; Rubin, Mark A.

2017-01-01

Chemotherapy-resistant urothelial carcinoma (UC) has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs UC’s evolution and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 UCs including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated UC is characterized by intra-patient mutational heterogeneity and the majority of mutations are not shared, (ii) both branching evolution and metastatic spread are very early events in the natural history of UC; (iii) chemotherapy-treated UC is enriched with clonal mutations involving L1-cell adhesion molecule (L1CAM) and integrin signaling pathways; (iv) APOBEC induced-mutagenesis is clonally-enriched in chemotherapy-treated UC and continues to shape UC’s evolution throughout its lifetime. PMID:27749842

Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.

PubMed

Tarusawa, Etsuko; Sanbo, Makoto; Okayama, Atsushi; Miyashita, Toshio; Kitsukawa, Takashi; Hirayama, Teruyoshi; Hirabayashi, Takahiro; Hasegawa, Sonoko; Kaneko, Ryosuke; Toyoda, Shunsuke; Kobayashi, Toshihiro; Kato-Itoh, Megumi; Nakauchi, Hiromitsu; Hirabayashi, Masumi; Yagi, Takeshi; Yoshimura, Yumiko

2016-12-02

The specificity of synaptic connections is fundamental for proper neural circuit function. Specific neuronal connections that underlie information processing in the sensory cortex are initially established without sensory experiences to a considerable extent, and then the connections are individually refined through sensory experiences. Excitatory neurons arising from the same single progenitor cell are preferentially connected in the postnatal cortex, suggesting that cell lineage contributes to the initial wiring of neurons. However, the postnatal developmental process of lineage-dependent connection specificity is not known, nor how clonal neurons, which are derived from the same neural stem cell, are stamped with the identity of their common neural stem cell and guided to form synaptic connections. We show that cortical excitatory neurons that arise from the same neural stem cell and reside within the same layer preferentially establish reciprocal synaptic connections in the mouse barrel cortex. We observed a transient increase in synaptic connections between clonal but not nonclonal neuron pairs during postnatal development, followed by selective stabilization of the reciprocal connections between clonal neuron pairs. Furthermore, we demonstrate that selective stabilization of the reciprocal connections between clonal neuron pairs is impaired by the deficiency of DNA methyltransferase 3b (Dnmt3b), which determines DNA-methylation patterns of genes in stem cells during early corticogenesis. Dnmt3b regulates the postnatal expression of clustered protocadherin (cPcdh) isoforms, a family of adhesion molecules. We found that cPcdh deficiency in clonal neuron pairs impairs the whole process of the formation and stabilization of connections to establish lineage-specific connection reciprocity. Our results demonstrate that local, reciprocal neural connections are selectively formed and retained between clonal neurons in layer 4 of the barrel cortex during postnatal development, and that Dnmt3b and cPcdhs are required for the establishment of lineage-specific reciprocal connections. These findings indicate that lineage-specific connection reciprocity is predetermined by Dnmt3b during embryonic development, and that the cPcdhs contribute to postnatal cortical neuron identification to guide lineage-dependent synaptic connections in the neocortex.

The role of weak selection and high mutation rates in nearly neutral evolution.

PubMed

Lawson, Daniel John; Jensen, Henrik Jeldtoft

2009-04-21

Neutral dynamics occur in evolution if all types are 'effectively equal' in their reproductive success, where the definition of 'effectively equal' depends on the population size and the details of mutations. Empirically observed neutral genetic evolution in extremely large clonal populations can only be explained under current models if selection is completely absent. Such models typically consider the case where population dynamics occurs on a different timescale to evolution. However, this assumption is invalid when mutations are not rare in a whole population. We show that this has important consequences for the occurrence of neutral evolution in clonal populations. In highly connected type spaces, neutral dynamics can occur for all population sizes despite significant selective differences, via the forming of effectively neutral networks connecting rare neutral types. Biological implications include an explanation for the high diversity of rare types that survive in large clonal populations, and a theoretical justification for the use of neutral null models.

Selection for avian leukosis virus integration sites determines the clonal progression of B-cell lymphomas

PubMed Central

Malhotra, Sanandan; Justice, James; Morgan, Robin

2017-01-01

Avian leukosis virus (ALV) is a simple retrovirus that causes a wide range of tumors in chickens, the most common of which are B-cell lymphomas. The viral genome integrates into the host genome and uses its strong promoter and enhancer sequences to alter the expression of nearby genes, frequently inducing tumors. In this study, we compare the preferences for ALV integration sites in cultured cells and in tumors, by analysis of over 87,000 unique integration sites. In tissue culture we observed integration was relatively random with slight preferences for genes, transcription start sites and CpG islands. We also observed a preference for integrations in or near expressed and spliced genes. The integration pattern in cultured cells changed over the course of selection for oncogenic characteristics in tumors. In comparison to tissue culture, ALV integrations are more highly selected for proximity to transcription start sites in tumors. There is also a significant selection of ALV integrations away from CpG islands in the highly clonally expanded cells in tumors. Additionally, we utilized a high throughput method to quantify the magnitude of clonality in different stages of tumorigenesis. An ALV-induced tumor carries between 700 and 3000 unique integrations, with an average of 2.3 to 4 copies of proviral DNA per infected cell. We observed increasing tumor clonality during progression of B-cell lymphomas and identified gene players (especially TERT and MYB) and biological processes involved in tumor progression. PMID:29099869

Immortality of cancers

PubMed Central

Duesberg, Peter; McCormack, Amanda

2013-01-01

Immortality is a common characteristic of cancers, but its origin and purpose are still unclear. Here we advance a karyotypic theory of immortality based on the theory that carcinogenesis is a form of speciation. Accordingly, cancers are generated from normal cells by random karyotypic rearrangements and selection for cancer-specific reproductive autonomy. Since such rearrangements unbalance long-established mitosis genes, cancer karyotypes vary spontaneously but are stabilized perpetually by clonal selections for autonomy. To test this theory we have analyzed neoplastic clones, presumably immortalized by transfection with overexpressed telomerase or with SV40 tumor virus, for the predicted clonal yet flexible karyotypes. The following results were obtained: (1) All immortal tumorigenic lines from cells transfected with overexpressed telomerase had clonal and flexible karyotypes; (2) Searching for the origin of such karyotypes, we found spontaneously increasing, random aneuploidy in human fibroblasts early after transfection with overexpressed telomerase; (3) Late after transfection, new immortal tumorigenic clones with new clonal and flexible karyotypes were found; (4) Testing immortality of one clone during 848 unselected generations showed the chromosome number was stable, but the copy numbers of 36% of chromosomes drifted ± 1; (5) Independent immortal tumorigenic clones with individual, flexible karyotypes arose after individual latencies; (6) Immortal tumorigenic clones with new flexible karyotypes also arose late from cells of a telomerase-deficient mouse rendered aneuploid by SV40 virus. Because immortality and tumorigenicity: (1) correlated exactly with individual clonal but flexible karyotypes; (2) originated simultaneously with such karyotypes; and (3) arose in the absence of telomerase, we conclude that clonal and flexible karyotypes generate the immortality of cancers. PMID:23388461

Assessment of clonality and serotypes of Streptococcus mutans among children by multilocus sequence typing.

PubMed

Momeni, Stephanie S; Whiddon, Jennifer; Cheon, Kyounga; Moser, Stephen A; Childers, Noel K

2015-12-01

Studies using multilocus sequence typing (MLST) have demonstrated that Streptococcus mutans isolates are genetically diverse. Our laboratory previously demonstrated clonality of S. mutans using MLST but could not discount the possibility of sampling bias. In this study, the clonality of randomly selected S. mutans plaque isolates from African-American children was examined using MLST. Serotype and the presence of collagen-binding proteins (CBPs) encoded by cnm/cbm were also assessed. One-hundred S. mutans isolates were randomly selected for MLST analysis. Sequence analysis was performed and phylogenetic trees were generated using start2 and mega. Thirty-four sequence types were identified, of which 27 were unique to this population. Seventy-five per cent of the isolates clustered into 16 clonal groups. The serotypes observed were c (n = 84), e (n = 3), and k (n = 11). The prevalence of S. mutans isolates of serotype k was notably high, at 17.5%. All isolates were cnm/cbm negative. The clonality of S. mutans demonstrated in this study illustrates the importance of localized population studies and are consistent with transmission. The prevalence of serotype k, a recently proposed systemic pathogen, observed in this study, is higher than reported in most populations and is the first report of S. mutans serotype k in a United States population. © 2015 Eur J Oral Sci.

An artificial immune system approach with secondary response for misbehavior detection in mobile ad hoc networks.

PubMed

Sarafijanović, Slavisa; Le Boudec, Jean-Yves

2005-09-01

In mobile ad hoc networks, nodes act both as terminals and information relays, and they participate in a common routing protocol, such as dynamic source routing (DSR). The network is vulnerable to routing misbehavior, due to faulty or malicious nodes. Misbehavior detection systems aim at removing this vulnerability. In this paper, we investigate the use of an artificial immune system (AIS) to detect node misbehavior in a mobile ad hoc network using DSR. The system is inspired by the natural immune system (IS) of vertebrates. Our goal is to build a system that, like its natural counterpart, automatically learns, and detects new misbehavior. We describe our solution for the classification task of the AIS; it employs negative selection and clonal selection, the algorithms for learning and adaptation used by the natural IS. We define how we map the natural IS concepts such as self, antigen, and antibody to a mobile ad hoc network and give the resulting algorithm for classifying nodes as misbehaving. We implemented the system in the network simulator Glomosim; we present detection results and discuss how the system parameters affect the performance of primary and secondary response. Further steps will extend the design by using an analogy to the innate system, danger signal, and memory cells.

Automated analysis of clonal cancer cells by intravital imaging

PubMed Central

Coffey, Sarah Earley; Giedt, Randy J; Weissleder, Ralph

2013-01-01

Longitudinal analyses of single cell lineages over prolonged periods have been challenging particularly in processes characterized by high cell turn-over such as inflammation, proliferation, or cancer. RGB marking has emerged as an elegant approach for enabling such investigations. However, methods for automated image analysis continue to be lacking. Here, to address this, we created a number of different multicolored poly- and monoclonal cancer cell lines for in vitro and in vivo use. To classify these cells in large scale data sets, we subsequently developed and tested an automated algorithm based on hue selection. Our results showed that this method allows accurate analyses at a fraction of the computational time required by more complex color classification methods. Moreover, the methodology should be broadly applicable to both in vitro and in vivo analyses. PMID:24349895

Clinical implications of somatic mutations in aplastic anemia and myelodysplastic syndrome in genomic age.

PubMed

Maciejewski, Jaroslaw P; Balasubramanian, Suresh K

2017-12-08

Recent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution. © 2016 by The American Society of Hematology. All rights reserved.

Estimates of general combining ability in Hevea breeding at the Rubber Research Institute of Malaysia : I. Phases II and III A.

PubMed

Tan, H

1977-01-01

Estimates of general combining ability of parents for yield and girth obtained separately from seedlings and their corresponding clonal families in Phases II and IIIA of the RRIM breeding programme are compared. A highly significant positive correlation (r = 0.71***) is found between GCA estimates from seedling and clonal families for yield in Phase IIIA, but not in Phase II (r = -0.03(NS)) nor for girth (r= -0.27(NS)) in Phase IIIA. The correlations for Phase II yield and Phase IIIA girth, however, improve when the GCA estimates based on small sample size or reversed rankings are excluded.When the best selections (based on present clonal and seedling information) are compared, all five of the parents top-ranking for yield are common in Phase IIIA but only two parents are common for yield and girth in Phases II and IIIA respectively. However, only one parent for yield in Phase II and two parents for girth in Phase IIIA would, if selected on clonal performance, have been omitted from the top ranking selections made by previous workers using seedling information.These findings, therefore, justify the choice of parents based on GCA estimates for yield obtained from seedling performance. Similar justification cannot be offered for girth, for which analysis is confounded by uninterpretable site and seasonal effects.

Clonality in myeloproliferative disorders: Analysis by means of polymerase chain reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilliland, D.G.; Blanchard, K.L.; Levy, J.

1991-08-01

The myeloproliferative syndromes are acquired disorders of hematopoiesis that provide insights into the transition from somatic cell mutation to neoplasia. The clonal origin of specific blood cells can be assessed in patients with X chromosome-linked polymorphisms, taking advantage of random inactivation of the X chromosome. The authors have adapted the PCR for determination of clonality on as few as 100 cells, including individual colonies grown in culture. Amplifying a polymorphic portion of the X chromosome-linked phosphoglycerate kinase (PGK) gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme gave results fully concordant with standard Southern blottingmore » of DNA samples form normal (polyclonal) polymorphonuclear cells (PMN) as well as clonal PMN from patients with myelodysplastic syndrome and polycythemia vera (PCV). They have used this technique to demonstrate heterogeneity of lineage involvement in patients with PCV. The same clinical phenotype may arise from clonal proliferation of different hematopoietic progenitors.« less

Generation of genome-modified Drosophila cell lines using SwAP.

PubMed

Franz, Alexandra; Brunner, Erich; Basler, Konrad

2017-10-02

The ease of generating genetically modified animals and cell lines has been markedly increased by the recent development of the versatile CRISPR/Cas9 tool. However, while the isolation of isogenic cell populations is usually straightforward for mammalian cell lines, the generation of clonal Drosophila cell lines has remained a longstanding challenge, hampered by the difficulty of getting Drosophila cells to grow at low densities. Here, we describe a highly efficient workflow to generate clonal Cas9-engineered Drosophila cell lines using a combination of cell pools, limiting dilution in conditioned medium and PCR with allele-specific primers, enabling the efficient selection of a clonal cell line with a suitable mutation profile. We validate the protocol by documenting the isolation, selection and verification of eight independently Cas9-edited armadillo mutant Drosophila cell lines. Our method provides a powerful and simple workflow that improves the utility of Drosophila cells for genetic studies with CRISPR/Cas9.

Learning Effective Connectivity Network Structure from fMRI Data Based on Artificial Immune Algorithm

PubMed Central

Ji, Junzhong; Liu, Jinduo; Liang, Peipeng; Zhang, Aidong

2016-01-01

Many approaches have been designed to extract brain effective connectivity from functional magnetic resonance imaging (fMRI) data. However, few of them can effectively identify the connectivity network structure due to different defects. In this paper, a new algorithm is developed to infer the effective connectivity between different brain regions by combining artificial immune algorithm (AIA) with the Bayes net method, named as AIAEC. In the proposed algorithm, a brain effective connectivity network is mapped onto an antibody, and four immune operators are employed to perform the optimization process of antibodies, including clonal selection operator, crossover operator, mutation operator and suppression operator, and finally gets an antibody with the highest K2 score as the solution. AIAEC is then tested on Smith’s simulated datasets, and the effect of the different factors on AIAEC is evaluated, including the node number, session length, as well as the other potential confounding factors of the blood oxygen level dependent (BOLD) signal. It was revealed that, as contrast to other existing methods, AIAEC got the best performance on the majority of the datasets. It was also found that AIAEC could attain a relative better solution under the influence of many factors, although AIAEC was differently affected by the aforementioned factors. AIAEC is thus demonstrated to be an effective method for detecting the brain effective connectivity. PMID:27045295

Clonal hematopoiesis in acquired aplastic anemia.

PubMed

Ogawa, Seishi

2016-07-21

Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1 Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. © 2016 by The American Society of Hematology.

Clonal hematopoiesis in acquired aplastic anemia

PubMed Central

2016-01-01

Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. PMID:27121470

Effects of complex life cycles on genetic diversity: cyclical parthenogenesis.

PubMed

Rouger, R; Reichel, K; Malrieu, F; Masson, J P; Stoeckel, S

2016-11-01

Neutral patterns of population genetic diversity in species with complex life cycles are difficult to anticipate. Cyclical parthenogenesis (CP), in which organisms undergo several rounds of clonal reproduction followed by a sexual event, is one such life cycle. Many species, including crop pests (aphids), human parasites (trematodes) or models used in evolutionary science (Daphnia), are cyclical parthenogens. It is therefore crucial to understand the impact of such a life cycle on neutral genetic diversity. In this paper, we describe distributions of genetic diversity under conditions of CP with various clonal phase lengths. Using a Markov chain model of CP for a single locus and individual-based simulations for two loci, our analysis first demonstrates that strong departures from full sexuality are observed after only a few generations of clonality. The convergence towards predictions made under conditions of full clonality during the clonal phase depends on the balance between mutations and genetic drift. Second, the sexual event of CP usually resets the genetic diversity at a single locus towards predictions made under full sexuality. However, this single recombination event is insufficient to reshuffle gametic phases towards full-sexuality predictions. Finally, for similar levels of clonality, CP and acyclic partial clonality (wherein a fixed proportion of individuals are clonally produced within each generation) differentially affect the distribution of genetic diversity. Overall, this work provides solid predictions of neutral genetic diversity that may serve as a null model in detecting the action of common evolutionary or demographic processes in cyclical parthenogens (for example, selection or bottlenecks).

Cost of resistance to trematodes in freshwater snail populations with low clonal diversity.

PubMed

Dagan, Yael; Kosman, Evsey; Ben-Ami, Frida

2017-12-13

The persistence of high genetic variability in natural populations garners considerable interest among ecologists and evolutionary biologists. One proposed hypothesis for the maintenance of high levels of genetic diversity relies on frequency-dependent selection imposed by parasites on host populations (Red Queen hypothesis). A complementary hypothesis suggests that a trade-off between fitness costs associated with tolerance to stress factors and fitness costs associated with resistance to parasites is responsible for the maintenance of host genetic diversity. The present study investigated whether host resistance to parasites is traded off with tolerance to environmental stress factors (high/low temperatures, high salinity), by comparing populations of the freshwater snail Melanoides tuberculata with low vs. high clonal diversity. Since polyclonal populations were found to be more parasitized than populations with low clonal diversity, we expected them to be tolerant to environmental stress factors. We found that clonal diversity explained most of the variation in snail survival under high temperature, thereby suggesting that tolerance to high temperatures of clonally diverse populations is higher than that of populations with low clonal diversity. Our results suggest that resistance to parasites may come at a cost of reduced tolerance to certain environmental stress factors.

Clonal evolution models of tumor heterogeneity.

PubMed

Shlush, Liran I; Hershkovitz, Dov

2015-01-01

Somatic/clonal evolution is the process of sequential acquisition of vertically transmittable genetic/epigenetic elements in multicellular organisms. Cancer is the result of somatic evolution. Understanding the processes that shape the evolution of individual tumors might help us to treat cancer more efficiently. The initiating genetic/epigenetic events occur in functional cells and provide the cell of origin a selective advantage under a changing environment. The initiating genetic events tend to be enriched in specific tissues (and are sometimes specific for those tissues), as different tissues undergo different changes in the environment that will activate selective forces on different cells of origin. For the initial clonal expansion to occur premalignant clones need to have a relative fitness advantage over their competitors. It is estimated that the premalignant phase can take several years. Once the premalignant clonal expansion is established, the premalignant cells will contribute to the changing environment and will start competing among themselves. In late stages of cancer evolution the environmental changes might be similar across different tissues, including a lack of physical space, a shortage of energy, and activation of the immune system, and more and more of the hallmarks of cancer will evolve. In this review we will explore the possible clinical relevance of the heterogeneity that evolves during this long somatic evolution. Above all, it should be stressed that the earlier the clonal expansion is recognized, the less diverse and less fit for survival the cells in the population are.

Polymerase chain reaction-based clonality testing in tissue samples with reactive lymphoproliferations: usefulness and pitfalls. A report of the BIOMED-2 Concerted Action BMH4-CT98-3936.

PubMed

Langerak, A W; Molina, T J; Lavender, F L; Pearson, D; Flohr, T; Sambade, C; Schuuring, E; Al Saati, T; van Dongen, J J M; van Krieken, J H J M

2007-02-01

Lymphoproliferations are generally diagnosed via histomorphology and immunohistochemistry. Although mostly conclusive, occasionally the differential diagnosis between reactive lesions and malignant lymphomas is difficult. In such cases molecular clonality studies of immunoglobulin (Ig)/T-cell receptor (TCR) rearrangements can be useful. Here we address the issue of clonality assessment in 106 histologically defined reactive lesions, using the standardized BIOMED-2 Ig/TCR multiplex polymerase chain reaction (PCR) heteroduplex and GeneScan assays. Samples were reviewed nationally, except 10% random cases and cases with clonal results selected for additional international panel review. In total 75% (79/106) only showed polyclonal Ig/TCR targets (type I), whereas another 15% (16/106) represent probably polyclonal cases, with weak Ig/TCR (oligo)clonality in an otherwise polyclonal background (type II). Interestingly, in 10% (11/106) clear monoclonal Ig/TCR products were observed (types III/IV), which prompted further pathological review. Clonal cases included two missed lymphomas in national review and nine cases that could be explained as diagnostically difficult cases or probable lymphomas upon additional review. Our data show that the BIOMED-2 Ig/TCR multiplex PCR assays are very helpful in confirming the polyclonal character in the vast majority of reactive lesions. However, clonality detection in a minority should lead to detailed pathological review, including close interaction between pathologist and molecular biologist.

Age and distribution of an evergreen clonal shrub in the Coweeta basin: Rhododendron maximum L

Treesearch

Katherine J. Elliott; James M. Vose

2012-01-01

Rhododendron maximum L. is an evergreen, clonal shrub that forms a dominant sub-canopy layer and is a key species in southern Appalachian forests. We investigated the age and distribution of R. maximum across the Coweeta Basin, a 1626 ha watershed in western North Carolina. We selected 16 perennial, second-order streams and used a Global Positioning System to establish...

Construction of a transfer vector for a clonal isolate of LdNPV

Treesearch

Shivanand T. Hiremath; Martha Fikes; Audrey Ichida

1991-01-01

Deoxyribonucleic acid from a clonal isolate of LdNPV (CI A2-1), obtained by in vivo cloning procedures, was used to construct genomic libraries in phage (lamda Gem 11) and cosmid (pHC79) vectors. Overlapping clones were selected to generate a restriction enzyme map. The restriction enzyme map, covering about 85% of the CI A2-1 genome, was determined...

Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus

PubMed Central

Leedham, S J; Preston, S L; McDonald, S A C; Elia, G; Bhandari, P; Poller, D; Harrison, R; Novelli, M R; Jankowski, J A; Wright, N A

2008-01-01

Objectives: Current models of clonal expansion in human Barrett’s oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett’s segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett’s metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types. Methods: Individual crypts across Barrett’s biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns, p16 and p53 point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed. Results: Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a p16 point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett’s dysplasia. Conclusions: By studying clonality at the crypt level we demonstrate that Barrett’s heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett’s metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands. PMID:18305067

Effects of complex life cycles on genetic diversity: cyclical parthenogenesis

PubMed Central

Rouger, R; Reichel, K; Malrieu, F; Masson, J P; Stoeckel, S

2016-01-01

Neutral patterns of population genetic diversity in species with complex life cycles are difficult to anticipate. Cyclical parthenogenesis (CP), in which organisms undergo several rounds of clonal reproduction followed by a sexual event, is one such life cycle. Many species, including crop pests (aphids), human parasites (trematodes) or models used in evolutionary science (Daphnia), are cyclical parthenogens. It is therefore crucial to understand the impact of such a life cycle on neutral genetic diversity. In this paper, we describe distributions of genetic diversity under conditions of CP with various clonal phase lengths. Using a Markov chain model of CP for a single locus and individual-based simulations for two loci, our analysis first demonstrates that strong departures from full sexuality are observed after only a few generations of clonality. The convergence towards predictions made under conditions of full clonality during the clonal phase depends on the balance between mutations and genetic drift. Second, the sexual event of CP usually resets the genetic diversity at a single locus towards predictions made under full sexuality. However, this single recombination event is insufficient to reshuffle gametic phases towards full-sexuality predictions. Finally, for similar levels of clonality, CP and acyclic partial clonality (wherein a fixed proportion of individuals are clonally produced within each generation) differentially affect the distribution of genetic diversity. Overall, this work provides solid predictions of neutral genetic diversity that may serve as a null model in detecting the action of common evolutionary or demographic processes in cyclical parthenogens (for example, selection or bottlenecks). PMID:27436524

Somatic clonal evolution: A selection-centric perspective.

PubMed

Scott, Jacob; Marusyk, Andriy

2017-04-01

It is generally accepted that the initiation and progression of cancers is the result of somatic clonal evolution. Despite many peculiarities, evolution within populations of somatic cells should obey the same Darwinian principles as evolution within natural populations, i.e. variability of heritable phenotypes provides the substrate for context-specific selection forces leading to increased population frequencies of phenotypes, which are better adapted to their environment. Yet, within cancer biology, the more prevalent way to view evolution is as being entirely driven by the accumulation of "driver" mutations. Context-specific selection forces are either ignored, or viewed as constraints from which tumor cells liberate themselves during the course of malignant progression. In this review, we will argue that explicitly focusing on selection forces acting on the populations of neoplastic cells as the driving force of somatic clonal evolution might provide for a more accurate conceptual framework compared to the mutation-centric driver gene paradigm. Whereas little can be done to counteract the "bad luck" of stochastic occurrences of cancer-related mutations, changes in selective pressures and the phenotypic adaptations they induce can, in principle, be exploited to limit the incidence of cancers and to increase the efficiency of existing and future therapies. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby. Copyright © 2017 Elsevier B.V. All rights reserved.

Dynamic changes in clonal cytogenetic architecture during progression of chronic lymphocytic leukemia in patients and patient-derived murine xenografts

PubMed Central

Davies, Nicholas J.; Kwok, Marwan; Gould, Clive; Oldreive, Ceri E.; Mao, Jingwen; Parry, Helen; Smith, Edward; Agathanggelou, Angelo; Pratt, Guy; Taylor, Alexander Malcolm R.; Moss, Paul; Griffiths, Mike; Stankovic, Tatjana

2017-01-01

Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies. PMID:28496009

South American Plasmodium falciparum after the Malaria Eradication Era: Clonal Population Expansion and Survival of the Fittest Hybrids

PubMed Central

Griffing, Sean M.; Mixson-Hayden, Tonya; Sridaran, Sankar; Alam, Md Tauqeer; McCollum, Andrea M.; Cabezas, César; Marquiño Quezada, Wilmer; Barnwell, John W.; Macedo De Oliveira, Alexandre; Lucas, Carmen; Arrospide, Nancy; Escalante, Ananias A.; Bacon, David J.; Udhayakumar, Venkatachalam

2011-01-01

Malaria has reemerged in many regions where once it was nearly eliminated. Yet the source of these parasites, the process of repopulation, their population structure, and dynamics are ill defined. Peru was one of malaria eradication's successes, where Plasmodium falciparum was nearly eliminated for two decades. It reemerged in the 1990s. In the new era of malaria elimination, Peruvian P. falciparum is a model of malaria reinvasion. We investigated its population structure and drug resistance profiles. We hypothesized that only populations adapted to local ecological niches could expand and repopulate and originated as vestigial populations or recent introductions. We investigated the genetic structure (using microsatellites) and drug resistant genotypes of 220 parasites collected from patients immediately after peak epidemic expansion (1999–2000) from seven sites across the country. The majority of parasites could be grouped into five clonal lineages by networks and AMOVA. The distribution of clonal lineages and their drug sensitivity profiles suggested geographic structure. In 2001, artesunate combination therapy was introduced in Peru. We tested 62 parasites collected in 2006–2007 for changes in genetic structure. Clonal lineages had recombined under selection for the fittest parasites. Our findings illustrate that local adaptations in the post-eradication era have contributed to clonal lineage expansion. Within the shifting confluence of drug policy and malaria incidence, populations continue to evolve through genetic outcrossing influenced by antimalarial selection pressure. Understanding the population substructure of P. falciparum has implications for vaccine, drug, and epidemiologic studies, including monitoring malaria during and after the elimination phase. PMID:21949680

Cancer evolution, mutations, and clonal selection in relapse neuroblastoma.

PubMed

Schulte, Marc; Köster, Johannes; Rahmann, Sven; Schramm, Alexander

2018-05-01

The notion of cancer as a complex evolutionary system has been validated by in-depth molecular analyses of tumor progression over the last years. While a complex interplay of cell-autonomous programs and cell-cell interactions determines proliferation and differentiation during normal development, intrinsic and acquired plasticity of cancer cells allow for evasion of growth factor limitations, apoptotic signals, or attacks from the immune system. Treatment-induced molecular selection processes have been described by a number of studies already, but understanding of those events facilitating metastatic spread, organ-specific homing, and resistance to anoikis is still in its early days. In principle, somatic events giving rise to cancer progression should be easier to follow in childhood tumors bearing fewer mutations and genomic aberrations than their counterparts in adulthood. We have previously reported on the genetic events accompanying relapsing neuroblastoma, a solid tumor of early childhood. Our results indicated significantly higher single nucleotide variants in relapse tumors, gave hints for branched tumor evolution upon treatment and clonal selection as deduced from shifts in allelic frequencies between primary and relapsing neuroblastoma. Here, we will review these findings and give an outlook on dealing with intratumoral heterogeneity and sub-clonal diversity in neuroblastoma for future targeted treatments.

Managing the rate of increase in average co-ancestry in a rolling front tree breeding strategy.

PubMed

Kerr, R J; McRae, T A; Dutkowski, G W; Tier, B

2015-04-01

In breeding forest trees, as for livestock, the goal is to capture as much genetic gain as possible for the breeding objective, while limiting long- and short-term inbreeding. The Southern Tree Breeding Association (STBA) is responsible for breeding Australia's two main commercial forest tree species and has adopted algorithms and methods commonly used in animal breeding to achieve this balance. Discrete generation breeding is the norm for most tree breeding programmes. However, the STBA uses an overlapping generation strategy, with a new stream of breeding initiated each year. A feature of the species bred by the STBA (Pinus radiata and Eucalyptus globulus) is the long interval (up to 7 years) between when an individual is mated and when its progeny is first assessed in field trials and performance data included in the national performance database. Mate selection methods must therefore recognize the large pool of unmeasured progeny generated over recent years of crossing. In addition, the substantial delay between when an individual is selected in a field trial and when it is clonally copied into a mating facility (breeding arboretum) means that selection and mating must occur as a two-step process. In this article, we describe modifications to preselection and mate selection algorithms that allow unmeasured progeny (juveniles) to be recognized. We also demonstrate that the addition of hypothetical new progeny to the juvenile pool is important for computing the increase in average co-ancestry in the population. Methods outlined in this article may have relevance to animal breeding programmes where between mating and progeny measurement, new rounds of mating are initiated. © 2015 Blackwell Verlag GmbH.

Commentary on: "Clonal evolution of chemotherapy-resistant urothelial carcinoma." Faltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, Rosenberg J, Mosquera JM, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA.: Nat Genet. 2016 Oct 17. http://dx.doi.org/10.1038/ng.3692.

PubMed

Lee, Byron H

2017-09-01

Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights that are as follows: (1) chemotherapy-treated urothelial carcinoma is characterized by intrapatient mutational heterogeneity, and most mutations are not shared; (2) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (3) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell-adhesion molecule and integrin signaling pathways; and (4) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime. Copyright © 2017 Elsevier Inc. All rights reserved.

The association between polyploidy and clonal reproduction in diploid and tetraploid Chamerion angustifolium.

PubMed

Baldwin, Sarah J; Husband, Brian C

2013-04-01

Clonal reproduction is associated with the incidence of polyploidy in flowering plants. This pattern may arise through selection for increased clonality in polyploids compared to diploids to reduce mixed-ploidy mating. Here, we test whether clonal reproduction is greater in tetraploid than diploid populations of the mixed-ploidy plant, Chamerion angustifolium, through an analysis of the size and spatial distribution of clones in natural populations using AFLP genotyping and a comparison of root bud production in a greenhouse study. Natural tetraploid populations (N = 5) had significantly more AFLP genotypes (x¯ = 10.8) than diploid populations (x¯ = 6.0). Tetraploid populations tended to have fewer ramets per genotype and fewer genotypes with >1 ramet. In a spatial autocorrelation analysis, ramets within genotypes were more spatially aggregated in diploid populations than in tetraploid populations. In the greenhouse, tetraploids allocated 90.4% more dry mass to root buds than diploids, but tetraploids produced no more root buds and 44% fewer root buds per unit root mass than diploids. Our results indicate that clonal reproduction is significant in most populations, but tetraploid populations are not more clonal than diploids, nor are their clones more spatially aggregated. As a result, tetraploids may be less sheltered from mixed-ploidy mating and diploids more exposed to inbreeding, the balance of which could influence the establishment of tetraploids in diploid populations. © 2013 Blackwell Publishing Ltd.

Variegated clonality and rapid emergence of new molecular lesions in xenografts of acute lymphoblastic leukemia are associated with drug resistance.

PubMed

Nowak, Daniel; Liem, Natalia L M; Mossner, Maximilian; Klaumünzer, Marion; Papa, Rachael A; Nowak, Verena; Jann, Johann C; Akagi, Tadayuki; Kawamata, Norihiko; Okamoto, Ryoko; Thoennissen, Nils H; Kato, Motohiro; Sanada, Masashi; Hofmann, Wolf-Karsten; Ogawa, Seishi; Marshall, Glenn M; Lock, Richard B; Koeffler, H Phillip

2015-01-01

The use of genome-wide copy-number analysis and massive parallel sequencing has revolutionized the understanding of the clonal architecture of pediatric acute lymphoblastic leukemia (ALL) by demonstrating that this disease is composed of highly variable clonal ancestries following the rules of Darwinian selection. The current study aimed to analyze the molecular composition of childhood ALL biopsies and patient-derived xenografts with particular emphasis on mechanisms associated with acquired chemoresistance. Genomic DNA from seven primary pediatric ALL patient samples, 29 serially passaged xenografts, and six in vivo selected chemoresistant xenografts were analyzed with 250K single-nucleotide polymorphism arrays. Copy-number analysis of non-drug-selected xenografts confirmed a highly variable molecular pattern of variegated subclones. Whereas primary patient samples from initial diagnosis displayed a mean of 5.7 copy-number alterations per sample, serially passaged xenografts contained a mean of 8.2 and chemoresistant xenografts a mean of 10.5 copy-number alterations per sample, respectively. Resistance to cytarabine was explained by a new homozygous deletion of the DCK gene, whereas methotrexate resistance was associated with monoallelic deletion of FPGS and mutation of the remaining allele. This study demonstrates that selecting for chemoresistance in xenografted human ALL cells can reveal novel mechanisms associated with drug resistance. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Based Upon Repeat Pattern (BURP): an algorithm to characterize the long-term evolution of Staphylococcus aureus populations based on spa polymorphisms.

PubMed

Mellmann, Alexander; Weniger, Thomas; Berssenbrügge, Christoph; Rothgänger, Jörg; Sammeth, Michael; Stoye, Jens; Harmsen, Dag

2007-10-29

For typing of Staphylococcus aureus, DNA sequencing of the repeat region of the protein A (spa) gene is a well established discriminatory method for outbreak investigations. Recently, it was hypothesized that this region also reflects long-term epidemiology. However, no automated and objective algorithm existed to cluster different repeat regions. In this study, the Based Upon Repeat Pattern (BURP) implementation that is a heuristic variant of the newly described EDSI algorithm was investigated to infer the clonal relatedness of different spa types. For calibration of BURP parameters, 400 representative S. aureus strains with different spa types were characterized by MLST and clustered using eBURST as "gold standard" for their phylogeny. Typing concordance analysis between eBURST and BURP clustering (spa-CC) were performed using all possible BURP parameters to determine their optimal combination. BURP was subsequently evaluated with a strain collection reflecting the breadth of diversity of S. aureus (JCM 2002; 40:4544). In total, the 400 strains exhibited 122 different MLST types. eBURST grouped them into 23 clonal complexes (CC; 354 isolates) and 33 singletons (46 isolates). BURP clustering of spa types using all possible parameter combinations and subsequent comparison with eBURST CCs resulted in concordances ranging from 8.2 to 96.2%. However, 96.2% concordance was reached only if spa types shorter than 8 repeats were excluded, which resulted in 37% excluded spa types. Therefore, the optimal combination of the BURP parameters was "exclude spa types shorter than 5 repeats" and "cluster spa types into spa-CC if cost distances are less than 4" exhibiting 95.3% concordance to eBURST. This algorithm identified 24 spa-CCs, 40 singletons, and excluded only 7.8% spa types. Analyzing the natural population with these parameters, the comparison of whole-genome micro-array groupings (at the level of 0.31 Pearson correlation index) and spa-CCs gave a concordance of 87.1%; BURP spa-CCs vs. manually grouped spa types resulted in 95.7% concordance. BURP is the first automated and objective tool to infer clonal relatedness from spa repeat regions. It is able to extract an evolutionary signal rather congruent to MLST and micro-array data.

Clonal yeast biofilms can reap competitive advantages through cell differentiation without being obligatorily multicellular

PubMed Central

Hanghøj, Kristian Ebbesen; Andersen, Kaj Scherz; Boomsma, Jacobus J.

2016-01-01

How differentiation between cell types evolved is a fundamental question in biology, but few studies have explored single-gene phenotypes that mediate first steps towards division of labour with selective advantage for groups of cells. Here, we show that differential expression of the FLO11 gene produces stable fractions of Flo11+ and Flo11− cells in clonal Saccharomyces cerevisiae biofilm colonies on medium with intermediate viscosity. Differentiated Flo11+/− colonies, consisting of adhesive and non-adhesive cells, obtain a fourfold growth advantage over undifferentiated colonies by overgrowing glucose resources before depleting them, rather than depleting them while they grow as undifferentiated Flo11− colonies do. Flo11+/− colonies maintain their structure and differentiated state by switching non-adhesive cells to adhesive cells with predictable probability. Mixtures of Flo11+ and Flo11− cells from mutant strains that are unable to use this epigenetic switch mechanism produced neither integrated colonies nor growth advantages, so the condition-dependent selective advantages of differentiated FLO11 expression can only be reaped by clone-mate cells. Our results show that selection for cell differentiation in clonal eukaryotes can evolve before the establishment of obligate undifferentiated multicellularity, and without necessarily leading to more advanced organizational complexity. PMID:27807261

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.

PubMed

Clappier, Emmanuelle; Gerby, Bastien; Sigaux, François; Delord, Marc; Touzri, Farah; Hernandez, Lucie; Ballerini, Paola; Baruchel, André; Pflumio, Françoise; Soulier, Jean

2011-04-11

Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.

Rapid high-throughput cloning and stable expression of antibodies in HEK293 cells.

PubMed

Spidel, Jared L; Vaessen, Benjamin; Chan, Yin Yin; Grasso, Luigi; Kline, J Bradford

2016-12-01

Single-cell based amplification of immunoglobulin variable regions is a rapid and powerful technique for cloning antigen-specific monoclonal antibodies (mAbs) for purposes ranging from general laboratory reagents to therapeutic drugs. From the initial screening process involving small quantities of hundreds or thousands of mAbs through in vitro characterization and subsequent in vivo experiments requiring large quantities of only a few, having a robust system for generating mAbs from cloning through stable cell line generation is essential. A protocol was developed to decrease the time, cost, and effort required by traditional cloning and expression methods by eliminating bottlenecks in these processes. Removing the clonal selection steps from the cloning process using a highly efficient ligation-independent protocol and from the stable cell line process by utilizing bicistronic plasmids to generate stable semi-clonal cell pools facilitated an increased throughput of the entire process from plasmid assembly through transient transfections and selection of stable semi-clonal cell pools. Furthermore, the time required by a single individual to clone, express, and select stable cell pools in a high-throughput format was reduced from 4 to 6months to only 4 to 6weeks. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Dispersion of Multidrug-Resistant Enterococcus faecium Isolates Belonging to Major Clonal Complexes in Different Portuguese Settings▿

PubMed Central

Freitas, Ana R.; Novais, Carla; Ruiz-Garbajosa, Patricia; Coque, Teresa M.; Peixe, Luísa

2009-01-01

The population structure of 56 Enterococcus faecium isolates selected from a collection of enterococci from humans, animals, and the environment in Portugal (1997 to 2007) was analyzed by multilocus sequence typing. We identified 41 sequence types clustering into CC17, CC5, CC9, CC22 and CC94, all clonal lineages comprising isolates from different hosts. Our findings highlight the role of community-associated hosts as reservoirs of enterococci able to cause human infections. PMID:19447948

In-depth genome analyses of viruses from vaccine-derived rabies cases and corresponding live-attenuated oral rabies vaccines.

PubMed

Pfaff, Florian; Müller, Thomas; Freuling, Conrad M; Fehlner-Gardiner, Christine; Nadin-Davis, Susan; Robardet, Emmanuelle; Cliquet, Florence; Vuta, Vlad; Hostnik, Peter; Mettenleiter, Thomas C; Beer, Martin; Höper, Dirk

2018-02-10

Live-attenuated rabies virus strains such as those derived from the field isolate Street Alabama Dufferin (SAD) have been used extensively and very effectively as oral rabies vaccines for the control of fox rabies in both Europe and Canada. Although these vaccines are safe, some cases of vaccine-derived rabies have been detected during rabies surveillance accompanying these campaigns. In recent analysis it was shown that some commercial SAD vaccines consist of diverse viral populations, rather than clonal genotypes. For cases of vaccine-derived rabies, only consensus sequence data have been available to date and information concerning their population diversity was thus lacking. In our study, we used high-throughput sequencing to analyze 11 cases of vaccine-derived rabies, and compared their viral population diversity to the related oral rabies vaccines using pairwise Manhattan distances. This extensive deep sequencing analysis of vaccine-derived rabies cases observed during oral vaccination programs provided deeper insights into the effect of accidental in vivo replication of genetically diverse vaccine strains in the central nervous system of target and non-target species under field conditions. The viral population in vaccine-derived cases appeared to be clonal in contrast to their parental vaccines. The change from a state of high population diversity present in the vaccine batches to a clonal genotype in the affected animal may indicate the presence of a strong bottleneck during infection. In conclusion, it is very likely that these few cases are the consequence of host factors and not the result of the selection of a more virulent genotype. Furthermore, this type of vaccine-derived rabies leads to the selection of clonal genotypes and the selected variants were genetically very similar to potent SAD vaccines that have undergone a history of in vitro selection. Copyright © 2018. Published by Elsevier Ltd.

“Epidemic Clones” of Listeria monocytogenes Are Widespread and Ancient Clonal Groups

PubMed Central

Cantinelli, Thomas; Chenal-Francisque, Viviane; Diancourt, Laure; Frezal, Lise; Leclercq, Alexandre; Wirth, Thierry

2013-01-01

The food-borne pathogen Listeria monocytogenes is genetically heterogeneous. Although some clonal groups have been implicated in multiple outbreaks, there is currently no consensus on how “epidemic clones” should be defined. The objectives of this work were to compare the patterns of sequence diversity on two sets of genes that have been widely used to define L. monocytogenes clonal groups: multilocus sequence typing (MLST) and multi-virulence-locus sequence typing (MvLST). Further, we evaluated the diversity within clonal groups by pulsed-field gel electrophoresis (PFGE). Based on 125 isolates of diverse temporal, geographical, and source origins, MLST and MvLST genes (i) had similar patterns of sequence polymorphisms, recombination, and selection, (ii) provided concordant phylogenetic clustering, and (iii) had similar discriminatory power, which was not improved when we combined both data sets. Inclusion of representative strains of previous outbreaks demonstrated the correspondence of epidemic clones with previously recognized MLST clonal complexes. PFGE analysis demonstrated heterogeneity within major clones, most of which were isolated decades before their involvement in outbreaks. We conclude that the “epidemic clone” denominations represent a redundant but largely incomplete nomenclature system for MLST-defined clones, which must be regarded as successful genetic groups that are widely distributed across time and space. PMID:24006010

Mobile dune fixation by a fast-growing clonal plant: a full life-cycle analysis.

PubMed

Li, Shou-Li; Yu, Fei-Hai; Werger, Marinus J A; Dong, Ming; During, Heinjo J; Zuidema, Pieter A

2015-03-11

Desertification is a global environmental problem, and arid dunes with sparse vegetation are especially vulnerable to desertification. One way to combat desertification is to increase vegetation cover by planting plant species that can realize fast population expansion, even in harsh environments. To evaluate the success of planted species and provide guidance for selecting proper species to stabilize active dunes, demographic studies in natural habitats are essential. We studied the life history traits and population dynamics of a dominant clonal shrub Hedysarum laeve in Inner-Mongolia, northern China. Vital rates of 19057 ramets were recorded during three annual censuses (2007-2009) and used to parameterize Integral Projection Models to analyse population dynamics. The life history of H. laeve was characterized by high ramet turnover and population recruitment entirely depended on clonal propagation. Stochastic population growth rate was 1.32, suggesting that the populations were experiencing rapid expansion. Elasticity analysis revealed that clonal propagation was the key contributor to population growth. The capacity of high clonal propagation and rapid population expansion in mobile dunes makes H. laeve a suitable species to combat desertification. Species with similar life-history traits to H. laeve are likely to offer good opportunities for stabilizing active dunes in arid inland ecosystems.

Clonality and Micro-Diversity of a Nationwide Spreading Genotype of Mycobacterium tuberculosis in Japan

PubMed Central

Wada, Takayuki; Iwamoto, Tomotada; Tamaru, Aki; Seto, Junji; Ahiko, Tadayuki; Yamamoto, Kaori; Hase, Atushi; Maeda, Shinji; Yamamoto, Taro

2015-01-01

Mycobacterium tuberculosis transmission routes can be estimated from genotypic analysis of clinical isolates from patients. In Japan, still a middle-incidence country of TB, a unique genotype strain designated as ‘M-strain’ has been isolated nationwide recently. To ascertain the history of the wide spread of the strain, 10 clinical isolates from different areas were subjected to genome-wide analysis based on deep sequencers. Results show that all isolates possessed common mutations to those of referential strains. The greatest number of accumulated single nucleotide variants (SNVs) from the oldest coalescence was 13 nucleotides, indicating high clonality of these isolates. When an SNV common to the isolates was used as a surrogate marker of the clone, authentic clonal isolates with variation in a reliable subset of variable number of tandem repeat (VNTR) genotyping method can be selected successfully from clinical isolates populations of M. tuberculosis. When the authentic clones can also be assigned to sub-clonal groups by SNVs derived from the genomic comparison, they are classifiable into three sub-clonal groups with a bias of geographical origins. Feedback from genomic analysis of clinical isolates of M. tuberculosis to genotypic markers will be an efficient strategy for the big data in various settings for public health actions against TB. PMID:25734518

SIApopr: a computational method to simulate evolutionary branching trees for analysis of tumor clonal evolution.

PubMed

McDonald, Thomas O; Michor, Franziska

2017-07-15

SIApopr (Simulating Infinite-Allele populations) is an R package to simulate time-homogeneous and inhomogeneous stochastic branching processes under a very flexible set of assumptions using the speed of C ++. The software simulates clonal evolution with the emergence of driver and passenger mutations under the infinite-allele assumption. The software is an application of the Gillespie Stochastic Simulation Algorithm expanded to a large number of cell types and scenarios, with the intention of allowing users to easily modify existing models or create their own. SIApopr is available as an R library on Github ( https://github.com/olliemcdonald/siapopr ). Supplementary data are available at Bioinformatics online. michor@jimmy.harvard.edu. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

The Current Status of Feline Sporotrichosis in Malaysia.

PubMed

Siew, Han Hock

2017-01-01

Feline sporotrichosis has been reported in Malaysia since the 1990's. Since then, studies have revealed that clinical clade D, Sporothrix schenckii sensu stricto, of a single clonal strain is the most common cause of this disease in Malaysia. The prevalence of a single clonal strain from a clinical clade was never before reported in Asia in a specific geographical niche. This raises the possibility of a process of purifying selection and subsequent clonal proliferation. While agricultural practices may serve as the selective pressure, direct causality has yet to be established. Studies into the thermo-tolerability of the Malaysian clonal strain of S. schenckii sensu stricto revealed that a small minority of clinical isolates have the capacity to grow at 37℃, while the majority displayed low susceptibility to commonly used antifungals in clinical practice, such as itraconazole (ITZ) and terbinafine (TRB). Despite unestablished breakpoints, suspected resistance (MIC > 4 mg/mL) towards amphotericin B (AMB) and fluconazole (FLC) was recorded in the isolates. This explains the often lack of clinical response in feline patients treated with recommended doses of antifungals, including ITZ. Coupled with the potential zoonotic transmission to clients and veterinarians, protracted treatment period, and subsequent cost of treatment, prognosis of feline sporotrichosis is often regarded to be poor. The use of a higher dose of ITZ has been reported, and an adoption of this high-dose treatment regime is reported in this manuscript, with complete cure achieved in cases of recalcitrant and/or unresponsive feline sporotrichosis, which would otherwise be euthanized.

Prospects for genomic selection in cassava breeding

USDA-ARS?s Scientific Manuscript database

Cassava (Manihot esculenta Crantz) is a clonally propagated staple food crop in the tropics. Genomic selection (GS) has been implemented at three breeding institutions in Africa in order to reduce cycle times. Initial studies provided promising estimates of predictive abilities. Here, we expand on p...

Cancer stem cells: A product of clonal evolution?

PubMed

van Niekerk, Gustav; Davids, Lester M; Hattingh, Suzèl M; Engelbrecht, Anna-Mart

2017-03-01

The cancer stem cell (CSC) model has emerged as a prominent paradigm for explaining tumour heterogeneity. CSCs in tumour recurrence and drug resistance have also been implicated in a number of studies. In fact, CSCs are often identified by their expression of drug-efflux proteins which are also highly expressed in normal stem cells. Similarly, pro-survival or proliferation signalling often exhibited by stem cells is regularly reported as being upregulated by CSC. Here we review evidence suggesting that many aspects of CSCs are more readily described by clonal evolution. As an example, cancer cells often exhibit copy number gains of genes involved in drug-efflux proteins and pro-survival signalling. Consequently, clonal selection for stem cell traits may result in cancer cells developing "stemness" traits which impart a fitness advantage, without strictly following a CSC model. Finally, since symmetric cell division would give rise to more cells than asymmetric division, it is expected that more advanced tumours would depart from a CSC. Collectively, these observations suggest clonal evolution may explain many aspects of the CSC. © 2016 UICC.

Big Bang Tumor Growth and Clonal Evolution.

PubMed

Sun, Ruping; Hu, Zheng; Curtis, Christina

2018-05-01

The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Zebrafish as a model to assess cancer heterogeneity, progression and relapse

PubMed Central

Blackburn, Jessica S.; Langenau, David M.

2014-01-01

Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays. PMID:24973745

Modeling Tumor Clonal Evolution for Drug Combinations Design.

PubMed

Zhao, Boyang; Hemann, Michael T; Lauffenburger, Douglas A

2016-03-01

Cancer is a clonal evolutionary process. This presents challenges for effective therapeutic intervention, given the constant selective pressure towards drug resistance. Mathematical modeling from population genetics, evolutionary dynamics, and engineering perspectives are being increasingly employed to study tumor progression, intratumoral heterogeneity, drug resistance, and rational drug scheduling and combinations design. In this review, we discuss promising opportunities these inter-disciplinary approaches hold for advances in cancer biology and treatment. We propose that quantitative modeling perspectives can complement emerging experimental technologies to facilitate enhanced understanding of disease progression and improved capabilities for therapeutic drug regimen designs.

Indirect genetic effects from competition in the clonal herb Sedum album (Crassulaceae).

PubMed

Andersson, Stefan

2014-01-01

Recent years have seen increasing interest in indirect genetic effects, i.e. influences on the phenotype that depend on the genotype of other conspecific individuals; however, the empirical evidence for such effects is still limited, especially in wild plant species. The present study of the clonal herb Sedum album assessed direct and indirect genetic effects on performance-related traits in a 4-year experiment with clonally replicated genotypes, grown in pairs and differing in anthocyanin pigmentation to allow separation of individuals during data collection. In agreement with the existence of indirect genetic effects, the experimentally-paired plants not only expressed their own genotype but were also affected by the genotype of their pair mate. The effect of neighbour genotype explained up to one-fourth of the variation in performance and most likely resulted from competition, imposed by the close physical contact between paired individuals and the limiting conditions used in the garden environment. Indirect genetic effects from competition have the potential to enhance the efficacy of group-level selection relative to individual selection, given the nutrient-poor and spatially-confined substrate available to plants of S. album in the natural habitat.

Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

PubMed Central

Akunuru, Shailaja; Geiger, Hartmut

2016-01-01

Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies. PMID:27380967

Inter- and intra-patient clonal and subclonal heterogeneity of chronic lymphocytic leukaemia: evidence from circulating and lymph nodal compartments

PubMed Central

Bonina, Silvia; Messina, Monica; Chiaretti, Sabina; Ilari, Caterina; Cafforio, Luciana; Raponi, Sara; Mauro, Francesca Romana; Di Maio, Valeria; De Propris, Maria Stefania; Nanni, Mauro; Ciardullo, Carmela; Rossi, Davide; Gaidano, Gianluca; Guarini, Anna; Rabadan, Raul; Foà, Robin

2015-01-01

Summary Whole exome sequencing and copy number aberration (CNA) analysis was performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84.4%) were clonal in both compartments, 3 (4.7%) were PB-specific and 7 (10.9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0.5-5.3%). Of 41 CNAs, 27 (65.8%) were shared by both compartments and 7 (17.1%) were LN- or PB-specific. Overall, 6 of 9 cases (66.7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23.3-p11.1), del9(p24.3-p13.1) and gain 2(p25.3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse. PMID:26597680

Males are here to stay: fertilization enhances viable egg production by clonal queens of the little fire ant ( Wasmannia auropunctata)

NASA Astrophysics Data System (ADS)

Miyakawa, Misato O.; Mikheyev, Alexander S.

2015-04-01

Evolution of reproduction strategies is affected by both phylogenetic and physiological constraints. Although clonality may benefit females, it may not be selected if a male contribution is necessary to start egg laying and embryo development. In little fire ant, Wasmannia auropunctata, sexual populations employ a typical Hymenopteran system of reproduction. In clonal populations, however, queens and males are produced with only maternal and paternal genomes, respectively, whereas sterile workers are produced sexually. Although this system requires both sexes for worker production, previous work has shown that workers may also be produced clonally by the queens. If so, why are males maintained in this species? Our data suggest that fertilization is necessary to increase the hatching rate of eggs. Although clonal queens can indeed produce both workers and queens without mating, the hatching rate is far below the level necessary to maintain functional colonies. On the other hand, virgin queens from populations exhibiting the original Hymenopteran reproduction system also show low hatching rates, but produce only haploid male eggs. Reasons for the existence of W. auropunctata males have been disputed. However, our data suggest that physiological constraints, such as the requirement for insemination, must be considered in regard to evolution of reproduction systems, in addition to ecological data and theoretical considerations of fitness.

Evolution of proliferation and the angiogenic switch in tumors with high clonal diversity.

PubMed

Bickel, Scott T; Juliano, Joseph D; Nagy, John D

2014-01-01

Natural selection among tumor cell clones is thought to produce hallmark properties of malignancy. Efforts to understand evolution of one such hallmark--the angiogenic switch--has suggested that selection for angiogenesis can "run away" and generate a hypertumor, a form of evolutionary suicide by extreme vascular hypo- or hyperplasia. This phenomenon is predicted by models of tumor angiogenesis studied with the techniques of adaptive dynamics. These techniques also predict that selection drives tumor proliferative potential towards an evolutionarily stable strategy (ESS) that is also convergence-stable. However, adaptive dynamics are predicated on two key assumptions: (i) no more than two distinct clones or evolutionary strategies can exist in the tumor at any given time; and (ii) mutations cause small phenotypic changes. Here we show, using a stochastic simulation, that relaxation of these assumptions has no effect on the predictions of adaptive dynamics in this case. In particular, selection drives proliferative potential towards, and angiogenic potential away from, their respective ESSs. However, these simulations also show that tumor behavior is highly contingent on mutational history, particularly for angiogenesis. Individual tumors frequently grow to lethal size before the evolutionary endpoint is approached. In fact, most tumor dynamics are predicted to be in the evolutionarily transient regime throughout their natural history, so that clinically, the ESS is often largely irrelevant. In addition, we show that clonal diversity as measured by the Shannon Information Index correlates with the speed of approach to the evolutionary endpoint. This observation dovetails with results showing that clonal diversity in Barrett's esophagus predicts progression to malignancy.

Spontaneous heterosis in larval life-history traits of hemiclonal frog hybrids

PubMed Central

Hotz, Hansjürg; Semlitsch, Raymond D.; Gutmann, Eva; Guex, Gaston-Denis; Beerli, Peter

1999-01-01

European water frog hybrids Rana esculenta (Rana ridibunda × Rana lessonae) reproduce hemiclonally, transmitting only their ridibunda genome to gametes. We compared fitness-related larval life-history traits of natural R. esculenta from Poland with those of the two sympatric parental species and of newly generated F1 hybrids. Compared with either parental species, F1 hybrid offspring had higher survival, higher early growth rates, a more advanced developmental stage by day 49, and earlier metamorphosis, but similar mass at metamorphosis. R. esculenta from natural lineages had trait values intermediate between those of F1 offspring and of the two parental species. The data support earlier observations on natural R. esculenta that had faster larval growth, earlier metamorphosis, and higher resistance to hypoxic conditions compared with either parental species. Observing larval heterosis in F1 hybrids in survival, growth rate, and time to metamorphosis, however, at an even higher degree than in hybrids from natural lineages, demonstrates that heterosis is spontaneous and results from hybridity per se rather than from subsequent interclonal selection; in natural lineages the effects of hybridity and of clonal history are confounded. This is compelling evidence for spontaneous heterosis in hybrid clonals. Results on hemiclonal fish hybrids (Poeciliopsis) showed no spontaneous heterosis; thus, our frog data are not applicable to all hybrid clonals. Our data do show, however, that heterosis is an important potential source for the extensively observed ecological success of hybrid clonals. We suggest that heterosis and interclonal selection together shape fitness of natural R. esculenta lineages. PMID:10051613

Why are most aquatic plants widely distributed? Dispersal, clonal growth and small-scale heterogeneity in a stressful environment

NASA Astrophysics Data System (ADS)

Santamaría, Luis

2002-06-01

Non-marine aquatic vascular plants generally show broad distributional ranges. Climatic factors seem to have limited effects on their distributions, besides the determination of major disjunctions (tropical-temperate-subarctic). Dispersal should have been frequent enough to assure the quick colonisation of extensive areas following glacial retreat, but dispersal limitation is still apparent in areas separated by geographic barriers. Aquatic vascular plants also show limited taxonomic differentiation and low within-species genetic variation. Variation within populations is particularly low, but variation among populations seems to be relatively high, mainly due to the persistence of long-lived clones. Ecotypic differentiation is often related to factors that constrain clonal reproduction (salinity and ephemeral inundation). Inland aquatic habitats are heterogeneous environments, but this heterogeneity largely occurs at relatively small scales (within waterbodies and among neighbouring ones). They also represent a stressful environment for plants, characterised by low carbon availability, shaded conditions, sediment anoxia, mechanical damage by currents and waves, significant restrictions to sexual reproduction, and sometimes also osmotic stress and limited nutrient supply. I propose that the generality of broad distributions and low differentiation among the inland aquatic flora is best explained by a combination of: (1) selection for stress-tolerant taxa with broad tolerance ranges. (2) The selective advantages provided by clonal growth and multiplication, which increases plant tolerance to stress, genet survivorship and population viability. (3) Long-distance dispersal of sexual propagules and high local dispersal of asexual clones. (4) The generality of broad plastic responses, promoted by the combination of clonal growth, high local dispersal, small-scale spatial heterogeneity and temporal variability.

SU-F-R-10: Selecting the Optimal Solution for Multi-Objective Radiomics Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Z; Folkert, M; Wang, J

2016-06-15

Purpose: To develop an evidential reasoning approach for selecting the optimal solution from a Pareto solution set obtained by a multi-objective radiomics model for predicting distant failure in lung SBRT. Methods: In the multi-objective radiomics model, both sensitivity and specificity are considered as the objective functions simultaneously. A Pareto solution set with many feasible solutions will be resulted from the multi-objective optimization. In this work, an optimal solution Selection methodology for Multi-Objective radiomics Learning model using the Evidential Reasoning approach (SMOLER) was proposed to select the optimal solution from the Pareto solution set. The proposed SMOLER method used the evidentialmore » reasoning approach to calculate the utility of each solution based on pre-set optimal solution selection rules. The solution with the highest utility was chosen as the optimal solution. In SMOLER, an optimal learning model coupled with clonal selection algorithm was used to optimize model parameters. In this study, PET, CT image features and clinical parameters were utilized for predicting distant failure in lung SBRT. Results: Total 126 solution sets were generated by adjusting predictive model parameters. Each Pareto set contains 100 feasible solutions. The solution selected by SMOLER within each Pareto set was compared to the manually selected optimal solution. Five-cross-validation was used to evaluate the optimal solution selection accuracy of SMOLER. The selection accuracies for five folds were 80.00%, 69.23%, 84.00%, 84.00%, 80.00%, respectively. Conclusion: An optimal solution selection methodology for multi-objective radiomics learning model using the evidential reasoning approach (SMOLER) was proposed. Experimental results show that the optimal solution can be found in approximately 80% cases.« less

Clonal evolution in hematologic malignancies and therapeutic implications

PubMed Central

Landau, Dan A.; Carter, Scott L.; Getz, Gad; Wu, Catherine J.

2014-01-01

The ability of cancer to evolve and adapt is a principal challenge to therapy in general, and to the paradigm of targeted therapy in particular. This ability is fueled by the co-existence of multiple, genetically heterogeneous subpopulations within the cancer cell population. Increasing evidence has supported the idea that these subpopulations are selected in a Darwinian fashion, by which the genetic landscape of the tumor is continuously reshaped. Massively parallel sequencing has enabled a recent surge in our ability to study this process, adding to previous efforts using cytogenetic methods and targeted sequencing. Altogether, these studies reveal the complex evolutionary trajectories occurring across individual hematological malignancies. They also suggest that while clonal evolution may contribute to resistance to therapy, treatment may also hasten the evolutionary process. New insights into this process challenge us to understand the impact of treatment on clonal evolution, and inspire the development of novel prognostic and therapeutic strategies. PMID:23979521

Cancer in light of experimental evolution.

PubMed

Sprouffske, Kathleen; Merlo, Lauren M F; Gerrish, Philip J; Maley, Carlo C; Sniegowski, Paul D

2012-09-11

Cancer initiation, progression, and the emergence of therapeutic resistance are evolutionary phenomena of clonal somatic cell populations. Studies in microbial experimental evolution and the theoretical work inspired by such studies are yielding deep insights into the evolutionary dynamics of clonal populations, yet there has been little explicit consideration of the relevance of this rapidly growing field to cancer biology. Here, we examine how the understanding of mutation, selection, and spatial structure in clonal populations that is emerging from experimental evolution may be applicable to cancer. Along the way, we discuss some significant ways in which cancer differs from the model systems used in experimental evolution. Despite these differences, we argue that enhanced prediction and control of cancer may be possible using ideas developed in the context of experimental evolution, and we point out some prospects for future research at the interface between these traditionally separate areas. Copyright © 2012 Elsevier Ltd. All rights reserved.

Characterization of 21 microsatellite markers from cogongrass, Imperata cylindrica (Poaceae), a weed species distributed worldwide.

PubMed

Chiang, Yu-Chung; Tsai, Chi-Chu; Hsu, Tsai-Wen; Chou, Chang-Hung

2012-11-01

Microsatellite loci were developed from Imperata cylindrica, a traditional medicinal herb in Asia and among the top 10 worst invasive weeds in the world, to aid in the identification of the limits of asexual clonal individuals. A total of 21 microsatellite markers, including 18 polymorphic and three monomorphic loci, were developed from I. cylindrica using a magnetic bead enrichment protocol. The primers amplified dinucleotide, trinucleotide, and complex repeats. The number of alleles ranged from one to 19 per locus, with an observed heterozygosity ranging from 0.09 to 1.00. Several loci deviated significantly from the within-population Hardy-Weinberg equilibrium as a result of asexual clonal reproduction. These polymorphic markers should be useful tools in further studies on the identification of the range of clonal reproduction units and the selection and classification of the medicinal cultivar.

Cancer in Light of Experimental Evolution

PubMed Central

Sprouffske, Kathleen; Merlo, Lauren M.F.; Gerrish, Philip J.; Maley, Carlo C.; Sniegowski, Paul D.

2012-01-01

Cancer initiation, progression, and the emergence of therapeutic resistance are evolutionary phenomena of clonal somatic cell populations. Studies in microbial experimental evolution and the theoretical work inspired by such studies are yielding deep insights into the evolutionary dynamics of clonal populations, yet there has been little explicit consideration of the relevance of this rapidly growing field to cancer biology. Here, we examine how the understanding of mutation, selection, and spatial structure in clonal populations that is emerging from experimental evolution may be applicable to cancer. Along the way, we discuss some significant ways in which cancer differs from the model systems used in experimental evolution. Despite these differences, we argue that enhanced prediction and control of cancer may be possible using ideas developed in the context of experimental evolution, and we point out some prospects for future research at the interface between these traditionally separate areas. PMID:22975007

Comparative analysis of antibiotic resistance and phylogenetic group patterns in human and porcine urinary tract infectious Escherichia coli.

PubMed

Hancock, Viktoria; Nielsen, Eva Møller; Krag, Louise; Engberg, Jørgen; Klemm, Per

2009-11-01

Urinary tract infections (UTIs) are one of the most common infectious diseases in humans and domestic animals such as pigs. The most frequent infectious agent in such infections is Escherichia coli. Virulence characteristics of E. coli UTI strains range from highly virulent pyelonephritis strains to relatively benign asymptomatic bacteriuria strains. Here we analyse a spectrum of porcine and human UTI E. coli strains with respect to their antibiotic resistance patterns and their phylogenetic groups, determined by multiplex PCR. The clonal profiles of the strains differed profoundly; whereas human strains predominantly belonged to clonal types B2 and D, these were not seen among the porcine strains, which all belonged to the E. coli clonal groups A and B1. Contrary to the human strains, the majority of the porcine strains were multidrug resistant. The distinct profiles of the porcine strains suggest selective pressure due to extensive antibiotic use.

Selection and Clonal Propagation of High Artemisinin Genotypes of Artemisia annua

PubMed Central

Wetzstein, Hazel Y.; Porter, Justin A.; Janick, Jules; Ferreira, Jorge F. S.; Mutui, Theophilus M.

2018-01-01

Artemisinin, produced in the glandular trichomes of Artemisia annua L. is a vital antimalarial drug effective against Plasmodium falciparum resistant to quinine-derived medicines. Although work has progressed on the semi-synthetic production of artemisinin, field production of A. annua remains the principal commercial source of the compound. Crop production of artemisia must be increased to meet the growing worldwide demand for artemisinin combination therapies (ACTs) to treat malaria. Grower artemisinin yields rely on plants generated from seeds from open-pollinated parents. Although selection has considerably increased plant artemisinin concentration in the past 15 years, seed-generated plants have highly variable artemisinin content that lowers artemisinin yield per hectare. Breeding efforts to produce improved F1 hybrids have been hampered by the inability to produce inbred lines due to self-incompatibility. An approach combining conventional hybridization and selection with clonal propagation of superior genotypes is proposed as a means to enhance crop yield and artemisinin production. Typical seed-propagated artemisia plants produce less than 1% (dry weight) artemisinin with yields below 25 kg/ha. Genotypes were identified producing high artemisinin levels of over 2% and possessing improved agronomic characteristics such as high leaf area and shoot biomass production. Field studies of clonally-propagated high-artemisinin plants verified enhanced plant uniformity and an estimated gross primary productivity of up to 70 kg/ha artemisinin, with a crop density of one plant m-2. Tissue culture and cutting protocols for the mass clonal propagation of A. annua were developed for shoot regeneration, rooting, acclimatization, and field cultivation. Proof of concept studies showed that both tissue culture-regenerated plants and rooted cutting performed better than plants derived from seed in terms of uniformity, yield, and consistently high artemisinin content. Use of this technology to produce plants with homogeneously-high artemisinin can help farmers markedly increase the artemisinin yield per cultivated area. This would lead to increased profit to farmers and decreased prices of ACT. PMID:29636758

BRILIA: Integrated Tool for High-Throughput Annotation and Lineage Tree Assembly of B-Cell Repertoires.

PubMed

Lee, Donald W; Khavrutskii, Ilja V; Wallqvist, Anders; Bavari, Sina; Cooper, Christopher L; Chaudhury, Sidhartha

2016-01-01

The somatic diversity of antigen-recognizing B-cell receptors (BCRs) arises from Variable (V), Diversity (D), and Joining (J) (VDJ) recombination and somatic hypermutation (SHM) during B-cell development and affinity maturation. The VDJ junction of the BCR heavy chain forms the highly variable complementarity determining region 3 (CDR3), which plays a critical role in antigen specificity and binding affinity. Tracking the selection and mutation of the CDR3 can be useful in characterizing humoral responses to infection and vaccination. Although tens to hundreds of thousands of unique BCR genes within an expressed B-cell repertoire can now be resolved with high-throughput sequencing, tracking SHMs is still challenging because existing annotation methods are often limited by poor annotation coverage, inconsistent SHM identification across the VDJ junction, or lack of B-cell lineage data. Here, we present B-cell repertoire inductive lineage and immunosequence annotator (BRILIA), an algorithm that leverages repertoire-wide sequencing data to globally improve the VDJ annotation coverage, lineage tree assembly, and SHM identification. On benchmark tests against simulated human and mouse BCR repertoires, BRILIA correctly annotated germline and clonally expanded sequences with 94 and 70% accuracy, respectively, and it has a 90% SHM-positive prediction rate in the CDR3 of heavily mutated sequences; these are substantial improvements over existing methods. We used BRILIA to process BCR sequences obtained from splenic germinal center B cells extracted from C57BL/6 mice. BRILIA returned robust B-cell lineage trees and yielded SHM patterns that are consistent across the VDJ junction and agree with known biological mechanisms of SHM. By contrast, existing BCR annotation tools, which do not account for repertoire-wide clonal relationships, systematically underestimated both the size of clonally related B-cell clusters and yielded inconsistent SHM frequencies. We demonstrate BRILIA's utility in B-cell repertoire studies related to VDJ gene usage, mechanisms for adenosine mutations, and SHM hot spot motifs. Furthermore, we show that the complete gene usage annotation and SHM identification across the entire CDR3 are essential for studying the B-cell affinity maturation process through immunosequencing methods.

Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis

PubMed Central

Schwarz, Roland F.; Ng, Charlotte K. Y.; Cooke, Susanna L.; Newman, Scott; Temple, Jillian; Piskorz, Anna M.; Gale, Davina; Sayal, Karen; Murtaza, Muhammed; Baldwin, Peter J.; Rosenfeld, Nitzan; Earl, Helena M.; Sala, Evis; Jimenez-Linan, Mercedes; Parkinson, Christine A.; Markowetz, Florian; Brenton, James D.

2015-01-01

Background The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease. Methods and Findings Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22–46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66–1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy. Conclusions This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse. PMID:25710373

Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.

PubMed

Schwarz, Roland F; Ng, Charlotte K Y; Cooke, Susanna L; Newman, Scott; Temple, Jillian; Piskorz, Anna M; Gale, Davina; Sayal, Karen; Murtaza, Muhammed; Baldwin, Peter J; Rosenfeld, Nitzan; Earl, Helena M; Sala, Evis; Jimenez-Linan, Mercedes; Parkinson, Christine A; Markowetz, Florian; Brenton, James D

2015-02-01

The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease. Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66-1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy. This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.

Insights into the prevalence and underlying causes of clonal variation through transcriptomic analysis in Pichia pastoris.

PubMed

Aw, Rochelle; Barton, Geraint R; Leak, David J

2017-06-01

Clonal variation, wherein a range of specific productivities of secreted proteins are observed from supposedly identical transformants, is an accepted aspect of working with Pichia pastoris. It means that a significant number of transformants need to be tested to obtain a representative sample, and in commercial protein production, companies regularly screen thousands of transformants to select for the highest secretor. Here, we have undertaken a detailed investigation of this phenomenon by characterising clones transformed with the human serum albumin gene. The titers of nine clones, each containing a single copy of the human serum albumin gene (identified by qPCR), were measured and the clones grouped into three categories, namely, high-, mid- and low-level secretors. Transcriptomic analysis, using microarrays, showed that no regulatory patterns consistently correlated with titer, suggesting that the causes of clonal variation are varied. However, a number of physiological changes appeared to underlie the differences in titer, suggesting there is more than one biochemical signature for a high-secreting strain. An anomalous low-secreting strain displaying high transcript levels that appeared to be nutritionally starved further emphasises the complicated nature of clonal variation.

Serial measurement of type-specific human papillomavirus load enables classification of cervical intraepithelial neoplasia lesions according to occurring human papillomavirus-induced pathway.

PubMed

Verhelst, Stefanie; Poppe, Willy A J; Bogers, Johannes J; Depuydt, Christophe E

2017-03-01

This retrospective study examined whether human papillomavirus (HPV) type-specific viral load changes measured in two or three serial cervical smears are predictive for the natural evolution of HPV infections and correlate with histological grades of cervical intraepithelial neoplasia (CIN), allowing triage of HPV-positive women. A cervical histology database was used to select consecutive women with biopsy-proven CIN in 2012 who had at least two liquid-based cytology samples before the diagnosis of CIN. Before performing cytology, 18 different quantitative PCRs allowed HPV type-specific viral load measurement. Changes in HPV-specific load between measurements were assessed by linear regression, with calculation of coefficient of determination (R) and slope. All infections could be classified into one of five categories: (i) clonal progressing process (R≥0.85; positive slope), (ii) simultaneously occurring clonal progressive and transient infection, (iii) clonal regressing process (R≥0.85; negative slope), (iv) serial transient infection with latency [R<0.85; slopes (two points) between 0.0010 and -0.0010 HPV copies/cell/day], and (v) transient productive infection (R<0.85; slope: ±0.0099 HPV copies/cell/day). Three hundred and seven women with CIN were included; 124 had single-type infections and 183 had multiple HPV types. Only with three consecutive measurements could a clonal process be identified in all CIN3 cases. We could clearly demonstrate clonal regressing lesions with a persistent linear decrease in viral load (R≥0.85; -0.003 HPV copies/cell/day) in all CIN categories. Type-specific viral load increase/decrease in three consecutive measurements enabled classification of CIN lesions in clonal HPV-driven transformation (progression/regression) and nonclonal virion-productive (serial transient/transient) processes.

Modeling Tumor Clonal Evolution for Drug Combinations Design

PubMed Central

Zhao, Boyang; Hemann, Michael T.; Lauffenburger, Douglas A.

2016-01-01

Cancer is a clonal evolutionary process. This presents challenges for effective therapeutic intervention, given the constant selective pressure towards drug resistance. Mathematical modeling from population genetics, evolutionary dynamics, and engineering perspectives are being increasingly employed to study tumor progression, intratumoral heterogeneity, drug resistance, and rational drug scheduling and combinations design. In this review, we discuss promising opportunities these inter-disciplinary approaches hold for advances in cancer biology and treatment. We propose that quantitative modeling perspectives can complement emerging experimental technologies to facilitate enhanced understanding of disease progression and improved capabilities for therapeutic drug regimen designs. PMID:28435907

Narrowing the Gap: Preserving Repertoire Diversity Despite Clonal Selection during the CD4 T Cell Response.

PubMed

Merkenschlager, Julia; Kassiotis, George

2015-01-01

T cell immunity relies on the generation and maintenance of a diverse repertoire of T cell antigen receptors (TCRs). The strength of signaling emanating from the TCR dictates the fate of T cells during development, as well as during the immune response. Whereas development of new T cells in the thymus increases the available TCR repertoire, clonal selection during the immune response narrows TCR diversity through the outgrowth of clonotypes with the fittest TCR. To ensure maintenance of TCR diversity in the antigen-selected repertoire, specific mechanisms can be envisaged that facilitate the participation of T cell clonotypes with less than best fit TCRs. Here, we summarize the evidence for the existence of such mechanisms that can prevent the loss of diversity. A number of T cell-autonomous or extrinsic factors can reverse clonotypic hierarchies set by TCR affinity for given antigen. Although not yet complete, understanding of these factors and their mechanism of action will be critical in interventional attempts to mold the antigen-selected TCR repertoire.

Selection of Phage Display Peptides Targeting Human Pluripotent Stem Cell-Derived Progenitor Cell Lines.

PubMed

Bignone, Paola A; Krupa, Rachel A; West, Michael D; Larocca, David

2016-01-01

The ability of human pluripotent stem cells (hPS) to both self-renew and differentiate into virtually any cell type makes them a promising source of cells for cell-based regenerative therapies. However, stem cell identity, purity, and scalability remain formidable challenges that need to be overcome for translation of pluripotent stem cell research into clinical applications. Directed differentiation from hPS cells is inefficient and residual contamination with pluripotent cells that have the potential to form tumors remains problematic. The derivation of scalable (self-renewing) embryonic progenitor stem cell lines offers a solution because they are well defined and clonally pure. Clonally pure progenitor stem cell lines also provide a means for identifying cell surface targeting reagents that are useful for identification, tracking, and repeated derivation of the corresponding progenitor stem cell types from additional hPS cell sources. Such stem cell targeting reagents can then be applied to the manufacture of genetically diverse banks of human embryonic progenitor cell lines for drug screening, disease modeling, and cell therapy. Here we present methods to identify human embryonic progenitor stem cell targeting peptides by selection of phage display libraries on clonal embryonic progenitor cell lines and demonstrate their use for targeting quantum dots (Qdots) for stem cell labeling.

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

PubMed Central

Plevova, Karla; Francova, Hana Skuhrova; Burckova, Katerina; Brychtova, Yvona; Doubek, Michael; Pavlova, Sarka; Malcikova, Jitka; Mayer, Jiri; Tichy, Boris; Pospisilova, Sarka

2014-01-01

In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia. PMID:24038023

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.

PubMed

Saida, Satoshi; Watanabe, Ken-ichiro; Sato-Otsubo, Aiko; Terui, Kiminori; Yoshida, Kenichi; Okuno, Yusuke; Toki, Tsutomu; Wang, RuNan; Shiraishi, Yuichi; Miyano, Satoru; Kato, Itaru; Morishima, Tatsuya; Fujino, Hisanori; Umeda, Katsutsugu; Hiramatsu, Hidefumi; Adachi, Souichi; Ito, Etsuro; Ogawa, Seishi; Ito, Mamoru; Nakahata, Tatsutoshi; Heike, Toshio

2013-05-23

Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

Selfish Spermatogonial Selection: Evidence from an Immunohistochemical Screen in Testes of Elderly Men

PubMed Central

Turner, Gareth D. H.; Dudka-Ruszkowska, Wioleta; Taylor, Stephen; Meyts, Ewa Rajpert-De; Goriely, Anne; Wilkie, Andrew O. M.

2012-01-01

The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia–caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively–represent classical examples of paternal age-effect mutation, a class that arises at particularly high frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply that normal testes are mosaic for clusters of mutant cells: these clusters are predicted to have altered growth and signalling properties leading to their clonal expansion (selfish spermatogonial selection), but DNA extraction eliminates the possibility to study such processes at a tissue level. Using a panel of antibodies optimised for the detection of spermatocytic seminoma, a rare tumour of spermatogonial origin, we demonstrate that putative clonal events are frequent within normal testes of elderly men (mean age: 73.3 yrs) and can be classed into two broad categories. We found numerous small (less than 200 cells) cellular aggregations with distinct immunohistochemical characteristics, localised to a portion of the seminiferous tubule, which are of uncertain significance. However more infrequently we identified additional regions where entire seminiferous tubules had a circumferentially altered immunohistochemical appearance that extended through multiple serial sections that were physically contiguous (up to 1 mm in length), and exhibited enhanced staining for antibodies both to FGFR3 and a marker of downstream signal activation, pAKT. These findings support the concept that populations of spermatogonia in individual seminiferous tubules in the testes of older men are clonal mosaics with regard to their signalling properties and activation, thus fulfilling one of the specific predictions of selfish spermatogonial selection. PMID:22879958

Spatial structure increases the waiting time for cancer

PubMed Central

Martens, Erik A.; Kostadinov, Rumen; Maley, Carlo C.; Hallatschek, Oskar

2012-01-01

Cancer results from a sequence of genetic and epigenetic changes which lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells, and thus, to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been experiencing increasing interest in recent years. Many efforts have been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones, decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale Lc. These characteristic features of clonal interference may help to predict the onset of cancers with pronounced spatial structure and to interpret spatially-sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer, and possibly other cancers where spatial structure matters. PMID:22707911

Clonal selection versus clonal cooperation: the integrated perception of immune objects

PubMed Central

Nataf, Serge

2016-01-01

Analogies between the immune and nervous systems were first envisioned by the immunologist Niels Jerne who introduced the concepts of antigen "recognition" and immune "memory". However, since then, it appears that only the cognitive immunology paradigm proposed by Irun Cohen, attempted to further theorize the immune system functions through the prism of neurosciences. The present paper is aimed at revisiting this analogy-based reasoning. In particular, a parallel is drawn between the brain pathways of visual perception and the processes allowing the global perception of an "immune object". Thus, in the visual system, distinct features of a visual object (shape, color, motion) are perceived separately by distinct neuronal populations during a primary perception task. The output signals generated during this first step instruct then an integrated perception task performed by other neuronal networks. Such a higher order perception step is by essence a cooperative task that is mandatory for the global perception of visual objects. Based on a re-interpretation of recent experimental data, it is suggested that similar general principles drive the integrated perception of immune objects in secondary lymphoid organs (SLOs). In this scheme, the four main categories of signals characterizing an immune object (antigenic, contextual, temporal and localization signals) are first perceived separately by distinct networks of immunocompetent cells.  Then, in a multitude of SLO niches, the output signals generated during this primary perception step are integrated by TH-cells at the single cell level. This process eventually generates a multitude of T-cell and B-cell clones that perform, at the scale of SLOs, an integrated perception of immune objects. Overall, this new framework proposes that integrated immune perception and, consequently, integrated immune responses, rely essentially on clonal cooperation rather than clonal selection. PMID:27830060

Spatial structure increases the waiting time for cancer

NASA Astrophysics Data System (ADS)

Martens, Erik A.; Kostadinov, Rumen; Maley, Carlo C.; Hallatschek, Oskar

2011-11-01

Cancer results from a sequence of genetic and epigenetic changes that lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells and thus to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been attracting increasing interest in recent years. A great deal of effort has been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones and decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale Lc. These characteristic features of clonal interference may help us to predict the onset of cancers with pronounced spatial structure and to interpret spatially sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer and possibly other cancers where spatial structure matters.

The Spheroplast Lysis Assay for Yeast in Microtiter Plate Format

PubMed Central

Ovalle, Rafael; Spencer, Moyah; Thiwanont, Monthiwa; Lipke, Peter N.

1999-01-01

A yeast lysis assay in the microtiter plate format improved precision and throughput and led to an improved algorithm for estimating lag time. The assay reproducibly revealed differences of 10% or greater in the maximal lysis rate and 50% or greater in the lag time. Clonal differences were determined to be the major source of variation. Microtiter-based assays should be useful for screening for drug susceptibility and for analyzing mutant phenotypes. PMID:10427014

Cutaneous T cell lymphoma: Current practices in blood assessment and the utility of T-cell receptor Vβ chain restriction

PubMed Central

Gibson, Juliet F; Huang, Jing; Liu, Kristina J; Carlson, Kacie R; Foss, Francine; Choi, Jaehyuk; Edelson, Richard; Hussong, Jerry W.; Mohl, Ramsey; Hill, Sally; Girardi, Sally

2016-01-01

Background Accurate quantification of malignant cells in the peripheral blood of patients with cutaneous T cell lymphoma (CTCL) is important for early detection, prognosis, and monitoring disease burden. Objective Determine the spectrum of current clinical practices; critically evaluate elements of current ISCL B1 and B2 staging criteria; and assess the potential role of TCR-Vβ analysis by flow cytometry. Methods We assessed current clinical practices by survey, and performed a retrospective analysis of 161 patients evaluated at Yale (2011-2014) to compare the sensitivity, specificity, PPV, and NPV of parameters for ISCL B2 staging. Results There was heterogeneity in clinical practices among institutions. ISCL B1 criteria did not capture five Yale cohort patients with immunophenotypic abnormalities who later progressed. TCR-Vβ testing was more specific than PCR and aided diagnosis in detecting clonality, but was of limited benefit in quantification of tumor burden. Limitations Because of limited follow-up involving a single center, further investigation will be necessary to conclude whether our proposed diagnostic algorithm is of general clinical benefit. Conclusion We propose further study of “modified B1 criteria”: CD4/CD8 ratio ≥5, %CD4+/CD26- ≥ 20%, %CD4+/CD7- ≥ 20%, with evidence of clonality. TCR-Vβ testing should be considered in future diagnostic and staging algorithms. PMID:26874819

Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer

PubMed Central

Strakova, Andrea; Ní Leathlobhair, Máire; Wang, Guo-Dong; Yin, Ting-Ting; Airikkala-Otter, Ilona; Allen, Janice L; Allum, Karen M; Bansse-Issa, Leontine; Bisson, Jocelyn L; Castillo Domracheva, Artemio; de Castro, Karina F; Corrigan, Anne M; Cran, Hugh R; Crawford, Jane T; Cutter, Stephen M; Delgadillo Keenan, Laura; Donelan, Edward M; Faramade, Ibikunle A; Flores Reynoso, Erika; Fotopoulou, Eleni; Fruean, Skye N; Gallardo-Arrieta, Fanny; Glebova, Olga; Häfelin Manrique, Rodrigo F; Henriques, Joaquim JGP; Ignatenko, Natalia; Koenig, Debbie; Lanza-Perea, Marta; Lobetti, Remo; Lopez Quintana, Adriana M; Losfelt, Thibault; Marino, Gabriele; Martincorena, Inigo; Martínez Castañeda, Simón; Martínez-López, Mayra F; Meyer, Michael; Nakanwagi, Berna; De Nardi, Andrigo B; Neunzig, Winifred; Nixon, Sally J; Onsare, Marsden M; Ortega-Pacheco, Antonio; Peleteiro, Maria C; Pye, Ruth J; Reece, John F; Rojas Gutierrez, Jose; Sadia, Haleema; Schmeling, Sheila K; Shamanova, Olga; Ssuna, Richard K; Steenland-Smit, Audrey E; Svitich, Alla; Thoya Ngoka, Ismail; Vițălaru, Bogdan A; de Vos, Anna P; de Vos, Johan P; Walkinton, Oliver; Wedge, David C; Wehrle-Martinez, Alvaro S; van der Wel, Mirjam G; Widdowson, Sophie AE; Murchison, Elizabeth P

2016-01-01

Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution. DOI: http://dx.doi.org/10.7554/eLife.14552.001 PMID:27185408

Divergent clonal selection dominates medulloblastoma at recurrence

PubMed Central

Morrissy, A. Sorana; Garzia, Livia; Shih, David J. H.; Zuyderduyn, Scott; Huang, Xi; Skowron, Patryk; Remke, Marc; Cavalli, Florence M. G.; Ramaswamy, Vijay; Lindsay, Patricia E.; Jelveh, Salomeh; Donovan, Laura K.; Wang, Xin; Luu, Betty; Zayne, Kory; Li, Yisu; Mayoh, Chelsea; Thiessen, Nina; Mercier, Eloi; Mungall, Karen L.; Ma, Yusanne; Tse, Kane; Zeng, Thomas; Shumansky, Karey; Roth, Andrew J. L.; Shah, Sohrab; Farooq, Hamza; Kijima, Noriyuki; Holgado, Borja L.; Lee, John J. Y.; Matan-Lithwick, Stuart; Liu, Jessica; Mack, Stephen C.; Manno, Alex; Michealraj, K. A.; Nor, Carolina; Peacock, John; Qin, Lei; Reimand, Juri; Rolider, Adi; Thompson, Yuan Y.; Wu, Xiaochong; Pugh, Trevor; Ally, Adrian; Bilenky, Mikhail; Butterfield, Yaron S. N.; Carlsen, Rebecca; Cheng, Young; Chuah, Eric; Corbett, Richard D.; Dhalla, Noreen; He, An; Lee, Darlene; Li, Haiyan I.; Long, William; Mayo, Michael; Plettner, Patrick; Qian, Jenny Q.; Schein, Jacqueline E.; Tam, Angela; Wong, Tina; Birol, Inanc; Zhao, Yongjun; Faria, Claudia C.; Pimentel, José; Nunes, Sofia; Shalaby, Tarek; Grotzer, Michael; Pollack, Ian F.; Hamilton, Ronald L.; Li, Xiao-Nan; Bendel, Anne E.; Fults, Daniel W.; Walter, Andrew W.; Kumabe, Toshihiro; Tominaga, Teiji; Collins, V. Peter; Cho, Yoon-Jae; Hoffman, Caitlin; Lyden, David; Wisoff, Jeffrey H.; Garvin, James H.; Stearns, Duncan S.; Massimi, Luca; Schüller, Ulrich; Sterba, Jaroslav; Zitterbart, Karel; Puget, Stephanie; Ayrault, Olivier; Dunn, Sandra E.; Tirapelli, Daniela P. C.; Carlotti, Carlos G.; Wheeler, Helen; Hallahan, Andrew R.; Ingram, Wendy; MacDonald, Tobey J.; Olson, Jeffrey J.; Van Meir, Erwin G.; Lee, Ji-Yeoun; Wang, Kyu-Chang; Kim, Seung-Ki; Cho, Byung-Kyu; Pietsch, Torsten; Fleischhack, Gudrun; Tippelt, Stephan; Ra, Young Shin; Bailey, Simon; Lindsey, Janet C.; Clifford, Steven C.; Eberhart, Charles G.; Cooper, Michael K.; Packer, Roger J.; Massimino, Maura; Garre, Maria Luisa; Bartels, Ute; Tabori, Uri; Hawkins, Cynthia E.; Dirks, Peter; Bouffet, Eric; Rutka, James T.; Wechsler-Reya, Robert J.; Weiss, William A.; Collier, Lara S.; Dupuy, Adam J.; Korshunov, Andrey; Jones, David T. W.; Kool, Marcel; Northcott, Paul A.; Pfister, Stefan M.; Largaespada, David A.; Mungall, Andrew J.; Moore, Richard A.; Jabado, Nada; Bader, Gary D.; Jones, Steven J. M.; Malkin, David; Marra, Marco A.; Taylor, Michael D.

2016-01-01

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy. PMID:26760213

A Big Bang model of human colorectal tumor growth.

PubMed

Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

2015-03-01

What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?

PubMed

Kelsen, Jens; Dige, Anders; Schwindt, Heinrich; D'Amore, Francesco; Pedersen, Finn S; Agnholt, Jørgen; Christensen, Lisbet A; Dahlerup, Jens F; Hvas, Christian L

2011-03-31

Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents.

Genome-wide DNA-(de)methylation is associated with Noninfectious Bud-failure exhibition in Almond (Prunus dulcis [Mill.] D.A.Webb)

PubMed Central

Fresnedo-Ramírez, Jonathan; Chan, Helen M.; Parfitt, Dan E.; Crisosto, Carlos H.; Gradziel, Thomas M.

2017-01-01

Noninfectious bud-failure (BF) remains a major threat to almond production in California, particularly with the recent rapid expansion of acreage and as more intensive cultural practices and modern cultivars are adopted. BF has been shown to be inherited in both vegetative and sexual progeny, with exhibition related to the age and propagation history of scion clonal sources. These characteristics suggest an epigenetic influence, such as the loss of juvenility mediated by DNA-(de)methylation. Various degrees of BF have been reported among cultivars as well as within sources of clonal propagation of the same cultivar. Genome-wide methylation profiles for different clones within almond genotypes were developed to examine their association with BF levels and association with the chronological time from initial propagation. The degree of BF exhibition was found to be associated with DNA-(de)methylation and clonal age, which suggests that epigenetic changes associated with ageing may be involved in the differential exhibition of BF within and among almond clones. Research is needed to investigate the potential of DNA-(de)methylation status as a predictor for BF as well as for effective strategies to improve clonal selection against age related deterioration. This is the first report of an epigenetic-related disorder threatening a major tree crop. PMID:28202904

Genome-wide DNA-(de)methylation is associated with Noninfectious Bud-failure exhibition in Almond (Prunus dulcis [Mill.] D.A.Webb).

PubMed

Fresnedo-Ramírez, Jonathan; Chan, Helen M; Parfitt, Dan E; Crisosto, Carlos H; Gradziel, Thomas M

2017-02-16

Noninfectious bud-failure (BF) remains a major threat to almond production in California, particularly with the recent rapid expansion of acreage and as more intensive cultural practices and modern cultivars are adopted. BF has been shown to be inherited in both vegetative and sexual progeny, with exhibition related to the age and propagation history of scion clonal sources. These characteristics suggest an epigenetic influence, such as the loss of juvenility mediated by DNA-(de)methylation. Various degrees of BF have been reported among cultivars as well as within sources of clonal propagation of the same cultivar. Genome-wide methylation profiles for different clones within almond genotypes were developed to examine their association with BF levels and association with the chronological time from initial propagation. The degree of BF exhibition was found to be associated with DNA-(de)methylation and clonal age, which suggests that epigenetic changes associated with ageing may be involved in the differential exhibition of BF within and among almond clones. Research is needed to investigate the potential of DNA-(de)methylation status as a predictor for BF as well as for effective strategies to improve clonal selection against age related deterioration. This is the first report of an epigenetic-related disorder threatening a major tree crop.

Hybridization-based antibody cDNA recovery for the production of recombinant antibodies identified by repertoire sequencing.

PubMed

Valdés-Alemán, Javier; Téllez-Sosa, Juan; Ovilla-Muñoz, Marbella; Godoy-Lozano, Elizabeth; Velázquez-Ramírez, Daniel; Valdovinos-Torres, Humberto; Gómez-Barreto, Rosa E; Martinez-Barnetche, Jesús

2014-01-01

High-throughput sequencing of the antibody repertoire is enabling a thorough analysis of B cell diversity and clonal selection, which may improve the novel antibody discovery process. Theoretically, an adequate bioinformatic analysis could allow identification of candidate antigen-specific antibodies, requiring their recombinant production for experimental validation of their specificity. Gene synthesis is commonly used for the generation of recombinant antibodies identified in silico. Novel strategies that bypass gene synthesis could offer more accessible antibody identification and validation alternatives. We developed a hybridization-based recovery strategy that targets the complementarity-determining region 3 (CDRH3) for the enrichment of cDNA of candidate antigen-specific antibody sequences. Ten clonal groups of interest were identified through bioinformatic analysis of the heavy chain antibody repertoire of mice immunized with hen egg white lysozyme (HEL). cDNA from eight of the targeted clonal groups was recovered efficiently, leading to the generation of recombinant antibodies. One representative heavy chain sequence from each clonal group recovered was paired with previously reported anti-HEL light chains to generate full antibodies, later tested for HEL-binding capacity. The recovery process proposed represents a simple and scalable molecular strategy that could enhance antibody identification and specificity assessment, enabling a more cost-efficient generation of recombinant antibodies.

Dynamics of Tumor Heterogeneity Derived from Clonal Karyotypic Evolution.

PubMed

Laughney, Ashley M; Elizalde, Sergi; Genovese, Giulio; Bakhoum, Samuel F

2015-08-04

Numerical chromosomal instability is a ubiquitous feature of human neoplasms. Due to experimental limitations, fundamental characteristics of karyotypic changes in cancer are poorly understood. Using an experimentally inspired stochastic model, based on the potency and chromosomal distribution of oncogenes and tumor suppressor genes, we show that cancer cells have evolved to exist within a narrow range of chromosome missegregation rates that optimizes phenotypic heterogeneity and clonal survival. Departure from this range reduces clonal fitness and limits subclonal diversity. Mapping of the aneuploid fitness landscape reveals a highly favorable, commonly observed, near-triploid state onto which evolving diploid- and tetraploid-derived populations spontaneously converge, albeit at a much lower fitness cost for the latter. Finally, by analyzing 1,368 chromosomal translocation events in five human cancers, we find that karyotypic evolution also shapes chromosomal translocation patterns by selecting for more oncogenic derivative chromosomes. Thus, chromosomal instability can generate the heterogeneity required for Darwinian tumor evolution. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.

PubMed

Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

2016-08-18

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.

Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases.

PubMed

De Mattos-Arruda, Leticia; Ng, Charlotte K Y; Piscuoglio, Salvatore; Gonzalez-Cao, Maria; Lim, Raymond S; De Filippo, Maria R; Fusco, Nicola; Schultheis, Anne M; Ortiz, Carolina; Viteri, Santiago; Arias, Alexandra; Macedo, Gabriel S; Oliveira, Mafalda; Gomez, Patricia; Teixidó, Cristina; Nuciforo, Paolo; Peg, Vicente; Saura, Cristina; Ramon Y Cajal, Santiago; Casas, Francesc Tresserra; Weigelt, Britta; Cortes, Javier; Seoane, Joan; Reis-Filho, Jorge S

2018-04-17

Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR , homozygous deletion in CDKN2A and amplification in KRAS . Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53 . Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.

Clonal heterogeneity as a driver of disease variability in the evolution of myeloproliferative neoplasms.

PubMed

Prick, Janine; de Haan, Gerald; Green, Anthony R; Kent, David G

2014-10-01

Myeloproliferative neoplasms (MPNs) are clonal hematological diseases in which cells of the myelo-erythroid lineage are overproduced and patients are predisposed to leukemic transformation. Hematopoietic stem cells are the suspected disease-initiating cells, and these cells must acquire a clonal advantage relative to nonmutant hematopoietic stem cells to perpetuate disease. In 2005, several groups identified a single gain-of-function point mutation in JAK2 that associated with the majority of MPNs, and subsequent studies have led to a comprehensive understanding of the mutational landscape in MPNs. However, confusion still exists as to how a single genetic aberration can be associated with multiple distinct disease entities. Many explanations have been proposed, including JAK2V617F homozygosity, individual patient heterogeneity, and the differential regulation of downstream JAK2 signaling pathways. Several groups have made knock-in mouse models expressing JAK2V617F and have observed divergent phenotypes, each recapitulating some aspects of disease. Intriguingly, most of these models do not observe a strong hematopoietic stem cell self-renewal advantage compared with wild-type littermate controls, raising the question of how a clonal advantage is established in patients with MPNs. This review summarizes the current molecular understanding of MPNs and the diversity of disease phenotypes and proposes that the increased proliferation induced by JAK2V617F applies a selection pressure on the mutant clone that results in highly diverse clonal evolution in individuals. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Long-term consequences of disturbances on reproductive strategies of the rare epiphytic lichen Lobaria pulmonaria: clonality a gift and a curse.

PubMed

Singh, Garima; Dal Grande, Francesco; Werth, Silke; Scheidegger, Christoph

2015-01-01

The effect of disturbance on symbiotic organisms such as lichens is particularly severe. In case of heterothallic lichen-forming fungi, disturbances may lead to unbalanced gene frequency and patchy distribution of mating types, thus inhibiting sexual reproduction and imposing clonality. The impact of disturbance on reproductive strategies and genetic diversity of clonal systems has so far received little attention. To infer the effects of disturbances on mating-type allele frequencies and population structure, we selected three populations in the Parc Jurassien Vaudois (Switzerland), which were affected by uneven-aged forestry, intensive logging and fire, respectively. We used microsatellite markers to infer genetic diversity, allelic richness and clonal diversity of the epiphytic lichen Lobaria pulmonaria and used L. pulmonaria-specific MAT1-1 and MAT1-2 markers to analyse the frequency and distribution of mating types of 889 individuals. Our study shows that stand-replacing disturbances affect the mating-type frequency and distribution, thus compromising the potential for sexual reproduction. The fire-disturbed area had a significantly lower genetic and genotypic diversity and a higher clonality. Furthermore, the majority of compatible mating pairs in this area were beyond the effective vegetative dispersal range of the species. We conclude that stand-replacing disturbances lead to lower chances of sex and symbiont reshuffling and thus have long-lasting negative consequences on the reproductive strategies and adaptive potential of epiphytic lichen symbioses. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Evolution of immune systems from self/not self to danger to artificial immune systems (AIS).

PubMed

Cooper, Edwin L

2010-03-01

This review will examine the evolution of immune mechanisms by emphasizing information from animal groups exclusive of all vertebrates. There will be a focus on concepts that propelled the immune system into prominent discourse in the life sciences. The self/not self hypothesis was crucial and so was the concern for immunologic memory or anamnesia, development of cancer, autoimmunity, and clonal selection. Now we may be able to deconstruct clonal selection since it is not applicable in the sense that it is not applicable to invertebrate mechanisms. Clonal selection seems to be purely as all evidence indicates a vertebrate strategy and therefore irrelevant to invertebrates. Some views may insist that anthropocentric mammalian immunologists utilized a tool to propel: the universal innate immune system of ubiquitous and plentiful invertebrates as an essential system for vertebrates. This was advantageous for all immunology; moreover innate immunity acquired an extended raison d'être. Innate immunity should help if there would be a failure of the adaptive immune system. Still to be answered are questions concerning immunologic surveillance that includes clonal selection. We can then ask does immunologic surveillance play a role in the survival of invertebrates that most universally seem to not develop cancer of vertebrates especially mammals; invertebrates only develop benign tumor. A recent proposal concerns an alternative explanation that is all embracing. Danger hypothesis operates in striking contrast to the self/not self hypothesis. This view holds that the immune system is adapted to intervene not because self is threatened but because of the system's sense of danger. This perception occurs by means of signals other than recognition of microbial pattern recognition molecules characteristic of invertebrates. Response to danger may be another way of analyzing innate immunity that does not trigger the production of clones and therefore does not rely entirely on the self/not self model. The review will end with certain perspectives on artificial immune systems new on the scene and the product of computational immunologists. The tentative view is to question if the immune systems of invertebrates might be amenable to such an analysis? This would offer more credence to the innate system, often pushed aside thus favoring the adaptive responses.

Different culture conditions affect the growth of human tendon stem/progenitor cells (TSPCs) within a mixed tendon cells (TCs) population.

PubMed

Viganò, M; Perucca Orfei, C; Colombini, A; Stanco, D; Randelli, P; Sansone, V; de Girolamo, L

2017-12-01

Tendon resident cells (TCs) are a mixed population made of terminally differentiated tenocytes and tendon stem/progenitor cells (TSPCs). Since the enrichment of progenitors proportion could enhance the effectiveness of treatments based on these cell populations, the interest on the effect of culture conditions on the TSPCs is growing. In this study the clonal selection and the culture in presence or absence of basic fibroblast growth factor (bFGF) were used to assess their influences on the stemness properties and phenotype specific features of tendon cells. Cells cultured with the different methods were analyzed in terms of clonogenic and differentiation abilities, stem and tendon specific genes expression and immunophenotype at passage 2 and passage 4. The clonal selection allowed to isolate cells with a higher multi-differentiation potential, but at the same time a lower proliferation rate in comparison to the whole population. Moreover, the clones express a higher amounts of stemness marker OCT4 and tendon specific transcription factor Scleraxis (SCX) mRNA, but a lower level of decorin (DCN). On the other hand, the number of cells obtained by clonal selection was extremely low and most of the clones were unable to reach a high number of passages in cultures. The presence of bFGF influences TCs morphology, enhance their proliferation rate and reduce their clonogenic ability. Interestingly, the expression of CD54, a known mesenchymal stem cell marker, is reduced in presence of bFGF at early passages. Nevertheless, bFGF does not affect the chondrogenic and osteogenic potential of TCs and the expression of tendon specific markers, while it was able to downregulate the OCT4 expression. This study showed that clonal selection enhance progenitors content in TCs populations, but the extremely low number of cells produced with this method could represent an insurmountable obstacle to its application in clinical approaches. We observed that the addition of bFGF to the culture medium promotes the maintenance of a higher number of differentiated cells, reducing the proportion of progenitors within the whole population. Overall our findings demonstrated the importance of the use of specific culture protocols to obtain tendon cells for possible clinical applications.

Evolution of immune systems from self/not self to danger to artificial immune systems (AIS)

NASA Astrophysics Data System (ADS)

Cooper, Edwin L.

2010-03-01

This review will examine the evolution of immune mechanisms by emphasizing information from animal groups exclusive of all vertebrates. There will be a focus on concepts that propelled the immune system into prominent discourse in the life sciences. The self/not self hypothesis was crucial and so was the concern for immunologic memory or anamnesia, development of cancer, autoimmunity, and clonal selection. Now we may be able to deconstruct clonal selection since it is not applicable in the sense that it is not applicable to invertebrate mechanisms. Clonal selection seems to be purely as all evidence indicates a vertebrate strategy and therefore irrelevant to invertebrates. Some views may insist that anthropocentric mammalian immunologists utilized a tool to propel: the universal innate immune system of ubiquitous and plentiful invertebrates as an essential system for vertebrates. This was advantageous for all immunology; moreover innate immunity acquired an extended raison d'être. Innate immunity should help if there would be a failure of the adaptive immune system. Still to be answered are questions concerning immunologic surveillance that includes clonal selection. We can then ask does immunologic surveillance play a role in the survival of invertebrates that most universally seem to not develop cancer of vertebrates especially mammals; invertebrates only develop benign tumor. A recent proposal concerns an alternative explanation that is all embracing. Danger hypothesis operates in striking contrast to the self/not self hypothesis. This view holds that the immune system is adapted to intervene not because self is threatened but because of the system's sense of danger. This perception occurs by means of signals other than recognition of microbial pattern recognition molecules characteristic of invertebrates. Response to danger may be another way of analyzing innate immunity that does not trigger the production of clones and therefore does not rely entirely on the self/not self model. The review will end with certain perspectives on artificial immune systems new on the scene and the product of computational immunologists. The tentative view is to question if the immune systems of invertebrates might be amenable to such an analysis? This would offer more credence to the innate system, often pushed aside thus favoring the adaptive responses.

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

PubMed Central

Oshima, Koichi; Khiabanian, Hossein; da Silva-Almeida, Ana C.; Tzoneva, Gannie; Abate, Francesco; Ambesi-Impiombato, Alberto; Sanchez-Martin, Marta; Carpenter, Zachary; Penson, Alex; Perez-Garcia, Arianne; Eckert, Cornelia; Nicolas, Concepción; Balbin, Milagros; Sulis, Maria Luisa; Kato, Motohiro; Koh, Katsuyoshi; Paganin, Maddalena; Basso, Giuseppe; Gastier-Foster, Julie M.; Devidas, Meenakshi; Loh, Mignon L.; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A.

2016-01-01

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy. PMID:27655895

Floral variation and environmental heterogeneity in a tristylous clonal aquatic of the Pantanal wetlands of Brazil

PubMed Central

Leme da Cunha, Nicolay; Fischer, Erich; Lorenz-Lemke, Aline P.; Barrett, Spencer C. H.

2014-01-01

Background and Aims The balance between stochastic forces and frequency-dependent mating largely governs style morph frequencies in heterostylous populations. In clonal species, deviations from equal morph ratios often result from founder events and unfavourable conditions for sexual reproduction. The aim of this study was to investigate whether different flooding regimes, because of their influence on sexual vs. clonal reproduction, are associated with regional variation in morph frequencies and floral trait differentiation in populations of the clonal, tristylous, aquatic Eichhornia azurea (Pontederiaceae) in the Pantanal wetlands of Brazil. Methods Style morph frequencies were sampled from 73 populations distributed across four flooding regimes differing in depth and duration. Measurements of flower size, sex-organ dimension, pollen size and pollen production were made in selected populations, and pollinator assemblages and their functional traits were recorded. Key Results Most populations of E. azurea were tristylous (78 %), but the majority exhibited uneven morph ratios. The frequency of the mid-styled morph was significantly lower than that of the long- and short-styled morphs. Morph evenness was positively associated with population size but not with flooding regime. There were significant phenotypic differences among flooding regimes for all floral traits, including populations with reduced flower size, sex-organ length and smaller pollen. Pollinator assemblages varied with flood duration. Conclusions The similar morph structure and evenness of populations, regardless of flooding regime, suggest that sexual reproduction and clonal dispersal are sufficiently common to prevent the signature of founder events from dominating in a region. However, the pervasive occurrence of biased morph ratios in most populations suggests that many are in a non-equilibrium state. The reduced frequency of the mid-styled morph in trimorphic and dimorphic populations may be associated with the weak self-incompatibility of this morph resulting in selfing and inbreeding depression. Clonality in E. azurea and the weak self-incompatibility of the mid-styled morph may make it more vulnerable to geitonogamous selfing. PMID:25180289

Evolutionary perspectives on clonal reproduction in vertebrate animals

PubMed Central

Avise, John C.

2015-01-01

A synopsis is provided of different expressions of whole-animal vertebrate clonality (asexual organismal-level reproduction), both in the laboratory and in nature. For vertebrate taxa, such clonal phenomena include the following: human-mediated cloning via artificial nuclear transfer; intergenerational clonality in nature via parthenogenesis and gynogenesis; intergenerational hemiclonality via hybridogenesis and kleptogenesis; intragenerational clonality via polyembryony; and what in effect qualifies as clonal replication via self-fertilization and intense inbreeding by simultaneous hermaphrodites. Each of these clonal or quasi-clonal mechanisms is described, and its evolutionary genetic ramifications are addressed. By affording an atypical vantage on standard vertebrate reproduction, clonality offers fresh perspectives on the evolutionary and ecological significance of recombination-derived genetic variety. PMID:26195735

Clonal Integration Enhances the Performance of a Clonal Plant Species under Soil Alkalinity Stress

PubMed Central

Sun, Juanjuan; Chen, Jishan; Zhang, Yingjun

2015-01-01

Clonal plants have been shown to successfully survive in stressful environments, including salinity stress, drought and depleted nutrients through clonal integration between original and subsequent ramets. However, relatively little is known about whether clonal integration can enhance the performance of clonal plants under alkalinity stress. We investigated the effect of clonal integration on the performance of a typical rhizomatous clonal plant, Leymus chinensis, using a factorial experimental design with four levels of alkalinity and two levels of rhizome connection treatments, connected (allowing integration) and severed (preventing integration). Clonal integration was estimated by comparing physiological and biomass features between the rhizome-connected and rhizome-severed treatments. We found that rhizome-connected treatment increased the biomass, height and leaf water potential of subsequent ramets at highly alkalinity treatments but did not affect them at low alkalinity treatments. However, rhizome-connected treatment decreased the root biomass of subsequent ramets and did not influence the photosynthetic rates of subsequent ramets. The biomass of original ramets was reduced by rhizome-connected treatment at the highest alkalinity level. These results suggest that clonal integration can increase the performance of clonal plants under alkalinity stress. Rhizome-connected plants showed dramatically increased survival of buds with negative effects on root weight, indicating that clonal integration influenced the resource allocation pattern of clonal plants. A cost-benefit analysis based on biomass measures showed that original and subsequent ramets significantly benefited from clonal integration in highly alkalinity stress, indicating that clonal integration is an important adaptive strategy by which clonal plants could survive in local alkalinity soil. PMID:25790352

Clonal relationship among Vibrio cholerae O1 El Tor strains isolated in Somalia.

PubMed

Scrascia, Maria; Pugliese, Nicola; Maimone, Francesco; Mohamud, Kadigia A; Grimont, Patrick A D; Materu, Sadiki F; Pazzani, Carlo

2009-03-01

One hundred and three Vibrio cholerae O1 strains, selected to represent the cholera outbreaks which occurred in Somalia in 1998-1999, were characterized by random amplified polymorphic DNA patterns, ribotyping, and antimicrobial susceptibility. All strains showed a unique amplified DNA pattern and 2 closely related ribotypes (B5a and B8a), among which B5a was the more frequently identified. Ninety-one strains were resistant to ampicillin, chloramphenicol, spectinomycin, streptomycin, sulfamethoxazole, and trimethoprim, conferred, except for spectinomycin, by a conjugative plasmid IncC. These findings indicated that the group of strains active in Somalia in the late 1990s had a clonal origin.

Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

PubMed Central

Qin, Y; Duquette, P; Zhang, Y; Talbot, P; Poole, R; Antel, J

1998-01-01

The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is characterized by increased concentrations of immunoglobulin (Ig), which on electrophoretic analysis shows restricted heterogeneity (oligoclonal bands). CSF Ig is composed of both serum and intrathecally produced components. To examine the properties of intrathecal antibody-producing B cells, we analyzed Ig heavy-chain variable (V(H)) region genes of B cells recovered from the CSF of 12 MS patients and 15 patients with other neurological diseases (OND). Using a PCR technique, we could detect rearrangements of Ig V(H) genes in all samples. Sequence analysis of complementarity-determining region 3 (CDR3) of rearranged VDJ genes revealed expansion of a dominant clone or clones in 10 of the 12 MS patients. B cell clonal expansion was identified in 3 of 15 OND. The nucleotide sequences of V(H) genes from clonally expanded CSF B cells in MS patients demonstrated the preferential usage of the V(H) IV family. There were numerous somatic mutations, mainly in the CDRs, with a high replacement-to-silent ratio; the mutations were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. Our results demonstrate that in MS CSF, there is a high frequency of clonally expanded B cells that have properties of postgerminal center memory or antibody-forming lymphocytes. PMID:9727074

An invasive clonal plant benefits from clonal integration more than a co-occurring native plant in nutrient-patchy and competitive environments.

PubMed

You, Wenhua; Fan, Shufeng; Yu, Dan; Xie, Dong; Liu, Chunhua

2014-01-01

Many notorious invasive plants are clonal, however, little is known about the different roles of clonal integration effects between invasive and native plants. Here, we hypothesize that clonal integration affect growth, photosynthetic performance, biomass allocation and thus competitive ability of invasive and native clonal plants, and invasive clonal plants benefit from clonal integration more than co-occurring native plants in heterogeneous habitats. To test these hypotheses, two stoloniferous clonal plants, Alternanthera philoxeroides (invasive), Jussiaea repens (native) were studied in China. The apical parts of both species were grown either with or without neighboring vegetation and the basal parts without competitors were in nutrient- rich or -poor habitats, with stolon connections were either severed or kept intact. Competition significantly reduced growth and photosynthetic performance of the apical ramets in both species, but not the biomass of neighboring vegetation. Without competition, clonal integration greatly improved the growth and photosynthetic performance of both species, especially when the basal parts were in nutrient-rich habitats. When grown with neighboring vegetation, growth of J. repens and photosynthetic performance of both species were significantly enhanced by clonal integration with the basal parts in both nutrient-rich and -poor habitats, while growth and relative neighbor effect (RNE) of A. philoxeroides were greatly improved by clonal integration only when the basal parts were in nutrient-rich habitats. Moreover, clonal integration increased A. philoxeroides's biomass allocation to roots without competition, but decreased it with competition, especially when the basal ramets were in nutrient-rich sections. Effects of clonal integration on biomass allocation of J. repens was similar to that of A. philoxeroides but with less significance. These results supported our hypothesis that invasive clonal plants A. philoxeroides benefits from clonal integration more than co-occurring native J. repens, suggesting that the invasiveness of A. philoxeroides may be closely related to clonal integration in heterogeneous environments.

An Invasive Clonal Plant Benefits from Clonal Integration More than a Co-Occurring Native Plant in Nutrient-Patchy and Competitive Environments

PubMed Central

You, Wenhua; Fan, Shufeng; Yu, Dan; Xie, Dong; Liu, Chunhua

2014-01-01

Many notorious invasive plants are clonal, however, little is known about the different roles of clonal integration effects between invasive and native plants. Here, we hypothesize that clonal integration affect growth, photosynthetic performance, biomass allocation and thus competitive ability of invasive and native clonal plants, and invasive clonal plants benefit from clonal integration more than co-occurring native plants in heterogeneous habitats. To test these hypotheses, two stoloniferous clonal plants, Alternanthera philoxeroides (invasive), Jussiaea repens (native) were studied in China. The apical parts of both species were grown either with or without neighboring vegetation and the basal parts without competitors were in nutrient- rich or -poor habitats, with stolon connections were either severed or kept intact. Competition significantly reduced growth and photosynthetic performance of the apical ramets in both species, but not the biomass of neighboring vegetation. Without competition, clonal integration greatly improved the growth and photosynthetic performance of both species, especially when the basal parts were in nutrient-rich habitats. When grown with neighboring vegetation, growth of J. repens and photosynthetic performance of both species were significantly enhanced by clonal integration with the basal parts in both nutrient-rich and -poor habitats, while growth and relative neighbor effect (RNE) of A. philoxeroides were greatly improved by clonal integration only when the basal parts were in nutrient-rich habitats. Moreover, clonal integration increased A. philoxeroides's biomass allocation to roots without competition, but decreased it with competition, especially when the basal ramets were in nutrient-rich sections. Effects of clonal integration on biomass allocation of J. repens was similar to that of A. philoxeroides but with less significance. These results supported our hypothesis that invasive clonal plants A. philoxeroides benefits from clonal integration more than co-occurring native J. repens, suggesting that the invasiveness of A. philoxeroides may be closely related to clonal integration in heterogeneous environments. PMID:24816849

Clonal Architecture of Secondary Acute Myeloid Leukemia

PubMed Central

Walter, Matthew J.; Shen, Dong; Ding, Li; Shao, Jin; Koboldt, Daniel C.; Chen, Ken; Larson, David E.; McLellan, Michael D.; Dooling, David; Abbott, Rachel; Fulton, Robert; Magrini, Vincent; Schmidt, Heather; Kalicki-Veizer, Joelle; O’Laughlin, Michelle; Fan, Xian; Grillot, Marcus; Witowski, Sarah; Heath, Sharon; Frater, John L.; Eades, William; Tomasson, Michael; Westervelt, Peter; DiPersio, John F.; Link, Daniel C.; Mardis, Elaine R.; Ley, Timothy J.; Wilson, Richard K.; Graubert, Timothy A.

2012-01-01

BACKGROUND The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. METHODS We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. RESULTS Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. CONCLUSIONS Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.) PMID:22417201

Novel synthetic monoketone transmute radiation-triggered NFκB-dependent TNFα cross-signaling feedback maintained NFκB and favors neuroblastoma regression.

PubMed

Aravindan, Sheeja; Natarajan, Mohan; Awasthi, Vibhudutta; Herman, Terence S; Aravindan, Natarajan

2013-01-01

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK-PN-DW, MC-IXC and SK-N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

PubMed Central

Aravindan, Sheeja; Natarajan, Mohan; Awasthi, Vibhudutta; Herman, Terence S.; Aravindan, Natarajan

2013-01-01

Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK–PN–DW, MC-IXC and SK–N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion. PMID:23967300

densityCut: an efficient and versatile topological approach for automatic clustering of biological data

PubMed Central

Ding, Jiarui; Shah, Sohrab; Condon, Anne

2016-01-01

Motivation: Many biological data processing problems can be formalized as clustering problems to partition data points into sensible and biologically interpretable groups. Results: This article introduces densityCut, a novel density-based clustering algorithm, which is both time- and space-efficient and proceeds as follows: densityCut first roughly estimates the densities of data points from a K-nearest neighbour graph and then refines the densities via a random walk. A cluster consists of points falling into the basin of attraction of an estimated mode of the underlining density function. A post-processing step merges clusters and generates a hierarchical cluster tree. The number of clusters is selected from the most stable clustering in the hierarchical cluster tree. Experimental results on ten synthetic benchmark datasets and two microarray gene expression datasets demonstrate that densityCut performs better than state-of-the-art algorithms for clustering biological datasets. For applications, we focus on the recent cancer mutation clustering and single cell data analyses, namely to cluster variant allele frequencies of somatic mutations to reveal clonal architectures of individual tumours, to cluster single-cell gene expression data to uncover cell population compositions, and to cluster single-cell mass cytometry data to detect communities of cells of the same functional states or types. densityCut performs better than competing algorithms and is scalable to large datasets. Availability and Implementation: Data and the densityCut R package is available from https://bitbucket.org/jerry00/densitycut_dev. Contact: condon@cs.ubc.ca or sshah@bccrc.ca or jiaruid@cs.ubc.ca Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153661

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones.

PubMed

Melchardt, Thomas; Hufnagl, Clemens; Weinstock, David M; Kopp, Nadja; Neureiter, Daniel; Tränkenschuh, Wolfgang; Hackl, Hubert; Weiss, Lukas; Rinnerthaler, Gabriel; Hartmann, Tanja N; Greil, Richard; Weigert, Oliver; Egle, Alexander

2016-08-09

Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using next-generation sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested. Primary tumor samples showed a median of 8 non-synonymous mutations (range: 0-24) with the used gene set. Lower numbers of non-synonymous mutations in the primary tumor were associated with a better median OS compared with higher numbers (28 versus 15 months, p=0.031). We observed three patterns of clonal evolution during relapse of disease: large global change, subclonal selection and no or minimal change possibly suggesting preprogrammed resistance. We conclude that targeted re-sequencing is a feasible and informative approach to characterize the molecular pattern of relapse and it creates novel insights into the role of dynamics of individual genes.

Cryopreserved storage of clonal germplasm in the USDA National Plant Germplasm System

USDA-ARS?s Scientific Manuscript database

The U.S. Department of Agriculture-Agricultural Research Service (USDA-ARS), National Plant Germplasm System (NPGS) plant collections are a critical source of genetic diversity for breeding and selection of improved crops, including vegetatively propagated plants. Information on these collections is...

A Big Bang model of human colorectal tumor growth

PubMed Central

Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A.; Salomon, Matthew P.; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F.; Shibata, Darryl; Curtis, Christina

2015-01-01

What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications. PMID:25665006

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.

PubMed

O'Leary, Ben; Hrebien, Sarah; Morden, James P; Beaney, Matthew; Fribbens, Charlotte; Huang, Xin; Liu, Yuan; Bartlett, Cynthia Huang; Koehler, Maria; Cristofanilli, Massimo; Garcia-Murillas, Isaac; Bliss, Judith M; Turner, Nicholas C

2018-03-01

CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

Infliximab Induces Clonal Expansion of γδ-T Cells in Crohn's Disease: A Predictor of Lymphoma Risk?

PubMed Central

Kelsen, Jens; Dige, Anders; Schwindt, Heinrich; D'Amore, Francesco; Pedersen, Finn S.; Agnholt, Jørgen; Christensen, Lisbet A.; Dahlerup, Jens F.; Hvas, Christian L.

2011-01-01

Background Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. Methodology/Principal Findings We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n = 20) or adalimumab (Humira®; n = 26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5–15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. Conclusion/Significance CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents. PMID:21483853

Epidemiological tracking and population assignment of the non-clonal bacterium, Burkholderia pseudomallei.

PubMed

Dale, Julia; Price, Erin P; Hornstra, Heidie; Busch, Joseph D; Mayo, Mark; Godoy, Daniel; Wuthiekanun, Vanaporn; Baker, Anthony; Foster, Jeffrey T; Wagner, David M; Tuanyok, Apichai; Warner, Jeffrey; Spratt, Brian G; Peacock, Sharon J; Currie, Bart J; Keim, Paul; Pearson, Talima

2011-12-01

Rapid assignment of bacterial pathogens into predefined populations is an important first step for epidemiological tracking. For clonal species, a single allele can theoretically define a population. For non-clonal species such as Burkholderia pseudomallei, however, shared allelic states between distantly related isolates make it more difficult to identify population defining characteristics. Two distinct B. pseudomallei populations have been previously identified using multilocus sequence typing (MLST). These populations correlate with the major foci of endemicity (Australia and Southeast Asia). Here, we use multiple Bayesian approaches to evaluate the compositional robustness of these populations, and provide assignment results for MLST sequence types (STs). Our goal was to provide a reference for assigning STs to an established population without the need for further computational analyses. We also provide allele frequency results for each population to enable estimation of population assignment even when novel STs are discovered. The ability for humans and potentially contaminated goods to move rapidly across the globe complicates the task of identifying the source of an infection or outbreak. Population genetic dynamics of B. pseudomallei are particularly complicated relative to other bacterial pathogens, but the work here provides the ability for broad scale population assignment. As there is currently no independent empirical measure of successful population assignment, we provide comprehensive analytical details of our comparisons to enable the reader to evaluate the robustness of population designations and assignments as they pertain to individual research questions. Finer scale subdivision and verification of current population compositions will likely be possible with genotyping data that more comprehensively samples the genome. The approach used here may be valuable for other non-clonal pathogens that lack simple group-defining genetic characteristics and provides a rapid reference for epidemiologists wishing to track the origin of infection without the need to compile population data and learn population assignment algorithms.

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.

PubMed

Kridel, Robert; Chan, Fong Chun; Mottok, Anja; Boyle, Merrill; Farinha, Pedro; Tan, King; Meissner, Barbara; Bashashati, Ali; McPherson, Andrew; Roth, Andrew; Shumansky, Karey; Yap, Damian; Ben-Neriah, Susana; Rosner, Jamie; Smith, Maia A; Nielsen, Cydney; Giné, Eva; Telenius, Adele; Ennishi, Daisuke; Mungall, Andrew; Moore, Richard; Morin, Ryan D; Johnson, Nathalie A; Sehn, Laurie H; Tousseyn, Thomas; Dogan, Ahmet; Connors, Joseph M; Scott, David W; Steidl, Christian; Marra, Marco A; Gascoyne, Randy D; Shah, Sohrab P

2016-12-01

Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

PubMed Central

Mottok, Anja; Boyle, Merrill; Tan, King; Meissner, Barbara; Bashashati, Ali; Roth, Andrew; Shumansky, Karey; Nielsen, Cydney; Giné, Eva; Moore, Richard; Morin, Ryan D.; Sehn, Laurie H.; Tousseyn, Thomas; Dogan, Ahmet; Scott, David W.; Steidl, Christian; Gascoyne, Randy D.; Shah, Sohrab P.

2016-01-01

Background Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Methods and Findings Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Conclusions Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies. PMID:27959929

Molecular epidemiology of clonal diploids: a quick overview and a short DIY (do it yourself) notice.

PubMed

De Meeûs, Thierry; Lehmann, Laurent; Balloux, François

2006-03-01

In this short review we report the basic notions needed for understanding the population genetics of clonal diploids. We focus on the consequences of clonality on the distribution of genetic diversity within individuals, between individuals and between populations. We then summarise how to detect clonality in mainly sexual populations, conversely, how to detect sexuality in mainly clonal populations and also how genetic differentiation between populations is affected by clonality in diploids. This information is then used for building recipes on how to analyse and interpret genetic polymorphism data in molecular epidemiology studies of clonal diploids.

[B lymphocyte clonal evolution of human reactive lymph nodes revealed by lineage tree analysis].

PubMed

Tabibian-Keissar, Hilla; Schiby, Ginette; Azogui-Rosenthal, Noemie; Hazanov, Helena; Rakovsky, Aviya Shapira; Michaeli, Miri; Rosenblatt, Kinneret; Mehr, Ramit; Barshack, Iris

2013-06-01

Hypermutation and selection processes, characterizing T-dependent B cell responses taking place in germinal centers of lymph nodes, lead to B cell receptor affinity maturation. Those immune responses lead to the development of memory B cells and plasma cells that secrete high amounts of antibody molecules. The dynamics of B cell clonal evolution during affinity maturation has significant importance in infectious and autoimmune diseases, malignancies and aging. Immunoglobulin (Ig) gene mutational Lineage tree construction by comparing variable regions of Ig-gene sequences to the Ig germline gene is an interesting approach for studying B cell cLonal evolution. Lineage tree shapes and Ig gene mutations can be evaluated not only qualitatively and intuitively, but also quantitatively, and thus reveal important information related to hypermutation and selection. In this paper we describe the experimental protocols that we used for PCR amplification of Igvariable region genes from human formalin fixed paraffin embedded reactive lymph node tissues and the subsequent bioinformatical analyses of sequencing data using Ig mutational lineage trees. B cell populations of three out of four reactive Lymph node tissues were composed of several clones. Most of the Ig gene mutational lineage trees were small and narrow. Significant differences were not detected by quantification of Lineage trees. B lymphocyte clones that were detected in human reactive lymph node tissues represent major responding clones in normal polyclonal immune response. This result is in line with the polyclonal profile of B Lymphocyte populations that reside in reactive lymph node tissues.

Selective Inhibition of Tumor Growth by Clonal NK Cells Expressing an ErbB2/HER2-Specific Chimeric Antigen Receptor

PubMed Central

Schönfeld, Kurt; Sahm, Christiane; Zhang, Congcong; Naundorf, Sonja; Brendel, Christian; Odendahl, Marcus; Nowakowska, Paulina; Bönig, Halvard; Köhl, Ulrike; Kloess, Stephan; Köhler, Sylvia; Holtgreve-Grez, Heidi; Jauch, Anna; Schmidt, Manfred; Schubert, Ralf; Kühlcke, Klaus; Seifried, Erhard; Klingemann, Hans G; Rieger, Michael A; Tonn, Torsten; Grez, Manuel; Wels, Winfried S

2015-01-01

Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy. PMID:25373520

Optimization for Service Routes of Pallet Service Center Based on the Pallet Pool Mode

PubMed Central

He, Shiwei; Song, Rui

2016-01-01

Service routes optimization (SRO) of pallet service center should meet customers' demand firstly and then, through the reasonable method of lines organization, realize the shortest path of vehicle driving. The routes optimization of pallet service center is similar to the distribution problems of vehicle routing problem (VRP) and Chinese postman problem (CPP), but it has its own characteristics. Based on the relevant research results, the conditions of determining the number of vehicles, the one way of the route, the constraints of loading, and time windows are fully considered, and a chance constrained programming model with stochastic constraints is constructed taking the shortest path of all vehicles for a delivering (recycling) operation as an objective. For the characteristics of the model, a hybrid intelligent algorithm including stochastic simulation, neural network, and immune clonal algorithm is designed to solve the model. Finally, the validity and rationality of the optimization model and algorithm are verified by the case. PMID:27528865

Clonal growth: invasion or stability? A comparative study of clonal architecture and diversity in native and introduced lineages of Phragmites australis (Poaceae).

PubMed

Douhovnikoff, Vladimir; Hazelton, Eric L G

2014-09-01

• The characteristics of clonal growth that are advantageous in invasive plants can also result in native plants' ability to resist invasion. In Maine, we compared the clonal architecture and diversity of an invasive lineage (introduced Phragmites) and a noninvasive lineage (native Phragmites) present in much of North America. This study is the first on stand-scale diversity using a sample size and systematic spatial-sampling scheme adequate for characterizing clonal structure in Phragmites. Our questions included: (1) Does the structure and extent of clonal growth suggest that the potential for clonal growth contributes to the invasiveness of the introduced lineage? (2) Is clonal growth common in the native lineage, acting as a possible source of ecological resistance and resilience?• Microsatellite markers were used to measure clonal sizes, architecture, and diversity within each lineage in stands within four marshes in Maine.• Clonal diversity measures indicated that clonal growth was significantly greater in stands of the native lineage than in the introduced. While lineage was a consistent predictor of clonal diversity relative ranking, the marsh location was a much stronger predictor of the absolute range of these values.• Our results indicate an important role for clonal growth in the space consolidation of native Phragmites and could explain why the introduced lineage, with stronger competitive traits, has not replaced the native where they co-occur. These results with regard to clone size, size distributions, singleton occurrence, and clonal architecture provide some evidence for stand development that follows a genotypic initial floristics model. © 2014 Botanical Society of America, Inc.

Selection and clonal propagation of high artemisinin genotypes of Artemisia annua

USDA-ARS?s Scientific Manuscript database

Artemisinin, produced in the glandular trichomes of Artemisia annua L. is a vital antimalarial drug effective against Plasmodium falciparum resistant to quinine-derived medicines. Although work has progressed on the semi-synthetic production of artemisinin, field production of A. annua remains the p...

Response of butternut selections to inoculation with Sirococcus clavigignenti-juglandacearum

Treesearch

M.E. Ostry; M. Moore

2008-01-01

Butternut trees (Juglans cinerea) clonally propagated via grafting from source trees with putative resistance to butternut canker were inoculated monthly with two isolates of Sirococcus clavigignenti-juglandacearum in a field planting in Minnesota. Significant differences in resulting canker length were found among (i) month of...

Sexual reproduction and the evolution of microbial pathogens.

PubMed

Heitman, Joseph

2006-09-05

Three common systemic human fungal pathogens--Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus--have retained all the machinery to engage in sexual reproduction, and yet their populations are often clonal with limited evidence for recombination. Striking parallels have emerged with four protozoan parasites that infect humans: Toxoplasma gondii, Trypanosoma brucei, Trypanosoma cruzi and Plasmodium falciparum. Limiting sexual reproduction appears to be a common virulence strategy, enabling generation of clonal populations well adapted to host and environmental niches, yet retaining the ability to engage in sexual or parasexual reproduction and respond to selective pressure. Continued investigation of the sexual nature of microbial pathogens should facilitate both laboratory investigation and an understanding of the complex interplay between pathogens, hosts, vectors, and their environments.

United we stand, divided we fall: a meta-analysis of experiments on clonal integration and its relationship to invasiveness.

PubMed

Song, Yao-Bin; Yu, Fei-Hai; Keser, Lidewij H; Dawson, Wayne; Fischer, Markus; Dong, Ming; van Kleunen, Mark

2013-02-01

Many ecosystems are dominated by clonal plants. Among the most distinctive characteristics of clonal plants is their potential for clonal integration (i.e. the translocation of resources between interconnected ramets), suggesting that integration may play a role in their success. However, a general synthesis of effects of clonal integration on plant performance is lacking. We conducted a meta-analysis on the effects of clonal integration on biomass production and asexual reproduction of the whole clone, the recipient part (i.e. the part of a clone that imports resources) and the donor part (i.e. the part of a clone that exports resources). The final dataset contained 389 effect sizes from 84 studies covering 57 taxa. Overall, clonal integration increased performance of recipient parts without decreasing that of donor parts, and thus increased performance of whole clones. Among the studies and taxa considered, the benefits of clonal integration did not differ between two types of experimental approaches, between stoloniferous and rhizomatous growth forms, between directions of resource translocation (from younger to older ramet or vice versa), or among types of translocated resources (water, nutrients and carbohydrates). Clonal taxa with larger benefits of integration on whole-clone performance were not more invasive globally, but taxa in which recipient parts in unfavorable patches benefited more from integration were. Our results demonstrate general performance benefits of clonal integration, at least in the short term, and suggest that clonal integration contributes to the success of clonal plants.

Noise-Driven Phenotypic Heterogeneity with Finite Correlation Time in Clonal Populations.

PubMed

Lee, UnJin; Skinner, John J; Reinitz, John; Rosner, Marsha Rich; Kim, Eun-Jin

2015-01-01

There has been increasing awareness in the wider biological community of the role of clonal phenotypic heterogeneity in playing key roles in phenomena such as cellular bet-hedging and decision making, as in the case of the phage-λ lysis/lysogeny and B. Subtilis competence/vegetative pathways. Here, we report on the effect of stochasticity in growth rate, cellular memory/intermittency, and its relation to phenotypic heterogeneity. We first present a linear stochastic differential model with finite auto-correlation time, where a randomly fluctuating growth rate with a negative average is shown to result in exponential growth for sufficiently large fluctuations in growth rate. We then present a non-linear stochastic self-regulation model where the loss of coherent self-regulation and an increase in noise can induce a shift from bounded to unbounded growth. An important consequence of these models is that while the average change in phenotype may not differ for various parameter sets, the variance of the resulting distributions may considerably change. This demonstrates the necessity of understanding the influence of variance and heterogeneity within seemingly identical clonal populations, while providing a mechanism for varying functional consequences of such heterogeneity. Our results highlight the importance of a paradigm shift from a deterministic to a probabilistic view of clonality in understanding selection as an optimization problem on noise-driven processes, resulting in a wide range of biological implications, from robustness to environmental stress to the development of drug resistance.

Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.

PubMed

Siravegna, Giulia; Mussolin, Benedetta; Buscarino, Michela; Corti, Giorgio; Cassingena, Andrea; Crisafulli, Giovanni; Ponzetti, Agostino; Cremolini, Chiara; Amatu, Alessio; Lauricella, Calogero; Lamba, Simona; Hobor, Sebastijan; Avallone, Antonio; Valtorta, Emanuele; Rospo, Giuseppe; Medico, Enzo; Motta, Valentina; Antoniotti, Carlotta; Tatangelo, Fabiana; Bellosillo, Beatriz; Veronese, Silvio; Budillon, Alfredo; Montagut, Clara; Racca, Patrizia; Marsoni, Silvia; Falcone, Alfredo; Corcoran, Ryan B; Di Nicolantonio, Federica; Loupakis, Fotios; Siena, Salvatore; Sartore-Bianchi, Andrea; Bardelli, Alberto

2015-07-01

Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.

Genetic tagging of tumor cells with retrovirus vectors: Clonal analysis of tumor growth and metastasis in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korczak; Robson, I.B.; Lamarche, C.

1988-08-01

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with ..delta..e..delta..rhoMoTn, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418/sup r/ colonies were obtained at a frequency of 4 x 10/sup -3/. Southern blot analysis of a number ofmore » clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal equation of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10/sup 5/ cells from a pooled mixture of 3.6 x 10/sup 2/ G418/sup r/ SP1HU9L or 10/sup 4/ G418/sup r/ SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds of thousands of uniquely marked clones had been injected.« less

Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia.

PubMed

Betensky, Marisol; Babushok, Daria; Roth, Jacquelyn J; Mason, Philip J; Biegel, Jaclyn A; Busse, Tracy M; Li, Yimei; Lind, Curt; Papazoglou, Anna; Monos, Dimitri; Podsakoff, Gregory; Bessler, Monica; Olson, Timothy S

2016-01-01

Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution. Copyright © 2016 Elsevier Inc. All rights reserved.

Exploring origins, invasion history and genetic diversity of Imperata cylindrica (L.) P. Beauv. (Cogongrass) in the United States using genotyping by sequencing.

PubMed

Burrell, A Millie; Pepper, Alan E; Hodnett, George; Goolsby, John A; Overholt, William A; Racelis, Alexis E; Diaz, Rodrigo; Klein, Patricia E

2015-05-01

Imperata cylindrica (Cogongrass, Speargrass) is a diploid C4 grass that is a noxious weed in 73 countries and constitutes a significant threat to global biodiversity and sustainable agriculture. We used a cost-effective genotyping-by-sequencing (GBS) approach to identify the reproductive system, genetic diversity and geographic origins of invasions in the south-eastern United States. In this work, we demonstrated the advantage of employing the closely related, fully sequenced crop species Sorghum bicolor (L.) Moench as a proxy reference genome to identify a set of 2320 informative single nucleotide and insertion-deletion polymorphisms. Genetic analyses identified four clonal lineages of cogongrass and one clonal lineage of Imperata brasiliensis Trin. in the United States. Each lineage was highly homogeneous, and we found no evidence of hybridization among the different lineages, despite geographical overlap. We found evidence that at least three of these lineages showed clonal reproduction prior to introduction to the United States. These results indicate that cogongrass has limited evolutionary potential to adapt to novel environments and further suggest that upon arrival to its invaded range, this species did not require local adaptation through hybridization/introgression or selection of favourable alleles from a broad genetic base. Thus, cogongrass presents a clear case of broad invasive success, across a diversity of environments, in a clonal organism with limited genetic diversity. © 2015 John Wiley & Sons Ltd.

Clonal Evolution and Clinical Significance of Copy Number Neutral Loss of Heterozygosity of Chromosome Arm 6p in Acquired Aplastic Anemia

PubMed Central

Betensky, Marisol; Babushok, Daria; Roth, Jacquelyn J.; Mason, Philip J; Biegel, Jaclyn A.; Busse, Tracy M; Li, Yimei; Lind, Curt; Papazoglou, Anna; Monos, Dimitri; Podsakoff, Gregory; Bessler, Monica; Olson, Timothy S.

2015-01-01

Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution. PMID:26702937

Resistance to phytophthora and graft compatibility with persian walnut among seedlings of chinese wingnut from different sources

USDA-ARS?s Scientific Manuscript database

Seedlings from seven open-pollinated selections of Chinese wingnut (Pterocarya stenoptera) (WN) representing collections of the USDA-ARS National Clonal Germplasm Repository at Davis CA and the University of California at Davis were evaluated as rootstocks for resistance to Phytophthora cinnamomi an...

Role of Mononuclear Phagocytes in the Pathogenesis of Human Immunodeficiency Virus Infection

DTIC Science & Technology

1990-01-01

interpretive problems. First, patient selection has been limited to individuals with late-stage, symptomatic HIV infection. The average time from...months. Such monocytes infected with HIV showed a frequency of infected cells in culture of 5-20% by immunofluorescence with mono- clonal anti -pl7 capsid...cells equally; viruses isolated in PHA/IL-2-treated lymphoblasts replicate only in T cells. Target cell selection of diverse HIV variants may underlie

Invasive clonal plant species have a greater root-foraging plasticity than non-invasive ones.

PubMed

Keser, Lidewij H; Dawson, Wayne; Song, Yao-Bin; Yu, Fei-Hai; Fischer, Markus; Dong, Ming; van Kleunen, Mark

2014-03-01

Clonality is frequently positively correlated with plant invasiveness, but which aspects of clonality make some clonal species more invasive than others is not known. Due to their spreading growth form, clonal plants are likely to experience spatial heterogeneity in nutrient availability. Plasticity in allocation of biomass to clonal growth organs and roots may allow these plants to forage for high-nutrient patches. We investigated whether this foraging response is stronger in species that have become invasive than in species that have not. We used six confamilial pairs of native European clonal plant species differing in invasion success in the USA. We grew all species in large pots under homogeneous or heterogeneous nutrient conditions in a greenhouse, and compared their nutrient-foraging response and performance. Neither invasive nor non-invasive species showed significant foraging responses to heterogeneity in clonal growth organ biomass or in aboveground biomass of clonal offspring. Invasive species had, however, a greater positive foraging response in terms of root and belowground biomass than non-invasive species. Invasive species also produced more total biomass. Our results suggest that the ability for strong root foraging is among the characteristics promoting invasiveness in clonal plants.

Effect of clonal integration on nitrogen cycling in rhizosphere of rhizomatous clonal plant, Phyllostachys bissetii, under heterogeneous light.

PubMed

Li, Yang; Chen, Jing-Song; Xue, Ge; Peng, Yuanying; Song, Hui-Xing

2018-07-01

Clonal integration plays an important role in clonal plant adapting to heterogeneous habitats. It was postulated that clonal integration could exhibit positive effects on nitrogen cycling in the rhizosphere of clonal plant subjected to heterogeneous light conditions. An in-situ experiment was conducted using clonal fragments of Phyllostachys bissetii with two successive ramets. Shading treatments were applied to offspring or mother ramets, respectively, whereas counterparts were treated to full sunlight. Rhizomes between two successive ramets were either severed or connected. Extracellular enzyme activities and nitrogen turnover were measured, as well as soil properties. Abundance of functional genes (archaeal or bacterial amoA, nifH) in the rhizosphere of shaded, offspring or mother ramets were determined using quantitative polymerase chain reaction. Carbon or nitrogen availabilities were significantly influenced by clonal integration in the rhizosphere of shaded ramets. Clonal integration significantly increased extracellular enzyme activities and abundance of functional genes in the rhizosphere of shaded ramets. When rhizomes were connected, higher nitrogen turnover (nitrogen mineralization or nitrification rates) was exhibited in the rhizosphere of shaded offspring ramets. However, nitrogen turnover was significantly decreased by clonal integration in the rhizosphere of shaded mother ramets. Path analysis indicated that nitrogen turnover in the rhizosphere of shaded, offspring or mother ramets were primarily driven by the response of soil microorganisms to dissolved organic carbon or nitrogen. This unique in-situ experiment provided insights into the mechanism of nutrient recycling mediated by clonal integration. It was suggested that effects of clonal integration on the rhizosphere microbial processes were dependent on direction of photosynthates transport in clonal plant subjected to heterogeneous light conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

Disturbance Is an Important Driver of Clonal Richness in Tropical Seagrasses

PubMed Central

McMahon, Kathryn M.; Evans, Richard D.; van Dijk, Kor-jent; Hernawan, Udhi; Kendrick, Gary A.; Lavery, Paul S.; Lowe, Ryan; Puotinen, Marji; Waycott, Michelle

2017-01-01

Clonality is common in many aquatic plant species, including seagrasses, where populations are maintained through a combination of asexual and sexual reproduction. One common measure used to describe the clonal structure of populations is clonal richness. Clonal richness is strongly dependent on the biological characteristics of the species, and how these interact with the environment but can also reflect evolutionary scale processes especially at the edge of species ranges. However, little is known about the spatial patterns and drivers of clonal richness in tropical seagrasses. This study assessed the spatial patterns of clonal richness in meadows of three tropical seagrass species, Thalassia hemprichii, Halodule uninervis, and Halophila ovalis, spanning a range of life-history strategies and spatial scales (2.5–4,711 km) in Indonesia and NW Australia. We further investigated the drivers of clonal richness using general additive mixed models for two of the species, H. uninervis and H. ovalis, over 8° latitude. No significant patterns were observed in clonal richness with latitude, yet disturbance combined with sea surface temperature strongly predicted spatial patterns of clonal richness. Sites with a high probability of cyclone disturbance had low clonal richness, whereas an intermediate probability of cyclone disturbance and the presence of dugong grazing combined with higher sea surface temperatures resulted in higher levels of clonal richness. We propose potential mechanisms for these patterns related to the recruitment and mortality rates of individuals as well as reproductive effort. Under a changing climate, increased severity of tropical cyclones and the decline in populations of mega-grazers have the potential to reduce clonal richness leading to less genetically diverse populations. PMID:29259609

Parallel computing of physical maps--a comparative study in SIMD and MIMD parallelism.

PubMed

Bhandarkar, S M; Chirravuri, S; Arnold, J

1996-01-01

Ordering clones from a genomic library into physical maps of whole chromosomes presents a central computational problem in genetics. Chromosome reconstruction via clone ordering is usually isomorphic to the NP-complete Optimal Linear Arrangement problem. Parallel SIMD and MIMD algorithms for simulated annealing based on Markov chain distribution are proposed and applied to the problem of chromosome reconstruction via clone ordering. Perturbation methods and problem-specific annealing heuristics are proposed and described. The SIMD algorithms are implemented on a 2048 processor MasPar MP-2 system which is an SIMD 2-D toroidal mesh architecture whereas the MIMD algorithms are implemented on an 8 processor Intel iPSC/860 which is an MIMD hypercube architecture. A comparative analysis of the various SIMD and MIMD algorithms is presented in which the convergence, speedup, and scalability characteristics of the various algorithms are analyzed and discussed. On a fine-grained, massively parallel SIMD architecture with a low synchronization overhead such as the MasPar MP-2, a parallel simulated annealing algorithm based on multiple periodically interacting searches performs the best. For a coarse-grained MIMD architecture with high synchronization overhead such as the Intel iPSC/860, a parallel simulated annealing algorithm based on multiple independent searches yields the best results. In either case, distribution of clonal data across multiple processors is shown to exacerbate the tendency of the parallel simulated annealing algorithm to get trapped in a local optimum.

Cutaneous T-cell lymphoma (CTCL): Current practices in blood assessment and the utility of T-cell receptor (TCR)-Vβ chain restriction.

PubMed

Gibson, Juliet F; Huang, Jing; Liu, Kristina J; Carlson, Kacie R; Foss, Francine; Choi, Jaehyuk; Edelson, Richard; Hussong, Jerry W; Mohl, Ramsey; Hill, Sally; Girardi, Michael

2016-05-01

Accurate quantification of malignant cells in the peripheral blood of patients with cutaneous T-cell lymphoma is important for early detection, prognosis, and monitoring disease burden. We sought to determine the spectrum of current clinical practices; critically evaluate elements of current International Society for Cutaneous Lymphomas (ISCL) B1 and B2 staging criteria; and assess the potential role of T-cell receptor-Vβ analysis by flow cytometry. We assessed current clinical practices by survey, and performed a retrospective analysis of 161 patients evaluated at Yale (2011-2014) to compare the sensitivity, specificity, positive predictive value, and negative predictive value of parameters for ISCL B2 staging. There was heterogeneity in clinical practices among institutions. ISCL B1 criteria did not capture 5 Yale cohort cases with immunophenotypic abnormalities that later progressed. T-cell receptor-Vβ testing was more specific than polymerase chain reaction and aided diagnosis in detecting clonality, but was of limited benefit in quantification of tumor burden. Because of limited follow-up involving a single center, further investigation will be necessary to conclude whether our proposed diagnostic algorithm is of general clinical benefit. We propose further study of modified B1 criteria: CD4/CD8 ratio 5 or greater, %CD4(+) CD26(-) 20% or greater, or %CD4(+) CD7(-) 20% or greater, with evidence of clonality. T-cell receptor-Vβ testing should be considered in future diagnostic and staging algorithms. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Cutibacterium acnes molecular typing: time to standardize the method.

PubMed

Dagnelie, M-A; Khammari, A; Dréno, B; Corvec, S

2018-03-12

The Gram-positive, anaerobic/aerotolerant bacterium Cutibacterium acnes is a commensal of healthy human skin; it is subdivided into six main phylogenetic groups or phylotypes: IA1, IA2, IB, IC, II and III. To decipher how far specific subgroups of C. acnes are involved in disease physiopathology, different molecular typing methods have been developed to identify these subgroups: i.e. phylotypes, clonal complexes, and types defined by single-locus sequence typing (SLST). However, as several molecular typing methods have been developed over the last decade, it has become a difficult task to compare the results from one article to another. Based on the scientific literature, the aim of this narrative review is to propose a standardized method to perform molecular typing of C. acnes, according to the degree of resolution needed (phylotypes, clonal complexes, or SLST types). We discuss the existing different typing methods from a critical point of view, emphasizing their advantages and drawbacks, and we identify the most frequently used methods. We propose a consensus algorithm according to the needed phylogeny resolution level. We first propose to use multiplex PCR for phylotype identification, MLST9 for clonal complex determination, and SLST for phylogeny investigation including numerous isolates. There is an obvious need to create a consensus about molecular typing methods for C. acnes. This standardization will facilitate the comparison of results between one article and another, and also the interpretation of clinical data. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Assignment of Streptococcus agalactiae isolates to clonal complexes using a small set of single nucleotide polymorphisms.

PubMed

Honsa, Erin; Fricke, Thomas; Stephens, Alex J; Ko, Danny; Kong, Fanrong; Gilbert, Gwendolyn L; Huygens, Flavia; Giffard, Philip M

2008-08-19

Streptococcus agalactiae (Group B Streptococcus (GBS)) is an important human pathogen, particularly of newborns. Emerging evidence for a relationship between genotype and virulence has accentuated the need for efficient and well-defined typing methods. The objective of this study was to develop a single nucleotide polymorphism (SNP) based method for assigning GBS isolates to multilocus sequence typing (MLST)-defined clonal complexes. It was found that a SNP set derived from the MLST database on the basis of maximization of Simpsons Index of Diversity provided poor resolution and did not define groups concordant with the population structure as defined by eBURST analysis of the MLST database. This was interpreted as being a consequence of low diversity and high frequency horizontal gene transfer. Accordingly, a different approach to SNP identification was developed. This entailed use of the "Not-N" bioinformatic algorithm that identifies SNPs diagnostic for groups of known sequence variants, together with an empirical process of SNP testing. This yielded a four member SNP set that divides GBS into 10 groups that are concordant with the population structure. A fifth SNP was identified that increased the sensitivity for the clinically significant clonal complex 17 to 100%. Kinetic PCR methods for the interrogation of these SNPs were developed, and used to genotype 116 well characterized isolates. A five SNP method for dividing GBS into biologically valid groups has been developed. These SNPs are ideal for high throughput surveillance activities, and combining with more rapidly evolving loci when additional resolution is required.

Assignment of Streptococcus agalactiae isolates to clonal complexes using a small set of single nucleotide polymorphisms

PubMed Central

Honsa, Erin; Fricke, Thomas; Stephens, Alex J; Ko, Danny; Kong, Fanrong; Gilbert, Gwendolyn L; Huygens, Flavia; Giffard, Philip M

2008-01-01

Background Streptococcus agalactiae (Group B Streptococcus (GBS)) is an important human pathogen, particularly of newborns. Emerging evidence for a relationship between genotype and virulence has accentuated the need for efficient and well-defined typing methods. The objective of this study was to develop a single nucleotide polymorphism (SNP) based method for assigning GBS isolates to multilocus sequence typing (MLST)-defined clonal complexes. Results It was found that a SNP set derived from the MLST database on the basis of maximisation of Simpsons Index of Diversity provided poor resolution and did not define groups concordant with the population structure as defined by eBURST analysis of the MLST database. This was interpreted as being a consequence of low diversity and high frequency horizontal gene transfer. Accordingly, a different approach to SNP identification was developed. This entailed use of the "Not-N" bioinformatic algorithm that identifies SNPs diagnostic for groups of known sequence variants, together with an empirical process of SNP testing. This yielded a four member SNP set that divides GBS into 10 groups that are concordant with the population structure. A fifth SNP was identified that increased the sensitivity for the clinically significant clonal complex 17 to 100%. Kinetic PCR methods for the interrogation of these SNPs were developed, and used to genotype 116 well characterized isolates. Conclusion A five SNP method for dividing GBS into biologically valid groups has been developed. These SNPs are ideal for high throughput surveillance activities, and combining with more rapidly evolving loci when additional resolution is required. PMID:18710585

Microsatellite alterations as clonal markers for the detection of human cancer.

PubMed Central

Mao, L; Lee, D J; Tockman, M S; Erozan, Y S; Askin, F; Sidransky, D

1994-01-01

Microsatellite instability has been reported to be an important feature of tumors from hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. The recent discovery of genetic instability in small cell lung carcinoma, a neoplasm not associated with HNPCC, led us to investigate the possible presence of microsatellite alterations in other tumor types. We examined 52 microsatellite repeat sequences in the DNA of normal and tumor pairs from 100 head and neck, bladder, and lung cancer patients by the polymerase chain reaction. Although alterations were rare in dinucleotide repeats, larger (tri- or tetranucleotide) repeats were found to be more prone to expansion or deletion. We screened 100 tumors with a panel of nine tri- and tetranucleotide repeat markers and identified 26 (26%) that displayed alterations in at least one locus. This observation prompted us to examine the possibility of using microsatellite alterations as markers to detect clonal tumor-derived cell populations in pathologic samples. The identical microsatellite alterations detected in the primary tumors were successfully identified in corresponding urine, sputum, and surgical margins from affected patients. This study demonstrates that appropriately selected microsatellite loci are commonly altered in many cancers and can serve as clonal markers for their detection. Images PMID:7937908

Intraspecific competition and light effect on reproduction of Ligularia virgaurea, an invasive native alpine grassland clonal herb

PubMed Central

Xie, Tian-peng; Zhang, Ge-fei; Zhao, Zhi-gang; Du, Guo-zhen; He, Gui-yong

2014-01-01

The relationship between sexual reproduction and clonal growth in clonal plants often shows up at the ramet level. However, only a few studies focus on the relationship at the genet level, which could finally account for evolution. The sexual reproduction and clonal growth of Ligularia virgaurea, a perennial herb widely distributed in the alpine grasslands of the Qinghai-Tibetan Plateau of China, were studied under different competition intensities and light conditions at the genet level through a potted experiment. The results showed that: (1) sexual reproduction did not depend on density or light, and increasing clonal growth with decreasing density and increasing light intensity indicated that intraspecific competition and light intensity may affect the clonal life history of L. virgaurea; (2) both sexual reproduction and clonal growth show a positive linear relationship with genet size under different densities and light conditions; (3) a threshold size is required for sexual reproduction and no evidence of a threshold size for clonal growth under different densities and light conditions; (4) light level affected the allocation of total biomass to clonal and sexual structures, with less allocation to clonal structures and more allocation to sexual structures in full sunlight than in shade; (5) light determined the onset of sexual reproduction, and the genets in the shade required a smaller threshold size for sexual reproduction to occur than the plants in full sunlight; and (6) no evidence was found of trade-offs between clonal growth and sexual reproduction under different densities and light conditions at the genet level, and the positive correlation between two reproductive modes indicated that these are two integrated processes. Clonal growth in this species may be viewed as a growth strategy that tends to maximize genet fitness. PMID:24683463

Next-Generation Sequencing of Antibody Display Repertoires

PubMed Central

Rouet, Romain; Jackson, Katherine J. L.; Langley, David B.; Christ, Daniel

2018-01-01

In vitro selection technology has transformed the development of therapeutic monoclonal antibodies. Using methods such as phage, ribosome, and yeast display, high affinity binders can be selected from diverse repertoires. Here, we review strategies for the next-generation sequencing (NGS) of phage- and other antibody-display libraries, as well as NGS platforms and analysis tools. Moreover, we discuss recent examples relating to the use of NGS to assess library diversity, clonal enrichment, and affinity maturation. PMID:29472918

An efficient and reproducible method for in vitro clonal multiplication of Rauvolfia tetraphylla L. and evaluation of genetic stability using DNA-based markers.

PubMed

Faisal, Mohammad; Alatar, Abdulrahman A; Ahmad, Naseem; Anis, Mohammad; Hegazy, Ahmad K

2012-12-01

An efficient protocol is described for the rapid in vitro clonal propagation of an endangered medicinal plant, Rauvolfia tetraphylla L., through high frequency shoot induction from nodal explants collected from young shoots of a field grown plant. Effects of growth regulators [6-benzyladenine (BA), kinetin (Kin) 2iP, or α-naphthalene acetic acid (NAA)], carbohydrates, different medium [Murashige and Skoog (MS), Woody Plant Medium (WPM), Gamborg medium (B5), Linsmier and Skoog medium (LS)], and various pH levels on in vitro morphogenesis were investigated. The highest frequency of shoot regeneration (90 %) and maximum number of shoot (35.4 ± 2.3) per explant were observed on WPM medium supplemented with 7.5 μM BA, 2.5 μM NAA, and 30 g/l sucrose at pH 5.8. Well-developed shoots, 4-5 cm in length, were successfully rooted ex vitro at 90 % by a 30-min pulse treatment with 150 μM IBA prior to their transfer in planting substrates. The survival rate of transplantation reached 90 % when transferred to field condition. Genetic stability of micropropagated plantlets was assessed and compared with mother plant using Random Amplified Polymorphic DNA and Inter Simple Sequence Repeats markers. No variation was observed in DNA fingerprinting patterns among the micropropagated plants, which were similar to that of the donor plant illustrating their genetic uniformity and clonal fidelity. This confirms that clonal propagation of this plant using axillary shoot buds can be used for commercial exploitation of the selected genotype where a high degree of fidelity is an essential prerequisite. The work contributed to a better in vitro regeneration and clonal mass multiplication of R. tetraphylla and to develop a strategy for the germplasm conservation of this endangered medicinal plant.

Microsatellites within the feline androgen receptor are suitable for X chromosome-linked clonality testing in archival material.

PubMed

Farwick, Nadine M; Klopfleisch, Robert; Gruber, Achim D; Weiss, Alexander Th A

2017-04-01

Objectives A hallmark of neoplasms is their origin from a single cell; that is, clonality. Many techniques have been developed in human medicine to utilise this feature of tumours for diagnostic purposes. One approach is X chromosome-linked clonality testing using polymorphisms of genes encoded by genes on the X chromosome. The aim of this study was to determine if the feline androgen receptor gene was suitable for X chromosome-linked clonality testing. Methods The feline androgen receptor gene was characterised and used to test clonality of feline lymphomas by PCR and polyacrylamide gel electrophoresis, using archival formalin-fixed, paraffin-embedded material. Results Clonality of the feline lymphomas under study was confirmed and the gene locus was shown to represent a suitable target in clonality testing. Conclusions and relevance Because there are some pitfalls of using X chromosome-linked clonality testing, further studies are necessary to establish this technique in the cat.

Begonia semperflorens FB08-59 and FB08-163 clonal germplasm

USDA-ARS?s Scientific Manuscript database

FB08-59 is a dark-foliage, red-flowered wax begonia clone adapted to hot humid summers. It is the product of a recurrent selection breeding procedure to combine and improve the environmental tolerances identified in B. semperflorens ’Kaylen’ and B. cucullata arenosicola into a dark-foliaged, perenn...

Tandem selection for fusiform rust sisease resistance to develop a clonal elite breeding population of loblolly pine

Treesearch

Steve McKeand; Saul Garcia; Josh Steiger; Jim Grissom; Ross Whetten; Fikret Isik

2012-01-01

The elite breeding populations of loblolly pine (Pinus taeda L.) in the North Carolina State University Cooperative Tree Improvement Program are intensively managed for short-term genetic gain. Fusiform rust disease, caused by the fungus Cronartium quercuum f. sp. fusiforme, is the most economically...

Diagnostic Utility of a Clonality Test for Lymphoproliferative Diseases in Koreans Using the BIOMED-2 PCR Assay

PubMed Central

Kim, Young; Choi, Yoo Duk; Choi, Chan

2013-01-01

Background A clonality test for immunoglobulin (IG) and T cell receptor (TCR) is a useful adjunctive method for the diagnosis of lymphoproliferative diseases (LPDs). Recently, the BIOMED-2 multiplex polymerase chain reaction (PCR) assay has been established as a standard method for assessing the clonality of LPDs. We tested clonality in LPDs in Koreans using the BIOMED-2 multiplex PCR and compared the results with those obtained in European, Taiwanese, and Thai participants. We also evaluated the usefulness of the test as an ancillary method for diagnosing LPDs. Methods Two hundred and nineteen specimens embedded in paraffin, including 78 B cell lymphomas, 80 T cell lymphomas and 61 cases of reactive lymphadenitis, were used for the clonality test. Results Mature B cell malignancies showed 95.7% clonality for IG, 2.9% co-existing clonality, and 4.3% polyclonality. Mature T cell malignancies exhibited 83.8% clonality for TCR, 8.1% co-existing clonality, and 16.2% polyclonality. Reactive lymphadenitis showed 93.4% polyclonality for IG and TCR. The majority of our results were similar to those obtained in Europeans. However, the clonality for IGK of B cell malignancies and TCRG of T cell malignancies was lower in Koreans than Europeans. Conclusions The BIOMED-2 multiplex PCR assay was a useful adjunctive method for diagnosing LPDs. PMID:24255634

Pre-leukemic clonal hematopoiesis and the risk of therapy-related myeloid neoplasms: a case-control study

PubMed Central

Takahashi, Koichi; Wang, Feng; Kantarjian, Hagop; Doss, Denaha; Khanna, Kanhav; Thompson, Erika; Zhao, Li; Patel, Keyur; Neelapu, Sattva; Gumbs, Curtis; Bueso-Ramos, Carlos; DiNardo, Courtney D; Colla, Simona; Ravandi, Farhad; Zhang, Jianhua; Huang, Xuelin; Wu, Xifeng; Samaniego, Felipe; Garcia-Manero, Guillermo; Andrew Futreal, P.

2017-01-01

Background Therapy-related myeloid neoplasms (t-MNs) are often fatal secondary malignancies. Risk factors for t-MNs are not well understood. Recent studies suggested that individuals with clonal hematopoiesis have higher risk of developing hematological malignancies. We hypothesized that cancer patients with clonal hematopoiesis have increased risk of developing t-MNs. Methods We conducted a retrospective case-control study to compare the prevalence of clonal hematopoiesis between patients who developed t-MNs (cases) and who did not develop t-MNs (control). For cases, we studied14 patients with various types of cancers who developed t-MNs and whose paired samples of t-MN bone marrow (BM) and peripheral blood (PB) that were previously obtained at the time of primary cancer diagnosis were available. Fifty four patients with lymphoma who received combination chemotherapy and did not develop t-MNs after at least 5 years of follow up were studied as a control. We performed molecular barcode sequencing of 32 genes on the pre-treatment PB samples to detect clonal hematopoiesis. For the t-MN cases, we also performed targeted gene sequencing on t-MN BM samples and investigated clonal evolution from clonal hematopoiesis to t-MNs. To confirm association between clonal hematopoiesis and t-MN development, we also analyzed prevalence of clonal hematopoiesis in a separate cohort of 74 patients with lymphoma. All of these patients were treated under the prospective randomized trial of frontline chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without melatonin and 5 (7%) of them had developed t-MNs. Findings In 14 patients with t-MNs, we detected pre-leukemic mutations in 10 of their prior PB samples (71%). In control, clonal hematopoiesis was detected in 17 patients (31%), and the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis (30% [95% CI: 16% – 51%] vs. 7% [95% CI: 2% – 21%], P = 0.016). In the separate cohort, 5 patients (7%) developed t-MNs and 4 (80%) of them had clonal hematopoiesis. The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis (29% [95% CI: 8%–53%] vs. 0% [95% CI: 0%–0%], P = 0.0009). Multivariate Fine and Gray model showed that having clonal hematopoiesis significantly increased the risk of t-MN development (HR = 13.7, P = 0.013). Interpretation Pre-leukemic clonal hematopoiesis is frequently detected in patients with t-MNs at the time of their primary cancer diagnosis and before patients were exposed to chemotherapy/radiation therapy. Detection of clonal hematopoiesis significantly increased the risk of t-MN development in patients with lymphoma. These data suggest potential approaches of screening clonal hematopoiesis in cancer patients to identify patients at risk of t-MNs and warrants a validation in prospective trial investigating a role of clonal hematopoiesis as a predictive marker for t-MNs. PMID:27923552

Lentiviral and targeted cellular barcoding reveals ongoing clonal dynamics of cell lines in vitro and in vivo

PubMed Central

2014-01-01

Background Cell lines are often regarded as clonal, even though this simplifies what is known about mutagenesis, transformation and other processes that destabilize them over time. Monitoring these clonal dynamics is important for multiple areas of biomedical research, including stem cell and cancer biology. Tracking the contributions of individual cells to large populations, however, has been constrained by limitations in sensitivity and complexity. Results We utilize cellular barcoding methods to simultaneously track the clonal contributions of tens of thousands of cells. We demonstrate that even with optimal culturing conditions, common cell lines including HeLa, K562 and HEK-293 T exhibit ongoing clonal dynamics. Starting a population with a single clone diminishes but does not eradicate this phenomenon. Next, we compare lentiviral and zinc-finger nuclease barcode insertion approaches, finding that the zinc-finger nuclease protocol surprisingly results in reduced clonal diversity. We also document the expected reduction in clonal complexity when cells are challenged with genotoxic stress. Finally, we demonstrate that xenografts maintain clonal diversity to a greater extent than in vitro culturing of the human non-small-cell lung cancer cell line HCC827. Conclusions We demonstrate the feasibility of tracking and quantifying the clonal dynamics of entire cell populations within multiple cultured cell lines. Our results suggest that cell heterogeneity should be considered in the design and interpretation of in vitro culture experiments. Aside from clonal cell lines, we propose that cellular barcoding could prove valuable in modeling the clonal behavior of heterogeneous cell populations over time, including tumor populations treated with chemotherapeutic agents. PMID:24886633

IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia.

PubMed

Bagnara, Davide; Callea, Vincenzo; Stelitano, Caterina; Morabito, Fortunato; Fabris, Sonia; Neri, Antonino; Zanardi, Sabrina; Ghiotto, Fabio; Ciccone, Ermanno; Grossi, Carlo Enrico; Fais, Franco

2006-04-01

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented V(H)DJ(H) clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V(L)J(L) rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s).

Recent advances in understanding clonal haematopoiesis in aplastic anaemia

PubMed Central

Stanley, Natasha; Olson, Timothy S.; Babushok, Daria V.

2016-01-01

Summary Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A. Here, we present the current knowledge of clonal haematopoiesis in AA as it relates to aging, inherited bone marrow failure, and the grey-zone overlap of AA and myelodysplastic syndrome (MDS). We conclude by discussing the significance of clonal haematopoiesis both for improved diagnosis of AA, as well as for a more precise, personalized approach to prognostication of outcomes and therapy choices. PMID:28107566

Recent advances in understanding clonal haematopoiesis in aplastic anaemia.

PubMed

Stanley, Natasha; Olson, Timothy S; Babushok, Daria V

2017-05-01

Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A. Here, we present the current knowledge of clonal haematopoiesis in AA as it relates to aging, inherited bone marrow failure, and the grey-zone overlap of AA and myelodysplastic syndrome (MDS). We conclude by discussing the significance of clonal haematopoiesis both for improved diagnosis of AA, as well as for a more precise, personalized approach to prognostication of outcomes and therapy choices. © 2017 John Wiley & Sons Ltd.

Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity.

PubMed

Marusyk, Andriy; Tabassum, Doris P; Altrock, Philipp M; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia

2014-10-02

Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

Clonality Testing in Veterinary Medicine: A Review With Diagnostic Guidelines.

PubMed

Keller, S M; Vernau, W; Moore, P F

2016-07-01

The accurate distinction of reactive and neoplastic lymphoid proliferations can present challenges. Given the different prognoses and treatment strategies, a correct diagnosis is crucial. Molecular clonality assays assess rearranged lymphocyte antigen receptor gene diversity and can help differentiate reactive from neoplastic lymphoid proliferations. Molecular clonality assays are commonly used to assess atypical, mixed, or mature lymphoid proliferations; small tissue fragments that lack architecture; and fluid samples. In addition, clonality testing can be utilized to track neoplastic clones over time or across anatomic sites. Molecular clonality assays are not stand-alone tests but useful adjuncts that follow clinical, morphologic, and immunophenotypic assessment. Even though clonality testing provides valuable information in a variety of situations, the complexities and pitfalls of this method, as well as its dependency on the experience of the interpreter, are often understated. In addition, a lack of standardized terminology, laboratory practices, and interpretational guidelines hinders the reproducibility of clonality testing across laboratories in veterinary medicine. The objectives of this review are twofold. First, the review is intended to familiarize the diagnostic pathologist or interested clinician with the concepts, potential pitfalls, and limitations of clonality testing. Second, the review strives to provide a basis for future harmonization of clonality testing in veterinary medicine by providing diagnostic guidelines. © The Author(s) 2016.

Synthesis of clonality and polyploidy in vertebrate animals by hybridization between two sexual species.

PubMed

Choleva, Lukáš; Janko, Karel; De Gelas, Koen; Bohlen, Jörg; Šlechtová, Věra; Rábová, Marie; Ráb, Petr

2012-07-01

Because most clonal vertebrates have hybrid genomic constitutions, tight linkages are assumed among hybridization, clonality, and polyploidy. However, predictions about how these processes mechanistically relate during the switch from sexual to clonal reproduction have not been validated. Therefore, we performed a crossing experiment to test the hypothesis that interspecific hybridization per se initiated clonal diploid and triploid spined loaches (Cobitis) and their gynogenetic reproduction. We reared two F1 families resulting from the crossing of 14 pairs of two sexual species, and found their diploid hybrid constitution and a 1:1 sex ratio. While males were infertile, females produced unreduced nonrecombinant eggs (100%). Synthetic triploid females and males (96.3%) resulted in each of nine backcrossed families from eggs of synthesized diploid F1s fertilized by haploid sperm from sexual males. Five individuals (3.7%) from one backcross family were genetically identical to the somatic cells of the mother and originated via gynogenesis; the sperm of the sexual male only triggered clonal development of the egg. Our reconstruction of the evolutionary route from sexuality to clonality and polyploidy in these fish shows that clonality and gynogenesis may have been directly triggered by interspecific hybridization and that polyploidy is a consequence, not a cause, of clonality. © 2012 The Author(s).

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

PubMed Central

Bárcena, Paloma; Jara-Acevedo, María; Tabernero, María Dolores; López, Antonio; Sánchez, María Luz; García-Montero, Andrés C.; Muñoz-García, Noemí; Vidriales, María Belén; Paiva, Artur; Lecrevisse, Quentin; Lima, Margarida; Langerak, Anton W.; Böttcher, Sebastian; van Dongen, Jacques J.M.

2015-01-01

Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality. PMID:26556869

Multidisciplinary insight into clonal expansion of HTLV-1-infected cells in adult T-cell leukemia via modeling by deterministic finite automata coupled with high-throughput sequencing.

PubMed

Farmanbar, Amir; Firouzi, Sanaz; Park, Sung-Joon; Nakai, Kenta; Uchimaru, Kaoru; Watanabe, Toshiki

2017-01-31

Clonal expansion of leukemic cells leads to onset of adult T-cell leukemia (ATL), an aggressive lymphoid malignancy with a very poor prognosis. Infection with human T-cell leukemia virus type-1 (HTLV-1) is the direct cause of ATL onset, and integration of HTLV-1 into the human genome is essential for clonal expansion of leukemic cells. Therefore, monitoring clonal expansion of HTLV-1-infected cells via isolation of integration sites assists in analyzing infected individuals from early infection to the final stage of ATL development. However, because of the complex nature of clonal expansion, the underlying mechanisms have yet to be clarified. Combining computational/mathematical modeling with experimental and clinical data of integration site-based clonality analysis derived from next generation sequencing technologies provides an appropriate strategy to achieve a better understanding of ATL development. As a comprehensively interdisciplinary project, this study combined three main aspects: wet laboratory experiments, in silico analysis and empirical modeling. We analyzed clinical samples from HTLV-1-infected individuals with a broad range of proviral loads using a high-throughput methodology that enables isolation of HTLV-1 integration sites and accurate measurement of the size of infected clones. We categorized clones into four size groups, "very small", "small", "big", and "very big", based on the patterns of clonal growth and observed clone sizes. We propose an empirical formal model based on deterministic finite state automata (DFA) analysis of real clinical samples to illustrate patterns of clonal expansion. Through the developed model, we have translated biological data of clonal expansion into the formal language of mathematics and represented the observed clonality data with DFA. Our data suggest that combining experimental data (absolute size of clones) with DFA can describe the clonality status of patients. This kind of modeling provides a basic understanding as well as a unique perspective for clarifying the mechanisms of clonal expansion in ATL.

ClonEvol: clonal ordering and visualization in cancer sequencing.

PubMed

Dang, H X; White, B S; Foltz, S M; Miller, C A; Luo, J; Fields, R C; Maher, C A

2017-12-01

Reconstruction of clonal evolution is critical for understanding tumor progression and implementing personalized therapies. This is often done by clustering somatic variants based on their cellular prevalence estimated via bulk tumor sequencing of multiple samples. The clusters, consisting of the clonal marker variants, are then ordered based on their estimated cellular prevalence to reconstruct clonal evolution trees, a process referred to as 'clonal ordering'. However, cellular prevalence estimate is confounded by statistical variability and errors in sequencing/data analysis, and therefore inhibits accurate reconstruction of the clonal evolution. This problem is further complicated by intra- and inter-tumor heterogeneity. Furthermore, the field lacks a comprehensive visualization tool to facilitate the interpretation of complex clonal relationships. To address these challenges we developed ClonEvol, a unified software tool for clonal ordering, visualization, and interpretation. ClonEvol uses a bootstrap resampling technique to estimate the cellular fraction of the clones and probabilistically models the clonal ordering constraints to account for statistical variability. The bootstrapping allows identification of the sample founding- and sub-clones, thus enabling interpretation of clonal seeding. ClonEvol automates the generation of multiple widely used visualizations for reconstructing and interpreting clonal evolution. ClonEvol outperformed three of the state of the art tools (LICHeE, Canopy and PhyloWGS) for clonal evolution inference, showing more robust error tolerance and producing more accurate trees in a simulation. Building upon multiple recent publications that utilized ClonEvol to study metastasis and drug resistance in solid cancers, here we show that ClonEvol rediscovered relapsed subclones in two published acute myeloid leukemia patients. Furthermore, we demonstrated that through noninvasive monitoring ClonEvol recapitulated the emerging subclones throughout metastatic progression observed in the tumors of a published breast cancer patient. ClonEvol has broad applicability for longitudinal monitoring of clonal populations in tumor biopsies, or noninvasively, to guide precision medicine. ClonEvol is written in R and is available at https://github.com/ChrisMaherLab/ClonEvol. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

[Effect of algorithms for calibration set selection on quantitatively determining asiaticoside content in Centella total glucosides by near infrared spectroscopy].

PubMed

Zhan, Xue-yan; Zhao, Na; Lin, Zhao-zhou; Wu, Zhi-sheng; Yuan, Rui-juan; Qiao, Yan-jiang

2014-12-01

The appropriate algorithm for calibration set selection was one of the key technologies for a good NIR quantitative model. There are different algorithms for calibration set selection, such as Random Sampling (RS) algorithm, Conventional Selection (CS) algorithm, Kennard-Stone(KS) algorithm and Sample set Portioning based on joint x-y distance (SPXY) algorithm, et al. However, there lack systematic comparisons between two algorithms of the above algorithms. The NIR quantitative models to determine the asiaticoside content in Centella total glucosides were established in the present paper, of which 7 indexes were classified and selected, and the effects of CS algorithm, KS algorithm and SPXY algorithm for calibration set selection on the accuracy and robustness of NIR quantitative models were investigated. The accuracy indexes of NIR quantitative models with calibration set selected by SPXY algorithm were significantly different from that with calibration set selected by CS algorithm or KS algorithm, while the robustness indexes, such as RMSECV and |RMSEP-RMSEC|, were not significantly different. Therefore, SPXY algorithm for calibration set selection could improve the predicative accuracy of NIR quantitative models to determine asiaticoside content in Centella total glucosides, and have no significant effect on the robustness of the models, which provides a reference to determine the appropriate algorithm for calibration set selection when NIR quantitative models are established for the solid system of traditional Chinese medcine.

Dynamics of morphological evolution in experimental Escherichia coli populations.

PubMed

Cui, F; Yuan, B

2016-08-30

Here, we applied a two-stage clonal expansion model of morphological (cell-size) evolution to a long-term evolution experiment with Escherichia coli. Using this model, we derived the incidence function of the appearance of cell-size stability, the waiting time until this morphological stability, and the conditional and unconditional probabilities of morphological stability. After assessing the parameter values, we verified that the calculated waiting time was consistent with the experimental results, demonstrating the effectiveness of the two-stage model. According to the relative contributions of parameters to the incidence function and the waiting time, cell-size evolution is largely determined by the promotion rate, i.e., the clonal expansion rate of selectively advantageous organisms. This rate plays a prominent role in the evolution of cell size in experimental populations, whereas all other evolutionary forces were found to be less influential.

Evaluation of field performance of poplar clones using selected competition indices.

Treesearch

Chandler Brodie; D.S. DeBell

2004-01-01

Use of competition indices in the analysis of forestry experiments may improve detection and understanding of treatment effects, and thereby improve the application of results. In this paper, we compared the performance of eight indices in an analysis of a spacing trial of four Populus clones planted in pure and mixed clonal plots. Indices were...

Diversity of Xylella fastidiosa host suitability among siblings from a non-traditional almond X peach cross

USDA-ARS?s Scientific Manuscript database

Ten F2 clones from an initial hybridization of Prunus webbii X P. persica cv Harrow Blood were evaluated under greenhouse conditions for their reaction to Xylella fastidiosa subsp. fastidiosa strain M23 during two growing seasons. Clonal accessions used for the study were selected on the basis of ho...

Early rooting of dormant hardwood cuttings of Populus: analysis of quantitative genetics and genotype x environment interactions

Treesearch

Ronald S., Jr. Zalesny; Don E. Riemenschneider; Richard B. Hall

2005-01-01

Rooting of hardwood cuttings is under strong genetic control, although genotype x environment interactions affect selection of promising genotypes. Our objectives were (1) to assess the variation in rooting ability among 21 Populus clones and (2) to examine genotype x environment interactions to refine clonal recommendations. The clones belonged to...

Molecular characterization of resistance, virulence and clonality in vancomycin-resistant Enterococcus faecium and Enterococcus faecalis: A hospital-based study in Beijing, China.

PubMed

Yang, Jing-xian; Li, Tong; Ning, Yong-zhong; Shao, Dong-hua; Liu, Jing; Wang, Shu-qin; Liang, Guo-wei

2015-07-01

The incidence of vancomycin-resistant enterococcus (VRE) in China is increasing, the molecular epidemiology of VRE in China is only partly known. This study was conducted to assess the molecular characterization of resistance, virulence and clonality of 69 vancomycin-resistant Enterococcus faecium (VREfm) and seven vancomycin-resistant Enterococcus faecalis (VREfs) isolates obtained from a Chinese hospital between July 2011 and July 2013. The glycopeptide resistance genes (VanA and VanB) were screened by multiplex PCR. The presence of five putative virulence genes (esp, gelE, asa1, hyl and cylA) were evaluated by another multiplex PCR. Multilocus sequence typing (MLST) scheme was used to assess the clonality. All 76 VRE isolates exhibited VanA phenotype and harbored VanA gene. Esp was the only gene detected both in VREfm and VREfs strains, accounting for 89.9% and 42.9%, respectively. The hyl gene was merely positive in 27.5% of VREfm strains. MLST analysis demonstrated three STs (ST6, ST4 and ST470) in VREfs and twelve STs (ST78, ST571, ST17, ST564, ST389, ST18, ST547, ST341, ST414, ST343, ST262 and ST203) in VREfm, which were all designated as CC17 by eBURST algorithm. An outbreak of VREfm belonging to ST571 was found to happen within the neurology ward in this hospital. To our knowledge, this is the first report of ST6 (CC2) VREfs strains in China and the first outbreak report of VREfm strains belonging to ST571 around the world. Our data could offer important information for understanding the molecular features of VRE in China. Copyright © 2015 Elsevier B.V. All rights reserved.

Evolutionary dynamics of paroxysmal nocturnal hemoglobinuria.

PubMed

Mon Père, Nathaniel; Lenaerts, Tom; Pacheco, Jorge M; Dingli, David

2018-06-01

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A gene within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A mutated cells due to an immune mediated attack on normal HSC, but the evidence supporting this hypothesis is inconclusive. An alternative (and simpler) explanation attributes clonal expansion to neutral drift, in which case selection neither favours nor inhibits expansion of PIG-A mutated HSC. Here we examine the implications of the neutral drift model by numerically evolving a Markov chain for the probabilities of all possible outcomes, and investigate the possible occurrence and evolution, within this framework, of multiple independently arising clones within the HSC pool. Predictions of the model agree well with the known incidence of the disease and average age at diagnosis. Notwithstanding the slight difference in clonal expansion rates between our results and those reported in the literature, our model results lead to a relative stability of clone size when averaging multiple cases, in accord with what has been observed in human trials. The probability of a patient harbouring a second clone in the HSC pool was found to be extremely low ([Formula: see text]). Thus our results suggest that in clinical cases of PNH where two independent clones of mutant cells are observed, only one of those is likely to have originated in the HSC pool.

Population Genetics of Lactobacillus sakei Reveals Three Lineages with Distinct Evolutionary Histories

PubMed Central

Chaillou, Stéphane; Lucquin, Isabelle; Najjari, Afef; Zagorec, Monique; Champomier-Vergès, Marie-Christine

2013-01-01

Lactobacillus sakei plays a major role in meat fermentation and in the preservation of fresh meat. The large diversity of L. sakei strains represents a valuable and exploitable asset in the development of a variety of industrial applications; however, an efficient method to identify and classify these strains has yet to be developed. In this study, we used multilocus sequence typing (MLST) to analyze the polymorphism and allelic distribution of eight loci within an L. sakei population of 232 strains collected worldwide. Within this population, we identified 116 unique sequence types with an average pairwise nucleotide diversity per site (π) of 0.13%. Results from Structure, goeBurst, and ClonalFrame software analyses demonstrated that the L. sakei population analyzed here is derived from three ancestral lineages, each of which shows evidence of a unique evolutionary history influenced by independent selection scenarios. However, the signature of selective events in the contemporary population of isolates was somewhat masked by the pervasive phenomenon of homologous recombination. Our results demonstrate that lineage 1 is a completely panmictic subpopulation in which alleles have been continually redistributed through the process of intra-lineage recombination. In contrast, lineage 2 was characterized by a high degree of clonality. Lineage 3, the earliest-diverging branch in the genealogy, showed evidence of both clonality and recombination. These evolutionary histories strongly indicate that the three lineages may correspond to distinct ecotypes, likely linked or specialized to different environmental reservoirs. The MLST scheme developed in this study represents an easy and straightforward tool that can be used to further analyze the population dynamics of L. sakei strains in food products. PMID:24069179

Population genetics of Lactobacillus sakei reveals three lineages with distinct evolutionary histories.

PubMed

Chaillou, Stéphane; Lucquin, Isabelle; Najjari, Afef; Zagorec, Monique; Champomier-Vergès, Marie-Christine

2013-01-01

Lactobacillus sakei plays a major role in meat fermentation and in the preservation of fresh meat. The large diversity of L. sakei strains represents a valuable and exploitable asset in the development of a variety of industrial applications; however, an efficient method to identify and classify these strains has yet to be developed. In this study, we used multilocus sequence typing (MLST) to analyze the polymorphism and allelic distribution of eight loci within an L. sakei population of 232 strains collected worldwide. Within this population, we identified 116 unique sequence types with an average pairwise nucleotide diversity per site (π) of 0.13%. Results from Structure, goeBurst, and ClonalFrame software analyses demonstrated that the L. sakei population analyzed here is derived from three ancestral lineages, each of which shows evidence of a unique evolutionary history influenced by independent selection scenarios. However, the signature of selective events in the contemporary population of isolates was somewhat masked by the pervasive phenomenon of homologous recombination. Our results demonstrate that lineage 1 is a completely panmictic subpopulation in which alleles have been continually redistributed through the process of intra-lineage recombination. In contrast, lineage 2 was characterized by a high degree of clonality. Lineage 3, the earliest-diverging branch in the genealogy, showed evidence of both clonality and recombination. These evolutionary histories strongly indicate that the three lineages may correspond to distinct ecotypes, likely linked or specialized to different environmental reservoirs. The MLST scheme developed in this study represents an easy and straightforward tool that can be used to further analyze the population dynamics of L. sakei strains in food products.

Marker-Based Estimates Reveal Significant Non-additive Effects in Clonally Propagated Cassava (Manihot esculenta): Implications for the Prediction of Total Genetic Value and the Selection of Varieties.

PubMed

Wolfe, Marnin D; Kulakow, Peter; Rabbi, Ismail Y; Jannink, Jean-Luc

2016-08-31

In clonally propagated crops, non-additive genetic effects can be effectively exploited by the identification of superior genetic individuals as varieties. Cassava (Manihot esculenta Crantz) is a clonally propagated staple food crop that feeds hundreds of millions. We quantified the amount and nature of non-additive genetic variation for three key traits in a breeding population of cassava from sub-Saharan Africa using additive and non-additive genome-wide marker-based relationship matrices. We then assessed the accuracy of genomic prediction for total (additive plus non-additive) genetic value. We confirmed previous findings based on diallel populations, that non-additive genetic variation is significant for key cassava traits. Specifically, we found that dominance is particularly important for root yield and epistasis contributes strongly to variation in CMD resistance. Further, we showed that total genetic value predicted observed phenotypes more accurately than additive only models for root yield but not for dry matter content, which is mostly additive or for CMD resistance, which has high narrow-sense heritability. We address the implication of these results for cassava breeding and put our work in the context of previous results in cassava, and other plant and animal species. Copyright © 2016 Author et al.

Facilitation of environmental adaptation and evolution by epigenetic phenotype variation: insights from clonal, invasive, polyploid, and domesticated animals

PubMed Central

Vogt, Günter

2017-01-01

Abstract There is increasing evidence, particularly from plants, that epigenetic mechanisms can contribute to environmental adaptation and evolution. The present article provides an overview on this topic for animals and highlights the special suitability of clonal, invasive, hybrid, polyploid, and domesticated species for environmental and evolutionary epigenetics. Laboratory and field studies with asexually reproducing animals have shown that epigenetically diverse phenotypes can be produced from the same genome either by developmental stochasticity or environmental induction. The analysis of invasions revealed that epigenetic phenotype variation may help to overcome genetic barriers typically associated with invasions such as bottlenecks and inbreeding. Research with hybrids and polyploids established that epigenetic mechanisms are involved in consolidation of speciation by contributing to reproductive isolation and restructuring of the genome in the neo-species. Epigenetic mechanisms may even have the potential to trigger speciation but evidence is still meager. The comparison of domesticated animals and their wild ancestors demonstrated heritability and selectability of phenotype modulating DNA methylation patterns. Hypotheses, model predictions, and empirical results are presented to explain how epigenetic phenotype variation could facilitate adaptation and speciation. Clonal laboratory lineages, monoclonal invaders, and adaptive radiations of different evolutionary age seem particularly suitable to empirically test the proposed ideas. A respective research agenda is presented. PMID:29492304

Reference gene selection for quantitative reverse transcription-polymerase chain reaction normalization during in vitro adventitious rooting in Eucalyptus globulus Labill.

PubMed

de Almeida, Márcia R; Ruedell, Carolina M; Ricachenevsky, Felipe K; Sperotto, Raul A; Pasquali, Giancarlo; Fett-Neto, Arthur G

2010-09-20

Eucalyptus globulus and its hybrids are very important for the cellulose and paper industry mainly due to their low lignin content and frost resistance. However, rooting of cuttings of this species is recalcitrant and exogenous auxin application is often necessary for good root development. To date one of the most accurate methods available for gene expression analysis is quantitative reverse transcription-polymerase chain reaction (qPCR); however, reliable use of this technique requires reference genes for normalization. There is no single reference gene that can be regarded as universal for all experiments and biological materials. Thus, the identification of reliable reference genes must be done for every species and experimental approach. The present study aimed at identifying suitable control genes for normalization of gene expression associated with adventitious rooting in E. globulus microcuttings. By the use of two distinct algorithms, geNorm and NormFinder, we have assessed gene expression stability of eleven candidate reference genes in E. globulus: 18S, ACT2, EF2, EUC12, H2B, IDH, SAND, TIP41, TUA, UBI and 33380. The candidate reference genes were evaluated in microccuttings rooted in vitro, in presence or absence of auxin, along six time-points spanning the process of adventitious rooting. Overall, the stability profiles of these genes determined with each one of the algorithms were very similar. Slight differences were observed in the most stable pair of genes indicated by each program: IDH and SAND for geNorm, and H2B and TUA for NormFinder. Both programs identified UBI and 18S as the most variable genes. To validate these results and select the most suitable reference genes, the expression profile of the ARGONAUTE1 gene was evaluated in relation to the most stable candidate genes indicated by each algorithm. Our study showed that expression stability varied between putative reference genes tested in E. globulus. Based on the AGO1 relative expression profile obtained using the genes suggested by the algorithms, H2B and TUA were considered as the most suitable reference genes for expression studies in E. globulus adventitious rooting. UBI and 18S were unsuitable for use as controls in qPCR related to this process. These findings will enable more accurate and reliable normalization of qPCR results for gene expression studies in this economically important woody plant, particularly related to rooting and clonal propagation.

Reference gene selection for quantitative reverse transcription-polymerase chain reaction normalization during in vitro adventitious rooting in Eucalyptus globulus Labill

PubMed Central

2010-01-01

Background Eucalyptus globulus and its hybrids are very important for the cellulose and paper industry mainly due to their low lignin content and frost resistance. However, rooting of cuttings of this species is recalcitrant and exogenous auxin application is often necessary for good root development. To date one of the most accurate methods available for gene expression analysis is quantitative reverse transcription-polymerase chain reaction (qPCR); however, reliable use of this technique requires reference genes for normalization. There is no single reference gene that can be regarded as universal for all experiments and biological materials. Thus, the identification of reliable reference genes must be done for every species and experimental approach. The present study aimed at identifying suitable control genes for normalization of gene expression associated with adventitious rooting in E. globulus microcuttings. Results By the use of two distinct algorithms, geNorm and NormFinder, we have assessed gene expression stability of eleven candidate reference genes in E. globulus: 18S, ACT2, EF2, EUC12, H2B, IDH, SAND, TIP41, TUA, UBI and 33380. The candidate reference genes were evaluated in microccuttings rooted in vitro, in presence or absence of auxin, along six time-points spanning the process of adventitious rooting. Overall, the stability profiles of these genes determined with each one of the algorithms were very similar. Slight differences were observed in the most stable pair of genes indicated by each program: IDH and SAND for geNorm, and H2B and TUA for NormFinder. Both programs indentified UBI and 18S as the most variable genes. To validate these results and select the most suitable reference genes, the expression profile of the ARGONAUTE1 gene was evaluated in relation to the most stable candidate genes indicated by each algorithm. Conclusion Our study showed that expression stability varied between putative reference genes tested in E. globulus. Based on the AGO1 relative expression profile obtained using the genes suggested by the algorithms, H2B and TUA were considered as the most suitable reference genes for expression studies in E. globulus adventitious rooting. UBI and 18S were unsuitable for use as controls in qPCR related to this process. These findings will enable more accurate and reliable normalization of qPCR results for gene expression studies in this economically important woody plant, particularly related to rooting and clonal propagation. PMID:20854682

Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.

PubMed

Yoshizato, Tetsuichi; Dumitriu, Bogdan; Hosokawa, Kohei; Makishima, Hideki; Yoshida, Kenichi; Townsley, Danielle; Sato-Otsubo, Aiko; Sato, Yusuke; Liu, Delong; Suzuki, Hiromichi; Wu, Colin O; Shiraishi, Yuichi; Clemente, Michael J; Kataoka, Keisuke; Shiozawa, Yusuke; Okuno, Yusuke; Chiba, Kenichi; Tanaka, Hiroko; Nagata, Yasunobu; Katagiri, Takamasa; Kon, Ayana; Sanada, Masashi; Scheinberg, Phillip; Miyano, Satoru; Maciejewski, Jaroslaw P; Nakao, Shinji; Young, Neal S; Ogawa, Seishi

2015-07-02

In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).

Frequency and clonality of peripheral γδ T cells in psoriasis patients receiving anti-tumour necrosis factor-α therapy

PubMed Central

Kelsen, J; Dige, A; Christensen, M; D'Amore, F; Iversen, L

2014-01-01

Hepatosplenic γδ T cell lymphoma (HSTCL) has been observed in patients with Crohn's disease (CD) who received anti-tumour necrosis factor (TNF)-α agents and thiopurines, but only one case was reported in a psoriasis patient worldwide. This difference could be due to differences in either the nature of the inflammatory diseases or in the use of immunomodulators. We investigated the impact of anti-TNF-α agents on the level and repertoire of γδ T cells in peripheral blood from psoriasis patients. Forty-five men and 10 women who were treated with anti-TNF-α agents for psoriasis were monitored for a median 11 months for the level and clonality of γδ T cells via flow cytometry and polymerase chain reaction (PCR) analysis of T cell receptor gamma (TCR-γ) gene rearrangements. Seventeen men had a repeated analysis within 48 h of the infliximab infusion to reveal a possible expansion of γδ T cells, as observed previously in CD patients. Ten psoriasis patients who were never exposed to biologicals and 20 healthy individuals served as controls. In the majority of psoriasis patients, the level and clonal pattern of γδ T cells was remarkably stable during infliximab treatment. A single male patient repeatedly experienced a significant increase in the level of γδ T cells after infliximab infusions. A monoclonal γδ T cell repertoire in a polyclonal background tended to be more frequent in anti-TNF-α-treated patients than naive patients, suggesting that anti-TNF-α therapy may promote the clonal selection of γδ T cells in psoriasis patients. PMID:24635218

Tissue-specific and time-dependent clonal expansion of ENU-induced mutant cells in gpt delta mice.

PubMed

Nakayama, Takafumi; Sawai, Tomoko; Masuda, Ikuko; Kaneko, Shinya; Yamauchi, Kazumi; Blyth, Benjamin J; Shimada, Yoshiya; Tachibana, Akira; Kakinuma, Shizuko

2017-10-01

DNA mutations play a crucial role in the origins of cancer, and the clonal expansion of mutant cells is one of the fundamental steps in multistage carcinogenesis. In this study, we correlated tumor incidence in B6C3F1 mice during the period after exposure to N-ethyl-N-nitrosourea (ENU) with the persistence of ENU-induced mutant clones in transgenic gpt delta B6C3F1 mice. The induced gpt mutations afforded no selective advantage in the mouse cells and could be distinguished by a mutational spectrum that is characteristic of ENU treatment. The gpt mutations were passengers of the mutant cell of origin and its daughter cells and thus could be used as neutral markers of clones that arose and persisted in the tissues. Female B6C3F1 mice exposed for 1 month to 200 ppm ENU in the drinking water developed early thymic lymphomas and late liver and lung tumors. To assay gpt mutations, we sampled the thymus, liver, lung, and small intestine of female gpt delta mice at 3 days, 4 weeks, and 8 weeks after the end of ENU exposure. Our results reveal that, in all four tissues, the ENU-induced gpt mutations persisted for weeks after the end of mutagen exposure. Clonal expansion of mutant cells was observed in the thymus and small intestine, with the thymus showing larger clone sizes. These results indicate that the clearance of mutant cells and the potential for clonal expansion during normal tissue growth depends on tissue type and that these factors may affect the sensitivity of different tissues to carcinogenesis. Environ. Mol. Mutagen. 58:592-606, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Phenotypic plasticity and specialization in clonal versus non-clonal plants: A data synthesis

NASA Astrophysics Data System (ADS)

Fazlioglu, Fatih; Bonser, Stephen P.

2016-11-01

Reproductive strategies can be associated with ecological specialization and generalization. Clonal plants produce lineages adapted to the maternal habitat that can lead to specialization. However, clonal plants frequently display high phenotypic plasticity (e.g. clonal foraging for resources), factors linked to ecological generalization. Alternately, sexual reproduction can be associated with generalization via increasing genetic variation or specialization through rapid adaptive evolution. Moreover, specializing to high or low quality habitats can determine how phenotypic plasticity is expressed in plants. The specialization hypothesis predicts that specialization to good environments results in high performance trait plasticity and specialization to bad environments results in low performance trait plasticity. The interplay between reproductive strategies, phenotypic plasticity, and ecological specialization is important for understanding how plants adapt to variable environments. However, we currently have a poor understanding of these relationships. In this study, we addressed following questions: 1) Is there a relationship between phenotypic plasticity, specialization, and reproductive strategies in plants? 2) Do good habitat specialists express greater performance trait plasticity than bad habitat specialists? We searched the literature for studies examining plasticity for performance traits and functional traits in clonal and non-clonal plant species from different habitat types. We found that non-clonal (obligate sexual) plants expressed greater performance trait plasticity and functional trait plasticity than clonal plants. That is, non-clonal plants exhibited a specialist strategy where they perform well only in a limited range of habitats. Clonal plants expressed less performance loss across habitats and a more generalist strategy. In addition, specialization to good habitats did not result in greater performance trait plasticity. This result was contrary to the predictions of the specialization hypothesis. Overall, reproductive strategies are associated with ecological specialization or generalization through phenotypic plasticity. While specialization is common in plant populations, the evolution of specialization does not control the nature of phenotypic plasticity as predicted under the specialization hypothesis.

Demographic consequences of greater clonal than sexual reproduction in Dicentra canadensis.

PubMed

Lin, Chia-Hua; Miriti, Maria N; Goodell, Karen

2016-06-01

Clonality is a widespread life history trait in flowering plants that may be essential for population persistence, especially in environments where sexual reproduction is unpredictable. Frequent clonal reproduction, however, could hinder sexual reproduction by spatially aggregating ramets that compete with seedlings and reduce inter-genet pollination. Nevertheless, the role of clonality in relation to variable sexual reproduction in population dynamics is often overlooked. We combined population matrix models and pollination experiments to compare the demographic contributions of clonal and sexual reproduction in three Dicentra canadensis populations, one in a well-forested landscape and two in isolated forest remnants. We constructed stage-based transition matrices from 3 years of census data to evaluate annual population growth rates, λ. We used loop analysis to evaluate the relative contribution of different reproductive pathways to λ. Despite strong temporal and spatial variation in seed set, populations generally showed stable growth rates. Although we detected some pollen limitation of seed set, manipulative pollination treatments did not affect population growth rates. Clonal reproduction contributed significantly more than sexual reproduction to population growth in the forest remnants. Only at the well-forested site did sexual reproduction contribute as much as clonal reproduction to population growth. Flowering plants were more likely to transition to a smaller size class with reduced reproductive potential in the following year than similarly sized nonflowering plants, suggesting energy trade-offs between sexual and clonal reproduction at the individual level. Seed production had negligible effects on growth and tuber production of individual plants. Our results demonstrate that clonal reproduction is vital for population persistence in a system where sexual reproduction is unpredictable. The bias toward clonality may be driven by low fitness returns for resource investment in sexual reproduction at the individual level. However, chronic failure in sexual reproduction may exacerbate the imbalance between sexual and clonal reproduction and eventually lead to irreversible loss of sex in the population.

Clonal growth and plant species abundance

PubMed Central

Herben, Tomáš; Nováková, Zuzana; Klimešová, Jitka

2014-01-01

Background and Aims Both regional and local plant abundances are driven by species' dispersal capacities and their abilities to exploit new habitats and persist there. These processes are affected by clonal growth, which is difficult to evaluate and compare across large numbers of species. This study assessed the influence of clonal reproduction on local and regional abundances of a large set of species and compared the predictive power of morphologically defined traits of clonal growth with data on actual clonal growth from a botanical garden. The role of clonal growth was compared with the effects of seed reproduction, habitat requirements and growth, proxied both by LHS (leaf–height–seed) traits and by actual performance in the botanical garden. Methods Morphological parameters of clonal growth, actual clonal reproduction in the garden and LHS traits (leaf-specific area – height – seed mass) were used as predictors of species abundance, both regional (number of species records in the Czech Republic) and local (mean species cover in vegetation records) for 836 perennial herbaceous species. Species differences in habitat requirements were accounted for by classifying the dataset by habitat type and also by using Ellenberg indicator values as covariates. Key Results After habitat differences were accounted for, clonal growth parameters explained an important part of variation in species abundance, both at regional and at local levels. At both levels, both greater vegetative growth in cultivation and greater lateral expansion trait values were correlated with higher abundance. Seed reproduction had weaker effects, being positive at the regional level and negative at the local level. Conclusions Morphologically defined traits are predictive of species abundance, and it is concluded that simultaneous investigation of several such traits can help develop hypotheses on specific processes (e.g. avoidance of self-competition, support of offspring) potentially underlying clonal growth effects on abundance. Garden performance parameters provide a practical approach to assessing the roles of clonal growth morphological traits (and LHS traits) for large sets of species. PMID:24482153

Clonality analysis of lymphoid proliferations using the BIOMED-2 clonality assays: a single institution experience

PubMed Central

Kokovic, Ira; Novakovic, Barbara Jezersek; Cerkovnik, Petra; Novakovic, Srdjan

2014-01-01

Background Clonality determination in patients with lymphoproliferative disorders can improve the final diagnosis. The aim of our study was to evaluate the applicative value of standardized BIOMED-2 gene clonality assay protocols for the analysis of clonality of lymphocytes in a group of different lymphoid proliferations. Materials and methods. With this purpose, 121 specimens from 91 patients with suspected lymphoproliferations submitted for routine diagnostics from January to December 2011 were retrospectively analyzed. According to the final diagnosis, our series comprised 32 cases of B-cell lymphomas, 38 cases of non-Hodgkin’s T-cell lymphomas and 51 cases of reactive lymphoid proliferations. Clonality testing was performed using the BIOMED-2 clonality assays. Results The determined sensitivity of the TCR assay was 91.9%, while the sensitivity of the IGH assay was 74.2%. The determined specificity of the IGH assay was 73.3% in the group of lymphomas and 87.2% in the group of reactive lesions. The determined specificity of the TCR assay was 62.5% in the group of lymphomas and 54.3% in the group of reactive lesions. Conclusions In the present study, we confirmed the utility of standardized BIOMED-2 clonality assays for the detection of clonality in a routine diagnostical setting of non-Hodgkin’s lymphomas. Reactions for the detection of the complete IGH rearrangements and reactions for the detection of the TCR rearrangements are a good choice for clonality testing of a wide range of lymphoid proliferations and specimen types while the reactions for the detection of incomplete IGH rearrangements have not shown any additional diagnostic value. PMID:24991205

Clonal integration facilitates spread of Paspalum paspaloides from terrestrial to cadmium-contaminated aquatic habitats.

PubMed

Luo, F-L; Xing, Y-P; Wei, G-W; Li, C-Y; Yu, F-H

2017-11-01

Cadmium (Cd) is a hazardous environmental pollutant with high toxicity to plants, which has been detected in many wetlands. Clonal integration (resource translocation) between connected ramets of clonal plants can increase their tolerance to stress. We hypothesised that clonal integration facilitates spread of amphibious clonal plants from terrestrial to Cd-contaminated aquatic habitats. The spread of an amphibious grass Paspalum paspaloides was simulated by growing basal older ramets in uncontaminated soil connected (allowing integration) or not connected (preventing integration) to apical younger ramets of the same fragments in Cd-contaminated water. Cd contamination of apical ramets of P. paspaloides markedly decreased growth and photosynthetic capacity of the apical ramets without connection to the basal ramets, but did not decrease these properties with connection. Cd contamination did not affect growth of the basal ramets without connection to the apical ramets, but Cd contamination of 4 and 12 mg·l -1 significantly increased growth with connection. Consequently, clonal integration increased growth of the apical ramets, basal ramets and whole clones when the apical ramets were grown in Cd-contaminated water of 4 and 12 mg·l -1 . Cd was detected in the basal ramets with connection to the apical ramets, suggesting Cd could be translocated due to clonal integration. Clonal integration, most likely through translocation of photosynthates, can support P. paspaloides to spread from terrestrial to Cd-contaminated aquatic habitats. Amphibious clonal plants with a high ability for clonal integration are particularly useful for re-vegetation of degraded aquatic habitats caused by Cd contamination. © 2017 German Society for Plant Sciences and The Royal Botanical Society of the Netherlands.

Clonal growth strategy, diversity and structure: A spatiotemporal response to sedimentation in tropical Cyperus papyrus swamps.

PubMed

Geremew, Addisie; Stiers, Iris; Sierens, Tim; Kefalew, Alemayehu; Triest, Ludwig

2018-01-01

Land degradation and soil erosion in the upper catchments of tropical lakes fringed by papyrus vegetation can result in a sediment load gradient from land to lakeward. Understanding the dynamics of clonal modules (ramets and genets) and growth strategies of plants on such a gradient in both space and time is critical for exploring a species adaptation and processes regulating population structure and differentiation. We assessed the spatial and temporal dynamics in clonal growth, diversity, and structure of an emergent macrophyte, Cyperus papyrus (papyrus), in response to two contrasting sedimentation regimes by combining morphological traits and genotype data using 20 microsatellite markers. A total of 636 ramets from six permanent plots (18 x 30 m) in three Ethiopian papyrus swamps, each with discrete sedimentation regimes (high vs. low) were sampled for two years. We found that ramets under the high sedimentation regime (HSR) were significantly clumped and denser than the sparse and spreading ramets under the low sedimentation regime (LSR). The HSR resulted in significantly different ramets with short culm height and girth diameter as compared to the LSR. These results indicated that C. papyrus ameliorates the effect of sedimentation by shifting clonal growth strategy from guerrilla (in LSR) to phalanx (in HSR). Clonal richness, size, dominance, and clonal subrange differed significantly between sediment regimes and studied time periods. Each swamp under HSR revealed a significantly high clonal richness (R = 0.80) as compared to the LSR (R = 0.48). Such discrepancy in clonal richness reflected the occurrence of initial and repeated seedling recruitment strategies as a response to different sedimentation regimes. Overall, our spatial and short-term temporal observations highlighted that HSR enhances clonal richness and decreases clonal subrange owing to repeated seedling recruitment and genets turnover.

Clonal growth strategy, diversity and structure: A spatiotemporal response to sedimentation in tropical Cyperus papyrus swamps

PubMed Central

Stiers, Iris; Sierens, Tim; Kefalew, Alemayehu; Triest, Ludwig

2018-01-01

Land degradation and soil erosion in the upper catchments of tropical lakes fringed by papyrus vegetation can result in a sediment load gradient from land to lakeward. Understanding the dynamics of clonal modules (ramets and genets) and growth strategies of plants on such a gradient in both space and time is critical for exploring a species adaptation and processes regulating population structure and differentiation. We assessed the spatial and temporal dynamics in clonal growth, diversity, and structure of an emergent macrophyte, Cyperus papyrus (papyrus), in response to two contrasting sedimentation regimes by combining morphological traits and genotype data using 20 microsatellite markers. A total of 636 ramets from six permanent plots (18 x 30 m) in three Ethiopian papyrus swamps, each with discrete sedimentation regimes (high vs. low) were sampled for two years. We found that ramets under the high sedimentation regime (HSR) were significantly clumped and denser than the sparse and spreading ramets under the low sedimentation regime (LSR). The HSR resulted in significantly different ramets with short culm height and girth diameter as compared to the LSR. These results indicated that C. papyrus ameliorates the effect of sedimentation by shifting clonal growth strategy from guerrilla (in LSR) to phalanx (in HSR). Clonal richness, size, dominance, and clonal subrange differed significantly between sediment regimes and studied time periods. Each swamp under HSR revealed a significantly high clonal richness (R = 0.80) as compared to the LSR (R = 0.48). Such discrepancy in clonal richness reflected the occurrence of initial and repeated seedling recruitment strategies as a response to different sedimentation regimes. Overall, our spatial and short-term temporal observations highlighted that HSR enhances clonal richness and decreases clonal subrange owing to repeated seedling recruitment and genets turnover. PMID:29338034

A Cancer Gene Selection Algorithm Based on the K-S Test and CFS.

PubMed

Su, Qiang; Wang, Yina; Jiang, Xiaobing; Chen, Fuxue; Lu, Wen-Cong

2017-01-01

To address the challenging problem of selecting distinguished genes from cancer gene expression datasets, this paper presents a gene subset selection algorithm based on the Kolmogorov-Smirnov (K-S) test and correlation-based feature selection (CFS) principles. The algorithm selects distinguished genes first using the K-S test, and then, it uses CFS to select genes from those selected by the K-S test. We adopted support vector machines (SVM) as the classification tool and used the criteria of accuracy to evaluate the performance of the classifiers on the selected gene subsets. This approach compared the proposed gene subset selection algorithm with the K-S test, CFS, minimum-redundancy maximum-relevancy (mRMR), and ReliefF algorithms. The average experimental results of the aforementioned gene selection algorithms for 5 gene expression datasets demonstrate that, based on accuracy, the performance of the new K-S and CFS-based algorithm is better than those of the K-S test, CFS, mRMR, and ReliefF algorithms. The experimental results show that the K-S test-CFS gene selection algorithm is a very effective and promising approach compared to the K-S test, CFS, mRMR, and ReliefF algorithms.

ERG Oncoprotein Expression in Prostate Cancer: Clonal Progression of ERG-Positive Tumor Cells and Potential for ERG-Based Stratification

DTIC Science & Technology

2010-01-01

staining results as ERG positive or negative. Analysis of ERG mRNA by branched-chain DNA ( bDNA ) signal amplification One 4-mm thick section was selected...patients treated with radical prostatectomy by using bDNA assay as described in Materials and Methods. Consecutive tissue slides from whole-mounted FFPE

Clonal propagation on Eucalyptus by cuttings in France

Treesearch

H. Chaperon

1983-01-01

A.FO.CEL has developed a technique for mass propagation by cuttings of Eucalyptus in France. This technique is described from the selection of the ortet to the mass propagation of the clone for afforestation: the first stage is the mobilization of the ortet, the second stage is called pre-propagation which includes rejuvenating and rooting conditioning, the third stage...

A statistical mechanics approach to autopoietic immune networks

NASA Astrophysics Data System (ADS)

Barra, Adriano; Agliari, Elena

2010-07-01

In this work we aim to bridge theoretical immunology and disordered statistical mechanics. We introduce a model for the behavior of B-cells which naturally merges the clonal selection theory and the autopoietic network theory as a whole. From the analysis of its features we recover several basic phenomena such as low-dose tolerance, dynamical memory of antigens and self/non-self discrimination.

Making sense of snapshot data: ergodic principle for clonal cell populations

PubMed Central

2017-01-01

Population growth is often ignored when quantifying gene expression levels across clonal cell populations. We develop a framework for obtaining the molecule number distributions in an exponentially growing cell population taking into account its age structure. In the presence of generation time variability, the average acquired across a population snapshot does not obey the average of a dividing cell over time, apparently contradicting ergodicity between single cells and the population. Instead, we show that the variation observed across snapshots with known cell age is captured by cell histories, a single-cell measure obtained from tracking an arbitrary cell of the population back to the ancestor from which it originated. The correspondence between cells of known age in a population with their histories represents an ergodic principle that provides a new interpretation of population snapshot data. We illustrate the principle using analytical solutions of stochastic gene expression models in cell populations with arbitrary generation time distributions. We further elucidate that the principle breaks down for biochemical reactions that are under selection, such as the expression of genes conveying antibiotic resistance, which gives rise to an experimental criterion with which to probe selection on gene expression fluctuations. PMID:29187636

Making sense of snapshot data: ergodic principle for clonal cell populations.

PubMed

Thomas, Philipp

2017-11-01

Population growth is often ignored when quantifying gene expression levels across clonal cell populations. We develop a framework for obtaining the molecule number distributions in an exponentially growing cell population taking into account its age structure. In the presence of generation time variability, the average acquired across a population snapshot does not obey the average of a dividing cell over time, apparently contradicting ergodicity between single cells and the population. Instead, we show that the variation observed across snapshots with known cell age is captured by cell histories, a single-cell measure obtained from tracking an arbitrary cell of the population back to the ancestor from which it originated. The correspondence between cells of known age in a population with their histories represents an ergodic principle that provides a new interpretation of population snapshot data. We illustrate the principle using analytical solutions of stochastic gene expression models in cell populations with arbitrary generation time distributions. We further elucidate that the principle breaks down for biochemical reactions that are under selection, such as the expression of genes conveying antibiotic resistance, which gives rise to an experimental criterion with which to probe selection on gene expression fluctuations. © 2017 The Author(s).

Detecting truly clonal alterations from multi-region profiling of tumours

PubMed Central

Werner, Benjamin; Traulsen, Arne; Sottoriva, Andrea; Dingli, David

2017-01-01

Modern cancer therapies aim at targeting tumour-specific alterations, such as mutations or neo-antigens, and maximal treatment efficacy requires that targeted alterations are present in all tumour cells. Currently, treatment decisions are based on one or a few samples per tumour, creating uncertainty on whether alterations found in those samples are actually present in all tumour cells. The probability of classifying clonal versus sub-clonal alterations from multi-region profiling of tumours depends on the earliest phylogenetic branching event during tumour growth. By analysing 181 samples from 10 renal carcinoma and 11 colorectal cancers we demonstrate that the information gain from additional sampling falls onto a simple universal curve. We found that in colorectal cancers, 30% of alterations identified as clonal with one biopsy proved sub-clonal when 8 samples were considered. The probability to overestimate clonal alterations fell below 1% in 7/11 patients with 8 samples per tumour. In renal cell carcinoma, 8 samples reduced the list of clonal alterations by 40% with respect to a single biopsy. The probability to overestimate clonal alterations remained as high as 92% in 7/10 renal cancer patients. Furthermore, treatment was associated with more unbalanced tumour phylogenetic trees, suggesting the need of denser sampling of tumours at relapse. PMID:28344344

Heterogeneous water supply affects growth and benefits of clonal integration between co-existing invasive and native Hydrocotyle species.

PubMed

Wang, Yong-Jian; Bai, Yun-Fei; Zeng, Shi-Qi; Yao, Bin; Wang, Wen; Luo, Fang-Li

2016-07-21

Spatial patchiness and temporal variability in water availability are common in nature under global climate change, which can remarkably influence adaptive responses of clonal plants, i.e. clonal integration (translocating resources between connected ramets). However, little is known about the effects of spatial patchiness and temporal heterogeneity in water on growth and clonal integration between congeneric invasive and native Hydrocotyle species. In a greenhouse experiment, we subjected severed or no severed (intact) fragments of Hydrocotyle vulgaris, a highly invasive species in China, and its co-existing, native congener H. sibthorpioides to different spatial patchiness (homogeneous and patchy) and temporal interval (low and high interval) in water supply. Clonal integration had significant positive effects on growth of both species. In the homogeneous water conditions, clonal integration greatly improved the growth in fragments of both species under low interval in water. However, in the patchy water conditions, clonal integration significantly increased growth in both ramets and fragments of H. vulgaris under high interval in water. Therefore, spatial patchiness and temporal interval in water altered the effects of clonal integration of both species, especially for H. vulgaris. The adaptation of H. vulgaris might lead to invasive growth and potential spread under the global water variability.

Detecting truly clonal alterations from multi-region profiling of tumours

NASA Astrophysics Data System (ADS)

Werner, Benjamin; Traulsen, Arne; Sottoriva, Andrea; Dingli, David

2017-03-01

Modern cancer therapies aim at targeting tumour-specific alterations, such as mutations or neo-antigens, and maximal treatment efficacy requires that targeted alterations are present in all tumour cells. Currently, treatment decisions are based on one or a few samples per tumour, creating uncertainty on whether alterations found in those samples are actually present in all tumour cells. The probability of classifying clonal versus sub-clonal alterations from multi-region profiling of tumours depends on the earliest phylogenetic branching event during tumour growth. By analysing 181 samples from 10 renal carcinoma and 11 colorectal cancers we demonstrate that the information gain from additional sampling falls onto a simple universal curve. We found that in colorectal cancers, 30% of alterations identified as clonal with one biopsy proved sub-clonal when 8 samples were considered. The probability to overestimate clonal alterations fell below 1% in 7/11 patients with 8 samples per tumour. In renal cell carcinoma, 8 samples reduced the list of clonal alterations by 40% with respect to a single biopsy. The probability to overestimate clonal alterations remained as high as 92% in 7/10 renal cancer patients. Furthermore, treatment was associated with more unbalanced tumour phylogenetic trees, suggesting the need of denser sampling of tumours at relapse.

Effects of Clonal Reproduction on Evolutionary Lag and Evolutionary Rescue.

PubMed

Orive, Maria E; Barfield, Michael; Fernandez, Carlos; Holt, Robert D

2017-10-01

Evolutionary lag-the difference between mean and optimal phenotype in the current environment-is of keen interest in light of rapid environmental change. Many ecologically important organisms have life histories that include stage structure and both sexual and clonal reproduction, yet how stage structure and clonality interplay to govern a population's rate of evolution and evolutionary lag is unknown. Effects of clonal reproduction on mean phenotype partition into two portions: one that is phenotype dependent, and another that is genotype dependent. This partitioning is governed by the association between the nonadditive genetic plus random environmental component of phenotype of clonal offspring and their parents. While clonality slows phenotypic evolution toward an optimum, it can dramatically increase population survival after a sudden step change in optimal phenotype. Increased adult survival slows phenotypic evolution but facilitates population survival after a step change; this positive effect can, however, be lost given survival-fecundity trade-offs. Simulations indicate that the benefits of increased clonality under environmental change greatly depend on the nature of that change: increasing population persistence under a step change while decreasing population persistence under a continuous linear change requiring de novo variation. The impact of clonality on the probability of persistence for species in a changing world is thus inexorably linked to the temporal texture of the change they experience.

Spatial constraints govern competition of mutant clones in human epidermis.

PubMed

Lynch, M D; Lynch, C N S; Craythorne, E; Liakath-Ali, K; Mallipeddi, R; Barker, J N; Watt, F M

2017-10-24

Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

Clonal sets of a binary relation

NASA Astrophysics Data System (ADS)

Zedam, Lemnaouar; Pérez-Fernández, Raúl; Bouremel, Hassane; De Baets, Bernard

2018-05-01

In a recent paper, we have introduced the notion of clone relation of a given binary relation. Intuitively, two elements are said to be "clones" if they are related in the same way w.r.t. every other element. In this paper, we generalize this notion from pairs of elements to sets of elements of any cardinality, resulting in the introduction of clonal sets. We investigate the most important properties of clonal sets, paying particular attention to the introduction of the clonal closure operator, to the analysis of the (lattice) structure of the set of clonal sets and to a distance metric expressing how close two elements are to being clones.

Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing.

PubMed

Masetti, Riccardo; Castelli, Ilaria; Astolfi, Annalisa; Bertuccio, Salvatore Nicola; Indio, Valentina; Togni, Marco; Belotti, Tamara; Serravalle, Salvatore; Tarantino, Giuseppe; Zecca, Marco; Pigazzi, Martina; Basso, Giuseppe; Pession, Andrea; Locatelli, Franco

2016-08-30

Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques.

Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia | Office of Cancer Genomics

Cancer.gov

There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden.

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

PubMed Central

McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles

2016-01-01

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

Analysis of allelic expression patterns in clonal somatic cells by single-cell RNA-seq

PubMed Central

Ramsköld, Daniel; Deng, Qiaolin; Johnsson, Per; Michaëlsson, Jakob; Frisén, Jonas; Sandberg, Rickard

2016-01-01

Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes (aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here, we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and in vivo human CD8+ T-cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells’ transcriptomes, with levels dependent on the cells’ transcriptional activity. Importantly, clonal aRME was detected but was surprisingly scarce (<1% of genes) and affected mainly the most low-expressed genes. Consequently, the overwhelming portion of aRME occurs transiently within individual cells and patterns of aRME are thus primarily scattered throughout somatic cell populations rather than, as previously hypothesized, confined to patches of clonally related cells. PMID:27668657

Analysis of allelic expression patterns in clonal somatic cells by single-cell RNA-seq.

PubMed

Reinius, Björn; Mold, Jeff E; Ramsköld, Daniel; Deng, Qiaolin; Johnsson, Per; Michaëlsson, Jakob; Frisén, Jonas; Sandberg, Rickard

2016-11-01

Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes (aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and freshly isolated human CD8 + T cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells' transcriptomes, with levels dependent on the cells' transcriptional activity. Notably, clonal aRME was detected, but it was surprisingly scarce (<1% of genes) and mainly affected the most weakly expressed genes. Consequently, the overwhelming majority of aRME occurs transiently within individual cells, and patterns of aRME are thus primarily scattered throughout somatic cell populations rather than, as previously hypothesized, confined to patches of clonally related cells.

Insights in Anaphylaxis and Clonal Mast Cell Disorders.

PubMed

González-de-Olano, David; Álvarez-Twose, Iván

2017-01-01

The prevalence of anaphylaxis among patients with clonal mast cell disorders (MCD) is clearly higher comparing to the general population. Due to a lower frequency of symptoms outside of acute episodes, clonal MCD in the absence of skin lesions might sometimes be difficult to identify which may lead to underdiagnosis, and anaphylaxis is commonly the presenting symptom in these patients. Although the release of mast cell (MC) mediators upon MC activation might present with a wide variety of symptoms, particular clinical features typically characterize MC mediator release episodes in patients with clonal MCD without skin involvement. Final diagnosis requires a bone marrow study, and it is recommended that this should be done in reference centers. In this article, we address the main triggers for anaphylaxis, risk factors, clinical presentation, diagnosis, and management of patients with MC activation syndromes (MCASs), with special emphasis on clonal MCAS [systemic mastocytosis and mono(clonal) MC activations syndromes].

Insights in Anaphylaxis and Clonal Mast Cell Disorders

PubMed Central

González-de-Olano, David; Álvarez-Twose, Iván

2017-01-01

The prevalence of anaphylaxis among patients with clonal mast cell disorders (MCD) is clearly higher comparing to the general population. Due to a lower frequency of symptoms outside of acute episodes, clonal MCD in the absence of skin lesions might sometimes be difficult to identify which may lead to underdiagnosis, and anaphylaxis is commonly the presenting symptom in these patients. Although the release of mast cell (MC) mediators upon MC activation might present with a wide variety of symptoms, particular clinical features typically characterize MC mediator release episodes in patients with clonal MCD without skin involvement. Final diagnosis requires a bone marrow study, and it is recommended that this should be done in reference centers. In this article, we address the main triggers for anaphylaxis, risk factors, clinical presentation, diagnosis, and management of patients with MC activation syndromes (MCASs), with special emphasis on clonal MCAS [systemic mastocytosis and mono(clonal) MC activations syndromes]. PMID:28740494

Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study.

PubMed

Takahashi, Koichi; Wang, Feng; Kantarjian, Hagop; Doss, Denaha; Khanna, Kanhav; Thompson, Erika; Zhao, Li; Patel, Keyur; Neelapu, Sattva; Gumbs, Curtis; Bueso-Ramos, Carlos; DiNardo, Courtney D; Colla, Simona; Ravandi, Farhad; Zhang, Jianhua; Huang, Xuelin; Wu, Xifeng; Samaniego, Felipe; Garcia-Manero, Guillermo; Futreal, P Andrew

2017-01-01

Therapy-related myeloid neoplasms are secondary malignancies that are often fatal, but their risk factors are not well understood. Evidence suggests that individuals with clonal haemopoiesis have increased risk of developing haematological malignancies. We aimed to identify whether patients with cancer who have clonal haemopoiesis are at an increased risk of developing therapy-related myeloid neoplasms. We did this retrospective case-control study to compare the prevalence of clonal haemopoiesis between patients treated for cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). All patients in both case and control groups were treated at MD Anderson Cancer Center (Houston, TX, USA) from 1997 to 2015. We used the institutional medical database to locate these patients. Patients were included as cases if they were treated for a primary cancer, subsequently developed therapy-related myeloid neoplasms, and had available paired samples of bone marrow from the time of therapy-related myeloid neoplasm diagnosis and peripheral blood from the time of primary cancer diagnosis. Patients were eligible for inclusion as age-matched controls if they were treated for lymphoma, received combination chemotherapy, and did not develop therapy-related myeloid neoplasms after at least 5 years of follow-up. We used molecular barcode sequencing of 32 genes on the pretreatment peripheral blood samples to detect clonal haemopoiesis. For cases, we also used targeted gene sequencing on bone marrow samples and investigated clonal evolution from clonal haemopoiesis to the development of therapy-related myeloid neoplasms. To further clarify the association between clonal haemopoiesis and therapy-related myeloid neoplasm development, we also analysed the prevalence of clonal haemopoiesis in an external cohort of patients with lymphoma who were treated in a randomised trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin. This trial was done at MD Anderson Cancer Center between 1999 and 2001 (protocol number 98-009). We identified 14 cases and 54 controls. Of the 14 cases, we detected clonal haemopoiesis in the peripheral blood samples of ten (71%) patients. We detected clonal haemopoiesis in 17 (31%) of the 54 controls. The cumulative incidence of therapy-related myeloid neoplasms in both cases and controls at 5 years was significantly higher in patients with clonal haemopoiesis (30%, 95% CI 16-51) than in those without (7%, 2-21; p=0·016). In the external cohort, five (7%) of 74 patients developed therapy-related myeloid neoplasms, of whom four (80%) had clonal haemopoiesis; 11 (16%) of 69 patients who did not develop therapy-related myeloid neoplasms had clonal haemopoiesis. In the external cohort, the cumulative incidence of therapy-related myeloid neoplasms at 10 years was significantly higher in patients with clonal haemopoiesis (29%, 95% CI 8-53) than in those without (0%, 0-0; p=0·0009). In a multivariate Fine and Gray model based on the external cohort, the presence of clonal haemopoiesis significantly increased the risk of therapy-related myeloid neoplasm development (hazard ratio 13·7, 95% CI 1·7-108·7; p=0·013). Preleukaemic clonal haemopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal haemopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms. A prospective trial to validate this concept is warranted. Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, NIH through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clonal diversity and genetic profiling of antibiotic resistance among multidrug/carbapenem-resistant Klebsiella pneumoniae isolates from a tertiary care hospital in Saudi Arabia.

PubMed

Zaman, Taher Uz; Alrodayyan, Maha; Albladi, Maha; Aldrees, Mohammed; Siddique, Mohammed Ismail; Aljohani, Sameera; Balkhy, Hanan H

2018-05-03

The nexus between resistance determinants, plasmid type, and clonality appears to play a crucial role in the dissemination and survival of carbapenem-resistant Klebsiella pneumoniae (CRKP). The incidence of infections involving CRKP in Saudi Arabia is increasing and there is a need for detailed molecular profiling of this pathogen for CRKP surveillance and control. The resistance determinants of 71 non-redundant CRKP isolates were investigated by polymerase chain reaction (PCR) and sequencing. Plasmid typing was performed using PCR-based replicon typing and the clonality of isolates was determined by multilocus sequence typing. Capsular polysaccharide synthesis genes and other virulence factors were examined using multiplex PCR. Diversity was calculated using DIVEIN, clonal relationship was determined using eBURST, and phylogenetic analysis was performed using SplitsTree4. A polyclonal OXA-48 gene alone was the most common carbapenemase detected in 48/71 (67.6%) isolates followed by NDM-1 alone in 9/71 (12.7%) isolates. Coproduction of OXA-48 and NDM-1 was observed in 6/71 (8.5%) isolates. Both carbapenemase genes could be transferred into an Escherichia coli recipient. CTX-M-15 was the most abundant extended-spectrum β-lactamase gene detected in 47/71 (66.2%) isolates, whereas clone-specific CTX-M-14 (ST-199 and -709) was found in 15/71 (21%) isolates. Sixty-seven of 71 isolates were positive for one or more plasmid replicons. The replicons detected were: IncFII; IncFIIK; IncFIA; IncFIB; L/M; IncI1; and IncN. FIIK and L/M were predominant, with 69 and 67% positivity, respectively. All isolates were negative for the magA (K1), rmpA, and K2 genes and presented a non-hypermucoviscous phenotype. A polyclonal CRKP reservoir of sequence types (STs)-37, - 199, and - 152 was observed and ST-152 appeared to be a "frequent carrier" of the NDM-1 gene. ST-199, a singleton not previously reported, showed a sequence diversity suggestive of positive selection. A significant association was evident between resistance determinants and the clonal types of K. pneumoniae: all ST-152 isolates were positive for NDM-1 but negative for OXA-48; ST-199 isolates were positive for OXA-48 but negative for NDM-1; and ST-709 and -199 isolates were positive for CTX-M-14. The incidence of certain clonal types in large numbers predicts an outbreak-like situation and warrants stringent surveillance and infection control.

Biological and Clinical Implications of Clonal Heterogeneity and Clonal Evolution in Multiple Myeloma.

PubMed

Bianchi, Giada; Ghobrial, Irene M

Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization, whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence. First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma (MM), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting MM cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in driving evolution from MGUS to MM is at present unclear. We present in this review a historical excursus on the concepts of clonal heterogeneity and clonal evolution in MM with a special emphasis on their role in the progression from MGUS to MM; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment and disease relapse/recurrence.

Biological and Clinical Implications of Clonal Heterogeneity and Clonal Evolution in Multiple Myeloma

PubMed Central

Bianchi, Giada; Ghobrial, Irene M.

2015-01-01

Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization, whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence. First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma (MM), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting MM cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in driving evolution from MGUS to MM is at present unclear. We present in this review a historical excursus on the concepts of clonal heterogeneity and clonal evolution in MM with a special emphasis on their role in the progression from MGUS to MM; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment and disease relapse/recurrence. PMID:25705146

Strong but diverging clonality - climate relationships of different plant clades explain weak overall pattern across China.

PubMed

Ye, Duo; Liu, Guofang; Song, Yao-Bin; Cornwell, William K; Dong, Ming; Cornelissen, Johannes H C

2016-06-01

The clonal strategy should be relatively important in stressful environments (i.e. of low resource availability or harsh climate), e.g. in cold habitats. However, our understanding of the distribution pattern of clonality along environmental gradients is still far from universal. The weakness and inconsistency of overall clonality-climate relationships across taxa, as reported in previous studies, may be due to different phylogenetic lineages having fundamental differences in functional traits other than clonality determining their climate response. Thus, in this study we compared the clonality-climate relationships along a latitudinal gradient within and between different lineages at several taxonomic levels, including four major angiosperm lineages (Magnoliidae, Monocotyledoneae, Superrosidae and Superasteridae), orders and families. To this aim we used a species clonality dataset for 4015 vascular plant species in 545 terrestrial communities across China. Our results revealed clear predictive patterns of clonality proportion in relation to environmental gradients for the predominant representatives of each of the taxonomic levels above, but the relationships differed in shape and strength between the 4 major angiosperm lineages, between the 12 orders and between the 12 families. These different relationships canceled out one another when all lineages at a certain taxonomic level were pooled. Our findings highlight the importance of explicitly accounting for the functional or taxonomic scale for studying variation in plant ecological strategy across environmental gradients.

The clonal origin and clonal evolution of epithelial tumours

PubMed Central

Garcia, Sergio Britto; Novelli, Marco; Wright, Nicholas A

2000-01-01

While the origin of tumours, whether from one cell or many, has been a source of fascination for experimental oncologists for some time, in recent years there has been a veritable explosion of information about the clonal architecture of tumours and their antecedents, stimulated, in the main, by the ready accessibility of new molecular techniques. While most of these new results have apparently confirmed the monoclonal origin of human epithelial (and other) tumours, there are a significant number of studies in which this conclusion just cannot be made. Moreover, analysis of many articles show that the potential impact of such considerations as patch size and clonal evolution on determinations of clonality have largely been ignored, with the result that a number of these studies are confounded. However, the clonal architecture of preneoplastic lesions provide some interesting insights — many lesions which might have been hitherto regarded as hyperplasias are apparently clonal in derivation. If this is indeed true, it calls into some question our hopeful corollary that a monoclonal origin presages a neoplastic habitus. Finally, it is clear, for many reasons, that methods of analysis which involve the disaggregation of tissues, albeit microdissected, are far from ideal and we should be putting more effort into techniques where the clonal architecture of normal tissues, preneoplastic and preinvasive lesions and their derivative tumours can be directly visualized in situ. PMID:10762440

Consequences of clonality for sexual fitness: Clonal expansion enhances fitness under spatially restricted dispersal.

PubMed

Van Drunen, Wendy E; van Kleunen, Mark; Dorken, Marcel E

2015-07-21

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.

Clonal growth and plant species abundance.

PubMed

Herben, Tomáš; Nováková, Zuzana; Klimešová, Jitka

2014-08-01

Both regional and local plant abundances are driven by species' dispersal capacities and their abilities to exploit new habitats and persist there. These processes are affected by clonal growth, which is difficult to evaluate and compare across large numbers of species. This study assessed the influence of clonal reproduction on local and regional abundances of a large set of species and compared the predictive power of morphologically defined traits of clonal growth with data on actual clonal growth from a botanical garden. The role of clonal growth was compared with the effects of seed reproduction, habitat requirements and growth, proxied both by LHS (leaf-height-seed) traits and by actual performance in the botanical garden. Morphological parameters of clonal growth, actual clonal reproduction in the garden and LHS traits (leaf-specific area - height - seed mass) were used as predictors of species abundance, both regional (number of species records in the Czech Republic) and local (mean species cover in vegetation records) for 836 perennial herbaceous species. Species differences in habitat requirements were accounted for by classifying the dataset by habitat type and also by using Ellenberg indicator values as covariates. After habitat differences were accounted for, clonal growth parameters explained an important part of variation in species abundance, both at regional and at local levels. At both levels, both greater vegetative growth in cultivation and greater lateral expansion trait values were correlated with higher abundance. Seed reproduction had weaker effects, being positive at the regional level and negative at the local level. Morphologically defined traits are predictive of species abundance, and it is concluded that simultaneous investigation of several such traits can help develop hypotheses on specific processes (e.g. avoidance of self-competition, support of offspring) potentially underlying clonal growth effects on abundance. Garden performance parameters provide a practical approach to assessing the roles of clonal growth morphological traits (and LHS traits) for large sets of species. © The Author 2014. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Rough sets and Laplacian score based cost-sensitive feature selection

PubMed Central

Yu, Shenglong

2018-01-01

Cost-sensitive feature selection learning is an important preprocessing step in machine learning and data mining. Recently, most existing cost-sensitive feature selection algorithms are heuristic algorithms, which evaluate the importance of each feature individually and select features one by one. Obviously, these algorithms do not consider the relationship among features. In this paper, we propose a new algorithm for minimal cost feature selection called the rough sets and Laplacian score based cost-sensitive feature selection. The importance of each feature is evaluated by both rough sets and Laplacian score. Compared with heuristic algorithms, the proposed algorithm takes into consideration the relationship among features with locality preservation of Laplacian score. We select a feature subset with maximal feature importance and minimal cost when cost is undertaken in parallel, where the cost is given by three different distributions to simulate different applications. Different from existing cost-sensitive feature selection algorithms, our algorithm simultaneously selects out a predetermined number of “good” features. Extensive experimental results show that the approach is efficient and able to effectively obtain the minimum cost subset. In addition, the results of our method are more promising than the results of other cost-sensitive feature selection algorithms. PMID:29912884

Rough sets and Laplacian score based cost-sensitive feature selection.

PubMed

Yu, Shenglong; Zhao, Hong

2018-01-01

Cost-sensitive feature selection learning is an important preprocessing step in machine learning and data mining. Recently, most existing cost-sensitive feature selection algorithms are heuristic algorithms, which evaluate the importance of each feature individually and select features one by one. Obviously, these algorithms do not consider the relationship among features. In this paper, we propose a new algorithm for minimal cost feature selection called the rough sets and Laplacian score based cost-sensitive feature selection. The importance of each feature is evaluated by both rough sets and Laplacian score. Compared with heuristic algorithms, the proposed algorithm takes into consideration the relationship among features with locality preservation of Laplacian score. We select a feature subset with maximal feature importance and minimal cost when cost is undertaken in parallel, where the cost is given by three different distributions to simulate different applications. Different from existing cost-sensitive feature selection algorithms, our algorithm simultaneously selects out a predetermined number of "good" features. Extensive experimental results show that the approach is efficient and able to effectively obtain the minimum cost subset. In addition, the results of our method are more promising than the results of other cost-sensitive feature selection algorithms.

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

PubMed Central

Babushok, Daria V.; Bessler, Monica; Olson, Timothy S.

2016-01-01

Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes. PMID:26693794

The influence of alternative plant propagation and stand establishment techniques on survival and growth of eastern cottonwood (Populus deltoids Bartr.) clones

Treesearch

Donald J. Kaczmarek; Randall Rousseau; Jeff A. Wright; Brian Wachelka

2014-01-01

Four eastern cottonwood clones, including standard operational clone ST66 and three advanced clonal selections were produced and included in a test utilizing five different plant propagation methods. Despite relatively large first-year growth differences among clones, all clones demonstrated similar responses to the treatments and clone × cutting treatment interactions...

High-definition reconstruction of clonal composition in cancer.

PubMed

Fischer, Andrej; Vázquez-García, Ignacio; Illingworth, Christopher J R; Mustonen, Ville

2014-06-12

The extensive genetic heterogeneity of cancers can greatly affect therapy success due to the existence of subclonal mutations conferring resistance. However, the characterization of subclones in mixed-cell populations is computationally challenging due to the short length of sequence reads that are generated by current sequencing technologies. Here, we report cloneHD, a probabilistic algorithm for the performance of subclone reconstruction from data generated by high-throughput DNA sequencing: read depth, B-allele counts at germline heterozygous loci, and somatic mutation counts. The algorithm can exploit the added information present in correlated longitudinal or multiregion samples and takes into account correlations along genomes caused by events such as copy-number changes. We apply cloneHD to two case studies: a breast cancer sample and time-resolved samples of chronic lymphocytic leukemia, where we demonstrate that monitoring the response of a patient to therapy regimens is feasible. Our work provides new opportunities for tracking cancer development. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Enforced Clonality Confers a Fitness Advantage

PubMed Central

Martínková, Jana; Klimešová, Jitka

2016-01-01

In largely clonal plants, splitting of a maternal plant into potentially independent plants (ramets) is usually spontaneous; however, such fragmentation also occurs in otherwise non-clonal species due to application of external force. This process might play an important yet largely overlooked role for otherwise non-clonal plants by providing a mechanism to regenerate after disturbance. Here, in a 5-year garden experiment on two short-lived, otherwise non-clonal species, Barbarea vulgaris and Barbarea stricta, we compared the fitness of plants fragmented by simulated disturbance (“enforced ramets”) both with plants that contemporaneously originate in seed and with individuals unscathed by the disturbance event. Because the ability to regrow from fragments is related to plant age and stored reserves, we compared the effects of disturbance applied during three different ontogenetic stages of the plants. In B. vulgaris, enforced ramet fitness was higher than the measured fitness values of both uninjured plants and plants established from seed after the disturbance. This advantage decreased with increasing plant age at the time of fragmentation. In B. stricta, enforced ramet fitness was lower than or similar to fitness of uninjured plants and plants grown from seed. Our results likely reflect the habitat preferences of the study species, as B. vulgaris occurs in anthropogenic, disturbed habitats where body fragmentation is more probable and enforced clonality thus more advantageous than in the more natural habitats preferred by B. stricta. Generalizing from our results, we see that increased fitness yielded by enforced clonality would confer an evolutionary advantage in the face of disturbance, especially in habitats where a seed bank has not been formed, e.g., during invasion or colonization. Our results thus imply that enforced clonality should be taken into account when studying population dynamics and life strategies of otherwise non-clonal species in disturbed habitats. PMID:26858732

Differential influence of clonal integration on morphological and growth responses to light in two invasive herbs.

PubMed

Xu, Cheng-Yuan; Schooler, Shon S; Van Klinken, Rieks D

2012-01-01

In contrast to seeds, high sensitivity of vegetative fragments to unfavourable environments may limit the expansion of clonal invasive plants. However, clonal integration promotes the establishment of propagules in less suitable habitats and may facilitate the expansion of clonal invaders into intact native communities. Here, we examine the influence of clonal integration on the morphology and growth of ramets in two invasive plants, Alternanthera philoxeroides and Phyla canescens, under varying light conditions. In a greenhouse experiment, branches, connected ramets and severed ramets of the same mother plant were exposed under full sun and 85% shade and their morphological and growth responses were assessed. The influence of clonal integration on the light reaction norm (connection×light interaction) of daughter ramets was species-specific. For A. philoxeroides, clonal integration evened out the light response (total biomass, leaf mass per area, and stem number, diameter and length) displayed in severed ramets, but these connection×light interactions were largely absent for P. canescens. Nevertheless, for both species, clonal integration overwhelmed light effect in promoting the growth of juvenile ramets during early development. Also, vertical growth, as an apparent shade acclimation response, was more prevalent in severed ramets than in connected ramets. Finally, unrooted branches displayed smaller organ size and slower growth than connected ramets, but the pattern of light reaction was similar, suggesting mother plants invest in daughter ramets prior to their own branches. Clonal integration modifies light reaction norms of morphological and growth traits in a species-specific manner for A. philoxeroides and P. canescens, but it improves the establishment of juvenile ramets of both species in light-limiting environments by promoting their growth during early development. This factor may be partially responsible for their ability to successfully colonize native plant communities.

Low incidence of clonality in cold water corals revealed through the novel use of standardized protocol adapted to deep sea sampling

USGS Publications Warehouse

Becheler, Ronan; Cassone, Anne-Laure; Noel, Philippe; Mouchel, Olivier; Morrison, Cheryl L.; Arnaud-Haond, Sophie

2017-01-01

Sampling in the deep sea is a technical challenge, which has hindered the acquisition of robust datasets that are necessary to determine the fine-grained biological patterns and processes that may shape genetic diversity. Estimates of the extent of clonality in deep-sea species, despite the importance of clonality in shaping the local dynamics and evolutionary trajectories, have been largely obscured by such limitations. Cold-water coral reefs along European margins are formed mainly by two reef-building species, Lophelia pertusa and Madrepora oculata. Here we present a fine-grained analysis of the genotypic and genetic composition of reefs occurring in the Bay of Biscay, based on an innovative deep-sea sampling protocol. This strategy was designed to be standardized, random, and allowed the georeferencing of all sampled colonies. Clonal lineages discriminated through their Multi-Locus Genotypes (MLG) at 6–7 microsatellite markers could thus be mapped to assess the level of clonality and the spatial spread of clonal lineages. High values of clonal richness were observed for both species across all sites suggesting a limited occurrence of clonality, which likely originated through fragmentation. Additionally, spatial autocorrelation analysis underlined the possible occurrence of fine-grained genetic structure in several populations of both L. pertusa and M. oculata. The two cold-water coral species examined had contrasting patterns of connectivity among canyons, with among-canyon genetic structuring detected in M. oculata, whereas L. pertusa was panmictic at the canyon scale. This study exemplifies that a standardized, random and georeferenced sampling strategy, while challenging, can be applied in the deep sea, and associated benefits outlined here include improved estimates of fine grained patterns of clonality and dispersal that are comparable across sites and among species.

Propagule Pressure, Habitat Conditions and Clonal Integration Influence the Establishment and Growth of an Invasive Clonal Plant, Alternanthera philoxeroides.

PubMed

You, Wen-Hua; Han, Cui-Min; Fang, Long-Xiang; Du, Dao-Lin

2016-01-01

Many notorious invasive plants are clonal, spreading mainly by vegetative propagules. Propagule pressure (the number of propagules) may affect the establishment, growth, and thus invasion success of these clonal plants, and such effects may also depend on habitat conditions. To understand how propagule pressure, habitat conditions and clonal integration affect the establishment and growth of the invasive clonal plants, an 8-week greenhouse with an invasive clonal plant, Alternanthera philoxeroides was conducted. High (five fragments) or low (one fragment) propagule pressure was established either in bare soil (open habitat) or dense native vegetation of Jussiaea repens (vegetative habitat), with the stolon connections either severed from or connected to the relatively older ramets. High propagule pressure greatly increased the establishment and growth of A. philoxeroides, especially when it grew in vegetative habitats. Surprisingly, high propagule pressure significantly reduced the growth of individual plants of A. philoxeroides in open habitats, whereas it did not affect the individual growth in vegetative habitats. A shift in the intraspecific interaction on A. philoxeroides from competition in open habitats to facilitation in vegetative habitats may be the main reason. Moreover, clonal integration significantly improved the growth of A. philoxeroides only in open habitats, especially with low propagule pressure, whereas it had no effects on the growth and competitive ability of A. philoxeroides in vegetative habitats, suggesting that clonal integration may be of most important for A. philoxeroides to explore new open space and spread. These findings suggest that propagule pressure may be crucial for the invasion success of A. philoxeroides, and such an effect also depends on habitat conditions.

Low incidence of clonality in cold water corals revealed through the novel use of a standardized protocol adapted to deep sea sampling

NASA Astrophysics Data System (ADS)

Becheler, Ronan; Cassone, Anne-Laure; Noël, Philippe; Mouchel, Olivier; Morrison, Cheryl L.; Arnaud-Haond, Sophie

2017-11-01

Sampling in the deep sea is a technical challenge, which has hindered the acquisition of robust datasets that are necessary to determine the fine-grained biological patterns and processes that may shape genetic diversity. Estimates of the extent of clonality in deep-sea species, despite the importance of clonality in shaping the local dynamics and evolutionary trajectories, have been largely obscured by such limitations. Cold-water coral reefs along European margins are formed mainly by two reef-building species, Lophelia pertusa and Madrepora oculata. Here we present a fine-grained analysis of the genotypic and genetic composition of reefs occurring in the Bay of Biscay, based on an innovative deep-sea sampling protocol. This strategy was designed to be standardized, random, and allowed the georeferencing of all sampled colonies. Clonal lineages discriminated through their Multi-Locus Genotypes (MLG) at 6-7 microsatellite markers could thus be mapped to assess the level of clonality and the spatial spread of clonal lineages. High values of clonal richness were observed for both species across all sites suggesting a limited occurrence of clonality, which likely originated through fragmentation. Additionally, spatial autocorrelation analysis underlined the possible occurrence of fine-grained genetic structure in several populations of both L. pertusa and M. oculata. The two cold-water coral species examined had contrasting patterns of connectivity among canyons, with among-canyon genetic structuring detected in M. oculata, whereas L. pertusa was panmictic at the canyon scale. This study exemplifies that a standardized, random and georeferenced sampling strategy, while challenging, can be applied in the deep sea, and associated benefits outlined here include improved estimates of fine grained patterns of clonality and dispersal that are comparable across sites and among species.

Noise and Epigenetic Inheritance of Single-Cell Division Times Influence Population Fitness.

PubMed

Cerulus, Bram; New, Aaron M; Pougach, Ksenia; Verstrepen, Kevin J

2016-05-09

The fitness effect of biological noise remains unclear. For example, even within clonal microbial populations, individual cells grow at different speeds. Although it is known that the individuals' mean growth speed can affect population-level fitness, it is unclear how or whether growth speed heterogeneity itself is subject to natural selection. Here, we show that noisy single-cell division times can significantly affect population-level growth rate. Using time-lapse microscopy to measure the division times of thousands of individual S. cerevisiae cells across different genetic and environmental backgrounds, we find that the length of individual cells' division times can vary substantially between clonal individuals and that sublineages often show epigenetic inheritance of division times. By combining these experimental measurements with mathematical modeling, we find that, for a given mean division time, increasing heterogeneity and epigenetic inheritance of division times increases the population growth rate. Furthermore, we demonstrate that the heterogeneity and epigenetic inheritance of single-cell division times can be linked with variation in the expression of catabolic genes. Taken together, our results reveal how a change in noisy single-cell behaviors can directly influence fitness through dynamics that operate independently of effects caused by changes to the mean. These results not only allow a better understanding of microbial fitness but also help to more accurately predict fitness in other clonal populations, such as tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Recombination-Driven Genome Evolution and Stability of Bacterial Species.

PubMed

Dixit, Purushottam D; Pang, Tin Yau; Maslov, Sergei

2017-09-01

While bacteria divide clonally, horizontal gene transfer followed by homologous recombination is now recognized as an important contributor to their evolution. However, the details of how the competition between clonality and recombination shapes genome diversity remains poorly understood. Using a computational model, we find two principal regimes in bacterial evolution and identify two composite parameters that dictate the evolutionary fate of bacterial species. In the divergent regime, characterized by either a low recombination frequency or strict barriers to recombination, cohesion due to recombination is not sufficient to overcome the mutational drift. As a consequence, the divergence between pairs of genomes in the population steadily increases in the course of their evolution. The species lacks genetic coherence with sexually isolated clonal subpopulations continuously formed and dissolved. In contrast, in the metastable regime, characterized by a high recombination frequency combined with low barriers to recombination, genomes continuously recombine with the rest of the population. The population remains genetically cohesive and temporally stable. Notably, the transition between these two regimes can be affected by relatively small changes in evolutionary parameters. Using the Multi Locus Sequence Typing (MLST) data, we classify a number of bacterial species to be either the divergent or the metastable type. Generalizations of our framework to include selection, ecologically structured populations, and horizontal gene transfer of nonhomologous regions are discussed as well. Copyright © 2017 by the Genetics Society of America.

A Network Selection Algorithm Considering Power Consumption in Hybrid Wireless Networks

NASA Astrophysics Data System (ADS)

Joe, Inwhee; Kim, Won-Tae; Hong, Seokjoon

In this paper, we propose a novel network selection algorithm considering power consumption in hybrid wireless networks for vertical handover. CDMA, WiBro, WLAN networks are candidate networks for this selection algorithm. This algorithm is composed of the power consumption prediction algorithm and the final network selection algorithm. The power consumption prediction algorithm estimates the expected lifetime of the mobile station based on the current battery level, traffic class and power consumption for each network interface card of the mobile station. If the expected lifetime of the mobile station in a certain network is not long enough compared the handover delay, this particular network will be removed from the candidate network list, thereby preventing unnecessary handovers in the preprocessing procedure. On the other hand, the final network selection algorithm consists of AHP (Analytic Hierarchical Process) and GRA (Grey Relational Analysis). The global factors of the network selection structure are QoS, cost and lifetime. If user preference is lifetime, our selection algorithm selects the network that offers longest service duration due to low power consumption. Also, we conduct some simulations using the OPNET simulation tool. The simulation results show that the proposed algorithm provides longer lifetime in the hybrid wireless network environment.

Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing.

PubMed

Hughes, Andrew E O; Magrini, Vincent; Demeter, Ryan; Miller, Christopher A; Fulton, Robert; Fulton, Lucinda L; Eades, William C; Elliott, Kevin; Heath, Sharon; Westervelt, Peter; Ding, Li; Conrad, Donald F; White, Brian S; Shao, Jin; Link, Daniel C; DiPersio, John F; Mardis, Elaine R; Wilson, Richard K; Ley, Timothy J; Walter, Matthew J; Graubert, Timothy A

2014-07-01

Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.

Clonal plasticity and diversity facilitates the adaptation of Rhododendron aureum Georgi to alpine environment

PubMed Central

Wang, Xiaolong; Zhao, Wei; Li, Lin; You, Jian; Ni, Biao

2018-01-01

Four small oval populations and five large intensive populations of Rhododendron aureum growing at the alpine in Changbai Mountain (China) were studied in two types of habitat (in the tundra and in Betula ermanii forest). Identification and delimitation of genets were inferred from excavation in small populations and from amplified fragment length polymorphism (AFLP) markers by the standardized sampling design in large populations. Clonal architecture and clonal diversity were then estimated. For the four small populations, they were monoclonal, the spacer length (18.6 ± 5.6 in tundra, 29.7 ± 9.7 in Betula ermanii forest, P < 0.05) was shorter and branching intensity (136.7 ± 32.9 in tundra, 43.4 ± 12.3 in Betula ermanii forest, P < 0.05) was higher in the tundra than that in Betula ermanii forest. For the five large populations, they were composed of multiple genets with high level of clonal diversity (Simpson’s index D = 0.84, clonal richness R = 0.25, Fager's evenness E = 0.85); the spatial distribution of genets showed that the clonal growth strategy of R. aureum exhibits both guerilla and phalanx. Our results indicate that the clonal plasticity of R. aureum could enhance exploitation of resource heterogeneity and in turn greatly contribute to maintenance or improvement of fitness and the high clonal diversity of R. aureum increase the evolutionary rates to adapt the harsh alpine environment in Changbai Mountain. PMID:29746526

Biomass Allocation of Stoloniferous and Rhizomatous Plant in Response to Resource Availability: A Phylogenetic Meta-Analysis

PubMed Central

Xie, Xiu-Fang; Hu, Yu-Kun; Pan, Xu; Liu, Feng-Hong; Song, Yao-Bin; Dong, Ming

2016-01-01

Resource allocation to different functions is central in life-history theory. Plasticity of functional traits allows clonal plants to regulate their resource allocation to meet changing environments. In this study, biomass allocation traits of clonal plants were categorized into absolute biomass for vegetative growth vs. for reproduction, and their relative ratios based on a data set including 115 species and derived from 139 published literatures. We examined general pattern of biomass allocation of clonal plants in response to availabilities of resource (e.g., light, nutrients, and water) using phylogenetic meta-analysis. We also tested whether the pattern differed among clonal organ types (stolon vs. rhizome). Overall, we found that stoloniferous plants were more sensitive to light intensity than rhizomatous plants, preferentially allocating biomass to vegetative growth, aboveground part and clonal reproduction under shaded conditions. Under nutrient- and water-poor condition, rhizomatous plants were constrained more by ontogeny than by resource availability, preferentially allocating biomass to belowground part. Biomass allocation between belowground and aboveground part of clonal plants generally supported the optimal allocation theory. No general pattern of trade-off was found between growth and reproduction, and neither between sexual and clonal reproduction. Using phylogenetic meta-analysis can avoid possible confounding effects of phylogeny on the results. Our results shown the optimal allocation theory explained a general trend, which the clonal plants are able to plastically regulate their biomass allocation, to cope with changing resource availability, at least in stoloniferous and rhizomatous plants. PMID:27200071

Cellular evidence for selfish spermatogonial selection in aged human testes.

PubMed

Maher, G J; Goriely, A; Wilkie, A O M

2014-05-01

Owing to a recent trend for delayed paternity, the genomic integrity of spermatozoa of older men has become a focus of increased interest. Older fathers are at higher risk for their children to be born with several monogenic conditions collectively termed paternal age effect (PAE) disorders, which include achondroplasia, Apert syndrome and Costello syndrome. These disorders are caused by specific mutations originating almost exclusively from the male germline, in genes encoding components of the tyrosine kinase receptor/RAS/MAPK signalling pathway. These particular mutations, occurring randomly during mitotic divisions of spermatogonial stem cells (SSCs), are predicted to confer a selective/growth advantage on the mutant SSC. This selective advantage leads to a clonal expansion of the mutant cells over time, which generates mutant spermatozoa at levels significantly above the background mutation rate. This phenomenon, termed selfish spermatogonial selection, is likely to occur in all men. In rare cases, probably because of additional mutational events, selfish spermatogonial selection may lead to spermatocytic seminoma. The studies that initially predicted the clonal nature of selfish spermatogonial selection were based on DNA analysis, rather than the visualization of mutant clones in intact testes. In a recent study that aimed to identify these clones directly, we stained serial sections of fixed testes for expression of melanoma antigen family A4 (MAGEA4), a marker of spermatogonia. A subset of seminiferous tubules with an appearance and distribution compatible with the predicted mutant clones were identified. In these tubules, termed 'immunopositive tubules', there is an increased density of spermatogonia positive for markers related to selfish selection (FGFR3) and SSC self-renewal (phosphorylated AKT). Here we detail the properties of the immunopositive tubules and how they relate to the predicted mutant clones, as well as discussing the utility of identifying the potential cellular source of PAE mutations. © 2013 American Society of Andrology and European Academy of Andrology.

Virulence, sporulation, and elicitin production in three clonal lineages of Phytophthora ramorum

USDA-ARS?s Scientific Manuscript database

Phytophthora ramorum populations are clonal and consist of three lineages. Recent studies have shown that the clonal lineages may have varying degrees of aggressiveness on some host species, such as Quercus rubra. In this study, we examined virulence, sporulation and elicitin production of five P. ...

SNP-based differentiation of Phytophthora infestans clonal lineages using locked nucleic acid probes and high resolution melt analysis

USDA-ARS?s Scientific Manuscript database

Phytophthora infestans, the cause of the devastating late blight disease of potato and tomato, exhibits a clonal reproductive lifestyle in North America. Phenotypes such as fungicide sensitivity and host preference are conserved among individuals within clonal lineages, while substantial phenotypic ...

Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality

USDA-ARS?s Scientific Manuscript database

To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytica...

Chromosome aberrations of clonal origin are present in astronauts' blood lymphocytes.

PubMed

George, K; Durante, M; Willingham, V; Cucinotta, F A

2004-01-01

Radiation-induced chromosome translocations remain in peripheral blood cells over many years, and can potentially be used to measure retrospective doses or prolonged low-dose rate exposures. However, several recent studies have indicated that some individuals possess clones of cells with balanced chromosome abnormalities, which can result in an overestimation of damage and, therefore, influence the accuracy of dose calculations. We carefully examined the patterns of chromosome damage found in the blood lymphocytes of twelve astronauts, and also applied statistical methods to screen for the presence of potential clones. Cells with clonal aberrations were identified in three of the twelve individuals. These clonal cells were present in samples collected both before and after space flight, and yields are higher than previously reported for healthy individuals in this age range (40-52 years of age). The frequency of clonal damage appears to be even greater in chromosomes prematurely condensed in interphase, when compared with equivalent analysis in metaphase cells. The individuals with clonal aberrations were followed-up over several months and the yields of all clones decreased during this period. Since clonal aberrations may be associated with increased risk of tumorigenesis, it is important to accurately identify cells containing clonal rearrangements for risk assessment as well as biodosimetry. Copyright 2003 S. Karger AG, Basel

Chromosome aberrations of clonal origin are present in astronauts' blood lymphocytes

NASA Technical Reports Server (NTRS)

George, K.; Durante, M.; Willingham, V.; Cucinotta, F. A.

2004-01-01

Radiation-induced chromosome translocations remain in peripheral blood cells over many years, and can potentially be used to measure retrospective doses or prolonged low-dose rate exposures. However, several recent studies have indicated that some individuals possess clones of cells with balanced chromosome abnormalities, which can result in an overestimation of damage and, therefore, influence the accuracy of dose calculations. We carefully examined the patterns of chromosome damage found in the blood lymphocytes of twelve astronauts, and also applied statistical methods to screen for the presence of potential clones. Cells with clonal aberrations were identified in three of the twelve individuals. These clonal cells were present in samples collected both before and after space flight, and yields are higher than previously reported for healthy individuals in this age range (40-52 years of age). The frequency of clonal damage appears to be even greater in chromosomes prematurely condensed in interphase, when compared with equivalent analysis in metaphase cells. The individuals with clonal aberrations were followed-up over several months and the yields of all clones decreased during this period. Since clonal aberrations may be associated with increased risk of tumorigenesis, it is important to accurately identify cells containing clonal rearrangements for risk assessment as well as biodosimetry. Copyright 2003 S. Karger AG, Basel.

Three-gene identity coefficients demonstrate that clonal reproduction promotes inbreeding and spatial relatedness in yellow-cedar, Callitropsis nootkatensis.

PubMed

Thompson, Stacey Lee; Bérubé, Yanik; Bruneau, Anne; Ritland, Kermit

2008-10-01

Asexual reproduction has the potential to promote population structuring through matings between clones as well as through limited dispersal of related progeny. Here we present an application of three-gene identity coefficients that tests whether clonal reproduction promotes inbreeding and spatial relatedness within populations. With this method, the first two genes are sampled to estimate pairwise relatedness or inbreeding, whereas the third gene is sampled from either a clone or a sexually derived individual. If three-gene coefficients are significantly greater for clones than nonclones, then clonality contributes excessively to genetic structure. First, we describe an estimator of three-gene identity and briefly evaluate its properties. We then use this estimator to test the effect of clonality on the genetic structure within populations of yellow-cedar (Callitropsis nootkatensis) using a molecular marker survey. Five microsatellite loci were genotyped for 485 trees sampled from nine populations. Our three-gene analyses show that clonal ramets promote inbreeding and spatial structure in most populations. Among-population correlations between clonal extent and genetic structure generally support these trends, yet with less statistical significance. Clones appear to contribute to genetic structure through the limited dispersal of offspring from replicated ramets of the same clonal genet, whereas this structure is likely maintained by mating among these relatives.

Poplar breeding and testing strategies in the north-central U.S.: Demonstration of potential yield and consideration of future research needs1

Treesearch

Don E. Riemenschneider; William E. Berguson; Donald I. Dickmann; Richard B. Hall; J. G. Isebrands; Carl A. Mohn; Glen R. Stanosz; Gerald A. Tuskan

2001-01-01

We present results from a Populus Regional Testing Program that has been conducted in Minnesota, Iowa, Wisconsin, and Michigan over the past six years. Our objectives have been to: 1) identify highly productive, disease resistant intra- and inter-specific clonal selections and 2) understand patterns of genotype x environment interactions within the region that would,...

Hybrid poplar grows poorly on acid spoil banks at high elevations in West Virginia

Treesearch

George R., Jr. Trimble

1963-01-01

In the early 1950s, a region-wide series of hybrid poplar clonal tests was begun in the Northeast to evaluate the performance of 50 selected clones under a variety of site and climatic conditions. The basic test unit was a block of 50 randomized plots-1 plot for each of the 50 clones. In each plot, 16 cuttings were planted at 4-foot spacing.

Cartilage regeneration by selected chondrogenic clonal mesenchymal stem cells in the collagenase-induced monkey osteoarthritis model.

PubMed

Jiang, Li; Ma, Anlun; Song, Lijun; Hu, Yanxin; Dun, Hao; Daloze, Pierre; Yu, Yonglin; Jiang, Jianyuan; Zafarullah, Muhammad; Chen, Huifang

2014-11-01

Osteoarthritis (OA) is the most common form of arthritis, in which cartilage is irreversibly degraded, causing severe pain and disability. Current therapeutic strategies cannot repair damaged cartilage. We evaluated the repair potential of selected chondrogenic clonal MSCs (sC-MSCs) by delivering them into the injured cartilage site in a collagenase-induced OA model in Cynomolgus monkeys. In vitro characterization showed that the isolated monkey sC-MSCs and polyclonal MSCs (P-MSCs) expressed mesenchymal stem cell markers and could differentiate into chondrocytes. The articular cartilage lesions in animals were treated with normal saline (NS), autologous P-MSCs and sC-MSCs, respectively, by direct delivery. The clinical parameters, radiographic images, histological and immunohistochemical examinations at weeks 8, 16 and 24 post-treatment demonstrated that the abrasions of articular cartilage were significantly improved and repaired by MSC-based treatment, particularly in the sC-MSC-treated group, which displayed consistently higher histological scores than those of other groups. In summary, treatment with sC-MSCs can effectively improve the healing of cartilage lesions in the Cynomolgus monkey collagenase-induced OA model. Due to the genetic proximity of monkey and human, the therapeutic strategy presented in this study will have broad applications in clinical practice. Copyright © 2013 John Wiley & Sons, Ltd.

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution

PubMed Central

Humphries, Adam; Cereser, Biancastella; Gay, Laura J.; Miller, Daniel S. J.; Das, Bibek; Gutteridge, Alice; Elia, George; Nye, Emma; Jeffery, Rosemary; Poulsom, Richard; Novelli, Marco R.; Rodriguez-Justo, Manuel; McDonald, Stuart A. C.; Wright, Nicholas A.; Graham, Trevor A.

2013-01-01

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO−) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis. PMID:23766371

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.

PubMed

Humphries, Adam; Cereser, Biancastella; Gay, Laura J; Miller, Daniel S J; Das, Bibek; Gutteridge, Alice; Elia, George; Nye, Emma; Jeffery, Rosemary; Poulsom, Richard; Novelli, Marco R; Rodriguez-Justo, Manuel; McDonald, Stuart A C; Wright, Nicholas A; Graham, Trevor A

2013-07-02

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO(-)) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis.

Clonal Expansion during Staphylococcus aureus Infection Dynamics Reveals the Effect of Antibiotic Intervention

PubMed Central

McVicker, Gareth; Prajsnar, Tomasz K.; Williams, Alexander; Wagner, Nelly L.; Boots, Michael; Renshaw, Stephen A.; Foster, Simon J.

2014-01-01

To slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population “bottleneck” whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs. PMID:24586163

Clonal variation in response to salinity and flooding stress in four marsh macrophytes of the northern gulf of Mexico, USA

USGS Publications Warehouse

Howard, R.J.; Rafferty, P.S.

2006-01-01

Intraspecific variation in stress tolerance can be an important factor influencing plant population structure in coastal wetland habitats. We studied clones of four species of emergent marsh macrophytes native to the northern coast of the Gulf of Mexico in Louisiana, USA, to examine variation in response to salinity and flooding stress under controlled greenhouse conditions. Clones of Distichlis spicata, Phragmites australis, Schoenoplectus californicus, and Schoenoplectus robustus were collected across the coastal zone of Louisiana. After vegetative propagation through at least three generations to remove acclimation to field conditions, four to six clones of each species were selected for use in the experiment. Treatments consisted of three salinity levels and two water depths, and species were assigned to either a brackish marsh (P. australis, S. californicus) or salt marsh (D. spicata, S. robustus) group for treatment application. Treatment effects on plant growth (stem number, total height, and mean height, and aboveground and belowground biomass) were examined, and physicochemical characteristics within treatments (redox potential, and interstitial water pH, salinity, temperature, and nutrients) were monitored. Clonal variation in growth was indicated in all species, and was more pronounced in D. spicata and P. australis than in S. californicus and S. robustus. Distichlis spicata and P. australis clones were assigned to relative categories of low, intermediate, and high tolerance to the imposed stressors. Similar generalizations on clonal stress tolerance were not possible for the two Schoenoplectus species. Overall species response to imposed stressors was also identified through non-statistical comparisons. Phragmites australis was more tolerant than S. californicus of increased salinity. Distichlis spicata was more tolerant of increased salinity but less tolerant of increased water depth than was S. robustus. Our results suggest that information on species and clone variations in growth and tolerance to salinity and flooding stressors can be used to select a variety of plant materials suitable for wetland restoration projects.

Clonal Spread in Second Growth Stands of Coast Redwood, Sequoia sempervirens

Treesearch

Vladimir Douhovnikoff; Richard S. Dodd

2007-01-01

Coast redwood (Sequoia sempervirens) is one of the rare conifers to reproduce successfully through clonal spread. The importance of this mode of reproduction in stand development is largely unknown. Understanding the importance of clonal spread and the spatial structure of clones is crucial for stand management strategies that would aim to maximize...

Growth and stem form quality of clonal Pinus taeda following fertilization in the Virginia Piedmont

Treesearch

Jeremy P. Stovall; Colleen A. Carlson; John R. Seiler; Thomas R. Fox

2013-01-01

Clonal forestry offers the opportunity to increase yields, enhance uniformity, and improve wood characteristics. Intensive silvicultural practices, including fertilization, will be required to capture the full growth potential of clonal plantations. However, variation in nutrient use efficiency that exists among clones could affect growth responses. Our research...

GACD: Integrated Software for Genetic Analysis in Clonal F1 and Double Cross Populations.

PubMed

Zhang, Luyan; Meng, Lei; Wu, Wencheng; Wang, Jiankang

2015-01-01

Clonal species are common among plants. Clonal F1 progenies are derived from the hybridization between 2 heterozygous clones. In self- and cross-pollinated species, double crosses can be made from 4 inbred lines. A clonal F1 population can be viewed as a double cross population when the linkage phase is determined. The software package GACD (Genetic Analysis of Clonal F1 and Double cross) is freely available public software, capable of building high-density linkage maps and mapping quantitative trait loci (QTL) in clonal F1 and double cross populations. Three functionalities are integrated in GACD version 1.0: binning of redundant markers (BIN); linkage map construction (CDM); and QTL mapping (CDQ). Output of BIN can be directly used as input of CDM. After adding the phenotypic data, the output of CDM can be used as input of CDQ. Thus, GACD acts as a pipeline for genetic analysis. GACD and example datasets are freely available from www.isbreeding.net. © The American Genetic Association. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Quantitative stability of hematopoietic stem and progenitor cell clonal output in rhesus macaques receiving transplants

PubMed Central

Koelle, Samson J.

2017-01-01

Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells, and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in 4 macaques observed for up to 49 months posttransplantation. A broad range of clonal behaviors characterized by contribution level and biases toward certain cell types were extremely stable over time. Correlations between granulocyte and monocyte clonalities were greatest, followed by correlations between these cell types and B cells. We also detected quantitative expansion of T cell–biased clones consistent with an adaptive immune response. In contrast to recent data from a nonquantitative murine model, there was little evidence for clonal succession after initial hematopoietic reconstitution. These findings have important implications for human hematopoiesis, given the similarities between macaque and human physiologies. PMID:28087539

[Comparison of clonal architecture between two divergent Leymus chinensis types in Songnen grassland].

PubMed

He, Nianpeng; Wu, Ling; Zhou, Daowei

2004-12-01

This paper studied the clonal architecture of two divergent Leymus chinensis types (grey-green type and yellow-green type) in Songnen grassland, and compared their internode length, spacer length, interbranching length, interbranching angle, and ramet population density and height under the same habitat. The results showed that there was no significant difference in these clonal characteristics except spacer length and ramet population density between the two types of L. chinensis, and yellow-green type, with less spacer length and more ramet density than grey-green type, should be more adaptable to the resourceful habitat. Moreover, the V-indices of the clonal architecture of two divergent L. chinensis types were all close to 1, and the difference was not significant. Therefore, both of the two types belonged to typical guerilla clonal plant.

Diagnostic value of immunoglobulin κ light chain gene rearrangement analysis in B-cell lymphomas.

PubMed

Kokovic, Ira; Jezersek Novakovic, Barbara; Novakovic, Srdjan

2015-03-01

Analysis of the immunoglobulin κ light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis.

Longevity of clonal plants: why it matters and how to measure it

PubMed Central

de Witte, Lucienne C.; Stöcklin, Jürg

2010-01-01

Background Species' life-history and population dynamics are strongly shaped by the longevity of individuals, but life span is one of the least accessible demographic traits, particularly in clonal plants. Continuous vegetative reproduction of genets enables persistence despite low or no sexual reproduction, affecting genet turnover rates and population stability. Therefore, the longevity of clonal plants is of considerable biological interest, but remains relatively poorly known. Scope Here, we critically review the present knowledge on the longevity of clonal plants and discuss its importance for population persistence. Direct life-span measurements such as growth-ring analysis in woody plants are relatively easy to take, although, for many clonal plants, these methods are not adequate due to the variable growth pattern of ramets and difficult genet identification. Recently, indirect methods have been introduced in which genet size and annual shoot increments are used to estimate genet age. These methods, often based on molecular techniques, allow the investigation of genet size and age structure of whole populations, a crucial issue for understanding their viability and persistence. However, indirect estimates of clonal longevity are impeded because the process of ageing in clonal plants is still poorly understood and because their size and age are not always well correlated. Alternative estimators for genet life span such as somatic mutations have recently been suggested. Conclusions Empirical knowledge on the longevity of clonal species has increased considerably in the last few years. Maximum age estimates are an indicator of population persistence, but are not sufficient to evaluate turnover rates and the ability of long-lived clonal plants to enhance community stability and ecosystem resilience. In order to understand the dynamics of populations it will be necessary to measure genet size and age structure, not only life spans of single individuals, and to use such data for modelling of genet dynamics. PMID:20880935

Intra-Species Genetic Diversity and Clonal Structure of Cryptosporidium parvum in Sheep Farms in a Confined Geographical Area in Northeastern Spain.

PubMed

Ramo, Ana; Monteagudo, Luis V; Del Cacho, Emilio; Sánchez-Acedo, Caridad; Quílez, Joaquín

2016-01-01

A multilocus fragment typing approach including eleven variable-number tandem-repeat (VNTR) loci and the GP60 gene was used to investigate the intra-farm and intra-host genetic diversity of Cryptosporidium parvum in sheep farms in a confined area in northeastern Spain. Genomic DNA samples of 113 C. parvum isolates from diarrheic pre-weaned lambs collected in 49 meat-type sheep farms were analyzed. Loci exhibited various degrees of polymorphism, the finding of 7-9 alleles in the four most variable and discriminatory markers (ML2, Cgd6_5400, Cgd6_3940, and GP60) being remarkable. The combination of alleles at the twelve loci identified a total of 74 multilocus subtypes (MLTs) and provided a Hunter-Gaston discriminatory index of 0.988 (95% CI, 0.979-0.996). The finding that most MLTs (n = 64) were unique to individual farms evidenced that cryptosporidial infection is mainly transmitted within sheep flocks, with herd-to-herd transmission playing a secondary role. Limited intra- host variability was found, since only five isolates were genotypically mixed. In contrast, a significant intra-farm genetic diversity was seen, with the presence of multiple MLTs on more than a half of the farms (28/46), suggesting frequent mutations or genetic exchange through recombination. Comparison with a previous study in calves in northern Spain using the same 12-loci typing approach showed differences in the identity of major alleles at most loci, with a single MLT being shared between lambs and calves. Analysis of evolutionary descent by the algorithm eBURST indicated a high degree of genetic divergence, with over 41% MLTs appearing as singletons along with a high number of clonal complexes, most of them linking only two MLTs. Bayesian Structure analysis and F statistics also revealed the genetic remoteness of most C. parvum isolates and no ancestral population size was chosen. Linkage analysis evidenced a prevalent pattern of clonality within the parasite population.

Exploiting temporal collateral sensitivity in tumor clonal evolution

PubMed Central

Zhao, Boyang; Sedlak, Joseph C.; Srinivas, Raja; Creixell, Pau; Pritchard, Justin R.; Tidor, Bruce; Lauffenburger, Douglas A.; Hemann, Michael T.

2016-01-01

SUMMARY The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities; a notion that we term ‘temporal collateral sensitivity’. Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph+ acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1 targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models, and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities. PMID:26924578

The Fate of a Normal Human Cell Traversed by a Single Charged Particle

NASA Astrophysics Data System (ADS)

Fournier, C.; Zahnreich, S.; Kraft, D.; Friedrich, T.; Voss, K.-O.; Durante, M.; Ritter, S.

2012-09-01

The long-term ``fate'' of normal human cells after single hits of charged particles is one of the oldest unsolved issues in radiation protection and cellular radiobiology. Using a high-precision heavy-ion microbeam we could target normal human fibroblasts with exactly one or five carbon ions and measured the early cytogenetic damage and the late behaviour using single-cell cloning. Around 70% of the first cycle cells presented visible aberrations in mFISH after a single ion traversal, and about 5% of the cells were still able to form colonies. In one third of selected high-proliferative colonies we observed clonal (radiation-induced) aberrations. Terminal differentiation and markers of senescence (PCNA, p16) in the descendants of cells traversed by one carbon ion occurred earlier than in controls, but no evidence of radiation-induced chromosomal instability was found. We conclude that cells surviving single-ion traversal, often carrying clonal chromosome aberrations, undergo accelerated senescence but maintain chromosomal stability.

The Fate of a Normal Human Cell Traversed by a Single Charged Particle

PubMed Central

Fournier, C.; Zahnreich, S.; Kraft, D.; Friedrich, T.; Voss, K.-O.; Durante, M.; Ritter, S.

2012-01-01

The long-term “fate” of normal human cells after single hits of charged particles is one of the oldest unsolved issues in radiation protection and cellular radiobiology. Using a high-precision heavy-ion microbeam we could target normal human fibroblasts with exactly one or five carbon ions and measured the early cytogenetic damage and the late behaviour using single-cell cloning. Around 70% of the first cycle cells presented visible aberrations in mFISH after a single ion traversal, and about 5% of the cells were still able to form colonies. In one third of selected high-proliferative colonies we observed clonal (radiation-induced) aberrations. Terminal differentiation and markers of senescence (PCNA, p16) in the descendants of cells traversed by one carbon ion occurred earlier than in controls, but no evidence of radiation-induced chromosomal instability was found. We conclude that cells surviving single-ion traversal, often carrying clonal chromosome aberrations, undergo accelerated senescence but maintain chromosomal stability. PMID:22966418

Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution.

PubMed

Zhao, Boyang; Sedlak, Joseph C; Srinivas, Raja; Creixell, Pau; Pritchard, Justin R; Tidor, Bruce; Lauffenburger, Douglas A; Hemann, Michael T

2016-03-24

The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph(+) acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities. Copyright © 2016 Elsevier Inc. All rights reserved.

Clonal evolution of colorectal cancer in IBD.

PubMed

Choi, Chang-Ho R; Bakir, Ibrahim Al; Hart, Ailsa L; Graham, Trevor A

2017-04-01

Optimizing the management of colorectal cancer (CRC) risk in IBD requires a fundamental understanding of the evolutionary process underpinning tumorigenesis. In IBD, clonal evolution begins long before the development of overt neoplasia, and is probably accelerated by the repeated cycles of epithelial wounding and repair that are characteristic of the condition. Here, we review the biological drivers of mutant clone selection in IBD with particular reference to the unique histological architecture of the intestinal epithelium coupled with the inflammatory microenvironment in IBD, and the unique mutation patterns seen in IBD-driven neoplasia when compared with sporadic adenomas and CRC. How these data can be leveraged as evolutionary-based biomarkers to predict cancer risk is discussed, as well as how the efficacy of CRC surveillance programmes and the management of dysplasia can be improved. From a research perspective, the longitudinal surveillance of patients with IBD provides an under-exploited opportunity to investigate the biology of the human gastrointestinal tract over space and time.

Rise and Persistence of Global M1T1 Clone of Streptococcus pyogenes

PubMed Central

Kotb, Malak

2008-01-01

The resurgence of severe invasive group A streptococcal infections in the 1980s is a typical example of the reemergence of an infectious disease. We found that this resurgence is a consequence of the diversification of particular strains of the bacteria. Among these strains is a highly virulent subclone of serotype M1T1 that has exhibited unusual epidemiologic features and virulence, unlike all other streptococcal strains. This clonal strain, commonly isolated from both noninvasive and invasive infection cases, is most frequently associated with severe invasive diseases. Because of its unusual prevalence, global spread, and increased virulence, we investigated the unique features that likely confer its unusual properties. In doing so, we found that the increased virulence of this clonal strain can be attributed to its diversification through phage mobilization and its ability to sense and adapt to different host environments; accordingly, the fittest members of this diverse bacterial community are selected to survive and invade host tissue. PMID:18826812

Treatment resistance in urothelial carcinoma: an evolutionary perspective.

PubMed

Vlachostergios, Panagiotis J; Faltas, Bishoy M

2018-05-02

The emergence of treatment-resistant clones is a critical barrier to cure in patients with urothelial carcinoma. Setting the stage for the evolution of resistance, urothelial carcinoma is characterized by extensive mutational heterogeneity, which is detectable even in patients with early stage disease. Chemotherapy and immunotherapy both act as selective pressures that shape the evolutionary trajectory of urothelial carcinoma throughout the course of the disease. A detailed understanding of the dynamics of evolutionary drivers is required for the rational development of curative therapies. Herein, we describe the molecular basis of the clonal evolution of urothelial carcinomas and the use of genomic approaches to predict treatment responses. We discuss various mechanisms of resistance to chemotherapy with a focus on the mutagenic effects of the DNA dC->dU-editing enzymes APOBEC3 family of proteins. We also review the evolutionary mechanisms underlying resistance to immunotherapy, such as the loss of clonal tumour neoantigens. By dissecting treatment resistance through an evolutionary lens, the field will advance towards true precision medicine for urothelial carcinoma.

Dissimilar Fitness Associated with Resistance to Fluoroquinolones Influences Clonal Dynamics of Various Multiresistant Bacteria.

PubMed

Fuzi, Miklos

2016-01-01

Fitness cost associated with resistance to fluoroquinolones was recently shown to vary across clones of methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing Klebsiella pneumoniae. The resulting dissimilar fitness should have influenced the clonal dynamics and thereby the rates of resistance for these pathogens. Moreover, a similar mechanism was recently proposed for the emergence of the H30 and H30R lineages of ESBL-producing E. coli and the major international clone (ribotype 027) of Clostridium difficile. Furthermore, several additional international clones of various multiresistant bacteria are suspect to have been selected by an analogous process. An ability to develop favorable mutations in the gyrase and topoisomerase IV genes seems to be a prerequisite for pathogens to retain fitness while showing high-level resistance to fluoroquinolones. Since, the consumption of other "non-fluoroquinolone" groups of antibiotics have also contributed to the rise in resistance rates a more judicious use of antibiotics in general and of fluoroquinolones in particular could ameliorate the international resistance situation.

A Feature and Algorithm Selection Method for Improving the Prediction of Protein Structural Class.

PubMed

Ni, Qianwu; Chen, Lei

2017-01-01

Correct prediction of protein structural class is beneficial to investigation on protein functions, regulations and interactions. In recent years, several computational methods have been proposed in this regard. However, based on various features, it is still a great challenge to select proper classification algorithm and extract essential features to participate in classification. In this study, a feature and algorithm selection method was presented for improving the accuracy of protein structural class prediction. The amino acid compositions and physiochemical features were adopted to represent features and thirty-eight machine learning algorithms collected in Weka were employed. All features were first analyzed by a feature selection method, minimum redundancy maximum relevance (mRMR), producing a feature list. Then, several feature sets were constructed by adding features in the list one by one. For each feature set, thirtyeight algorithms were executed on a dataset, in which proteins were represented by features in the set. The predicted classes yielded by these algorithms and true class of each protein were collected to construct a dataset, which were analyzed by mRMR method, yielding an algorithm list. From the algorithm list, the algorithm was taken one by one to build an ensemble prediction model. Finally, we selected the ensemble prediction model with the best performance as the optimal ensemble prediction model. Experimental results indicate that the constructed model is much superior to models using single algorithm and other models that only adopt feature selection procedure or algorithm selection procedure. The feature selection procedure or algorithm selection procedure are really helpful for building an ensemble prediction model that can yield a better performance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Detection of clonal aberrations by cytogenetic analysis after different culture methods and by FISH in 129 patients with Chronic Lymphocytic Leukemia.

PubMed

Jenderny, Jutta; Goldmann, Claudia; Thede, Rebekka; Ebrecht, Monika; Korioth, Frank

2014-01-01

There are only a few cytogenetic analysis (CA) studies that directly compare the novel cultivation technique using immunostimulatory CpG-oligonucleotide DSP30/interleukin-2 (DSP30/IL2) with other culture methods. Therefore, parallel cultures of peripheral blood of 129 chronic lymphocytic leukemia (CLL) patients were set up in unstimulated cultures, in the presence of pokeweed medium (PWM), and with DSP30/IL2. Furthermore, CA results were compared with data obtained by FISH. Clonal aberrations were observed by CA in 6% of the cases in unstimulated cultures, in 27% of the cases with PWM, and in 40% of the cases with DSP30/IL2. Some clonal aberrations were detected by CA only with one culture method. Using 3 different culture methods, clonal aberrations were detected in 41% of the cases by CA and in 71% of the cases by FISH. Altogether, 78% of the cases exhibited clonal aberrations discovered by CA and FISH. Also, CA detected clonal aberrations not targeted by FISH in 7% of the cases, and FISH identified clonal aberrations not detected by CA in 36% of the cases. Our study demonstrates that the combined use of CA with different culture methods together with FISH increases our knowledge of the genetic complexity and heterogeneity in CLL pathogenesis. © 2014 S. Karger AG, Basel.

Evolution of Tumor Clones in Adult Acute Lymphoblastic Leukemia.

PubMed

Smirnova, S Yu; Sidorova, Yu V; Ryzhikova, N V; Sychevskaya, K A; Parovichnikova, E N; Sudarikov, A B

2016-01-01

Clonal instability of a tumor cell population in acute lymphoblastic leukemia (ALL) may complicate the monitoring of a minimal residual disease (MRD) by means of patient-specific targets identified at the disease onset. Most of the data concerning the possible instability of rearranged clonal TCR and IG genes during disease recurrence were obtained for ALL in children. The appropriate features of adult ALL, which are known to differ from those of childhood ALL in certain biological characteristics and prognosis, remain insufficiently studied. The aim of this study was to assess the stability of IG and TCR gene rearrangements in adult ALL. Rearrangements were identified according to the BIOMED-2 protocol (PCR followed by fragment analysis). Mismatch in clonal rearrangements at onset and relapse was identified in 83% of patients, indicating clonal instability during treatment. Clonal evolution and diversity of IG and TCR gene rearrangements may be one of the tumor progression mechanisms. New rearrangements may emerge due to residual VDJ-recombinase activity in tumor cells. Also, many clonal IG and TCR gene rearrangements may be present at different levels at a diagnosis, but less abundant clones may be "invisible" due to limited detection sensitivity. Later, major clones may disappear in the course of chemotherapy, while others may proliferate. Investigation of clonal evolution and heterogeneity in ALL and their impact on the treatment efficacy will contribute to the identification of new prognostic factors and the development of therapeutic approaches.

Plant Clonal Integration Mediates the Horizontal Redistribution of Soil Resources, Benefiting Neighboring Plants.

PubMed

Ye, Xue-Hua; Zhang, Ya-Lin; Liu, Zhi-Lan; Gao, Shu-Qin; Song, Yao-Bin; Liu, Feng-Hong; Dong, Ming

2016-01-01

Resources such as water taken up by plants can be released into soils through hydraulic redistribution and can also be translocated by clonal integration within a plant clonal network. We hypothesized that the resources from one (donor) microsite could be translocated within a clonal network, released into different (recipient) microsites and subsequently used by neighbor plants in the recipient microsite. To test these hypotheses, we conducted two experiments in which connected and disconnected ramet pairs of Potentilla anserina were grown under both homogeneous and heterogeneous water regimes, with seedlings of Artemisia ordosica as neighbors. The isotopes [(15)N] and deuterium were used to trace the translocation of nitrogen and water, respectively, within the clonal network. The water and nitrogen taken up by P. anserina ramets in the donor microsite were translocated into the connected ramets in the recipient microsites. Most notably, portions of the translocated water and nitrogen were released into the recipient microsite and were used by the neighboring A. ordosica, which increased growth of the neighboring A. ordosica significantly. Therefore, our hypotheses were supported, and plant clonal integration mediated the horizontal hydraulic redistribution of resources, thus benefiting neighboring plants. Such a plant clonal integration-mediated resource redistribution in horizontal space may have substantial effects on the interspecific relations and composition of the community and consequently on ecosystem processes.

McTwo: a two-step feature selection algorithm based on maximal information coefficient.

PubMed

Ge, Ruiquan; Zhou, Manli; Luo, Youxi; Meng, Qinghan; Mai, Guoqin; Ma, Dongli; Wang, Guoqing; Zhou, Fengfeng

2016-03-23

High-throughput bio-OMIC technologies are producing high-dimension data from bio-samples at an ever increasing rate, whereas the training sample number in a traditional experiment remains small due to various difficulties. This "large p, small n" paradigm in the area of biomedical "big data" may be at least partly solved by feature selection algorithms, which select only features significantly associated with phenotypes. Feature selection is an NP-hard problem. Due to the exponentially increased time requirement for finding the globally optimal solution, all the existing feature selection algorithms employ heuristic rules to find locally optimal solutions, and their solutions achieve different performances on different datasets. This work describes a feature selection algorithm based on a recently published correlation measurement, Maximal Information Coefficient (MIC). The proposed algorithm, McTwo, aims to select features associated with phenotypes, independently of each other, and achieving high classification performance of the nearest neighbor algorithm. Based on the comparative study of 17 datasets, McTwo performs about as well as or better than existing algorithms, with significantly reduced numbers of selected features. The features selected by McTwo also appear to have particular biomedical relevance to the phenotypes from the literature. McTwo selects a feature subset with very good classification performance, as well as a small feature number. So McTwo may represent a complementary feature selection algorithm for the high-dimensional biomedical datasets.

Feature Selection Method Based on Neighborhood Relationships: Applications in EEG Signal Identification and Chinese Character Recognition

PubMed Central

Zhao, Yu-Xiang; Chou, Chien-Hsing

2016-01-01

In this study, a new feature selection algorithm, the neighborhood-relationship feature selection (NRFS) algorithm, is proposed for identifying rat electroencephalogram signals and recognizing Chinese characters. In these two applications, dependent relationships exist among the feature vectors and their neighboring feature vectors. Therefore, the proposed NRFS algorithm was designed for solving this problem. By applying the NRFS algorithm, unselected feature vectors have a high priority of being added into the feature subset if the neighboring feature vectors have been selected. In addition, selected feature vectors have a high priority of being eliminated if the neighboring feature vectors are not selected. In the experiments conducted in this study, the NRFS algorithm was compared with two feature algorithms. The experimental results indicated that the NRFS algorithm can extract the crucial frequency bands for identifying rat vigilance states and identifying crucial character regions for recognizing Chinese characters. PMID:27314346

Standardizing the Nomenclature for Clonal Lineages of the Sudden Oak Death Pathogen, Phytophthora ramorum

USDA-ARS?s Scientific Manuscript database

Phytophthora ramorum, the causal agent of sudden oak death and ramorum blight, is known to exist as three distinct clonal lineages based on a range of molecular marker systems. However, in the recent literature there exists no consensus on naming of lineages. Here we name clonal lineages of P. ramor...

Genetic Bee Colony (GBC) algorithm: A new gene selection method for microarray cancer classification.

PubMed

Alshamlan, Hala M; Badr, Ghada H; Alohali, Yousef A

2015-06-01

Naturally inspired evolutionary algorithms prove effectiveness when used for solving feature selection and classification problems. Artificial Bee Colony (ABC) is a relatively new swarm intelligence method. In this paper, we propose a new hybrid gene selection method, namely Genetic Bee Colony (GBC) algorithm. The proposed algorithm combines the used of a Genetic Algorithm (GA) along with Artificial Bee Colony (ABC) algorithm. The goal is to integrate the advantages of both algorithms. The proposed algorithm is applied to a microarray gene expression profile in order to select the most predictive and informative genes for cancer classification. In order to test the accuracy performance of the proposed algorithm, extensive experiments were conducted. Three binary microarray datasets are use, which include: colon, leukemia, and lung. In addition, another three multi-class microarray datasets are used, which are: SRBCT, lymphoma, and leukemia. Results of the GBC algorithm are compared with our recently proposed technique: mRMR when combined with the Artificial Bee Colony algorithm (mRMR-ABC). We also compared the combination of mRMR with GA (mRMR-GA) and Particle Swarm Optimization (mRMR-PSO) algorithms. In addition, we compared the GBC algorithm with other related algorithms that have been recently published in the literature, using all benchmark datasets. The GBC algorithm shows superior performance as it achieved the highest classification accuracy along with the lowest average number of selected genes. This proves that the GBC algorithm is a promising approach for solving the gene selection problem in both binary and multi-class cancer classification. Copyright © 2015 Elsevier Ltd. All rights reserved.

Revealing hidden clonal complexity in Mycobacterium tuberculosis infection by qualitative and quantitative improvement of sampling.

PubMed

Pérez-Lago, L; Palacios, J J; Herranz, M; Ruiz Serrano, M J; Bouza, E; García-de-Viedma, D

2015-02-01

The analysis of microevolution events, its functional relevance and impact on molecular epidemiology strategies, constitutes one of the most challenging aspects of the study of clonal complexity in infection by Mycobacterium tuberculosis. In this study, we retrospectively evaluated whether two improved sampling schemes could provide access to the clonal complexity that is undetected by the current standards (analysis of one isolate from one sputum). We evaluated in 48 patients the analysis by mycobacterial interspersed repetitive unit-variable number tandem repeat of M. tuberculosis isolates cultured from bronchial aspirate (BAS) or bronchoalveolar lavage (BAL) and, in another 16 cases, the analysis of a higher number of isolates from independent sputum samples. Analysis of the isolates from BAS/BAL specimens revealed clonal complexity in a very high proportion of cases (5/48); in most of these cases, complexity was not detected when the isolates from sputum samples were analysed. Systematic analysis of isolates from multiple sputum samples also improved the detection of clonal complexity. We found coexisting clonal variants in two of 16 cases that would have gone undetected in the analysis of the isolate from a single sputum specimen. Our results suggest that analysis of isolates from BAS/BAL specimens is highly efficient for recording the true clonal composition of M. tuberculosis in the lungs. When these samples are not available, we recommend increasing the number of isolates from independent sputum specimens, because they might not harbour the same pool of bacteria. Our data suggest that the degree of clonal complexity in tuberculosis has been underestimated because of the deficiencies inherent in a simplified procedure. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma.

PubMed

Jiang, Yanwen; Nie, Kui; Redmond, David; Melnick, Ari M; Tam, Wayne; Elemento, Olivier

2015-12-28

Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding the clonal composition changes that occur within a tumor in response to certain micro-environment or treatments may lead to the design of more sophisticated and effective approaches to eradicate tumor cells. However, tracking tumor clonal sub-populations has been challenging due to the lack of distinguishable markers. To address this problem, a VDJ-seq protocol was created to trace the clonal evolution patterns of diffuse large B cell lymphoma (DLBCL) relapse by exploiting VDJ recombination and somatic hypermutation (SHM), two unique features of B cell lymphomas. In this protocol, Next-Generation sequencing (NGS) libraries with indexing potential were constructed from amplified rearranged immunoglobulin heavy chain (IgH) VDJ region from pairs of primary diagnosis and relapse DLBCL samples. On average more than half million VDJ sequences per sample were obtained after sequencing, which contain both VDJ rearrangement and SHM information. In addition, customized bioinformatics pipelines were developed to fully utilize sequence information for the characterization of IgH-VDJ repertoire within these samples. Furthermore, the pipeline allows the reconstruction and comparison of the clonal architecture of individual tumors, which enables the examination of the clonal heterogeneity within the diagnosis tumors and deduction of clonal evolution patterns between diagnosis and relapse tumor pairs. When applying this analysis to several diagnosis-relapse pairs, we uncovered key evidence that multiple distinctive tumor evolutionary patterns could lead to DLBCL relapse. Additionally, this approach can be expanded into other clinical aspects, such as identification of minimal residual disease, monitoring relapse progress and treatment response, and investigation of immune repertoires in non-lymphoma contexts.

Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms.

PubMed

Alvarez-Twose, I; González-de-Olano, D; Sánchez-Muñoz, L; Matito, A; Jara-Acevedo, M; Teodosio, C; García-Montero, A; Morgado, J M; Orfao, A; Escribano, L

2012-01-01

A variable percentage of patients with systemic mast cell (MC) activation symptoms meet criteria for systemic mastocytosis (SM). We prospectively evaluated the clinical utility of the REMA score versus serum baseline tryptase (sBt) levels for predicting MC clonality and SM in 158 patients with systemic MC activation symptoms in the absence of mastocytosis in the skin (MIS). World Health Organization criteria for SM were applied in all cases. MC clonality was defined as the presence of KIT-mutated MC or by a clonal HUMARA test. The REMA score consisted of the assignment of positive or negative points as follows: male (+1), female (-1), sBt <15 μg/l (-1) or >25 μg/l (+2), presence (-2) or absence (+1) of pruritus, hives or angioedema and presence (+3) of presyncope or syncope. Efficiency of the REMA score for predicting MC clonality and SM was assessed by receiver operating characteristic (ROC) curve analyses and compared to those obtained by means of sBt levels alone. Molecular studies revealed the presence of clonal MC in 68/80 SM cases and in 11/78 patients who did not meet the criteria for SM. ROC curve analyses confirmed the greater sensitivity and a similar specificity of the REMA score versus sBt levels (84 vs. 59% and 74 vs. 70% for MC clonality and 87 vs. 62% and 73 vs. 71% for SM, respectively). Our results confirm the clinical utility of the REMA score to predict MC clonality and SM in patients suffering from systemic MC activation symptoms without MIS. Copyright © 2011 S. Karger AG, Basel.

Serotyping of Toxoplasma gondii in Cats (Felis domesticus) Reveals Predominance of Type II Infections in Germany

PubMed Central

Maksimov, Pavlo; Zerweck, Johannes; Dubey, Jitender P.; Pantchev, Nikola; Frey, Caroline F.; Maksimov, Aline; Reimer, Ulf; Schutkowski, Mike; Hosseininejad, Morteza; Ziller, Mario; Conraths, Franz J.; Schares, Gereon

2013-01-01

Background Cats are definitive hosts of Toxoplasma gondii and play an essential role in the epidemiology of this parasite. The study aims at clarifying whether cats are able to develop specific antibodies against different clonal types of T. gondii and to determine by serotyping the T. gondii clonal types prevailing in cats as intermediate hosts in Germany. Methodology To establish a peptide-microarray serotyping test, we identified 24 suitable peptides using serological T. gondii positive (n=21) and negative cat sera (n=52). To determine the clonal type-specific antibody response of cats in Germany, 86 field sera from T. gondii seropositive naturally infected cats were tested. In addition, we analyzed the antibody response in cats experimentally infected with non-canonical T. gondii types (n=7). Findings Positive cat reference sera reacted predominantly with peptides harbouring amino acid sequences specific for the clonal T. gondii type the cats were infected with. When the array was applied to field sera from Germany, 98.8% (85/86) of naturally-infected cats recognized similar peptide patterns as T. gondii type II reference sera and showed the strongest reaction intensities with clonal type II-specific peptides. In addition, naturally infected cats recognized type II-specific peptides significantly more frequently than peptides of other type-specificities. Cats infected with non-canonical types showed the strongest reactivity with peptides presenting amino-acid sequences specific for both, type I and type III. Conclusions Cats are able to mount a clonal type-specific antibody response against T. gondii. Serotyping revealed for most seropositive field sera patterns resembling those observed after clonal type II-T. gondii infection. This finding is in accord with our previous results on the occurrence of T. gondii clonal types in oocysts shed by cats in Germany. PMID:24244652

T-cell stimuli independently sum to regulate an inherited clonal division fate

PubMed Central

Marchingo, J. M.; Prevedello, G.; Kan, A.; Heinzel, S.; Hodgkin, P. D.; Duffy, K. R.

2016-01-01

In the presence of antigen and costimulation, T cells undergo a characteristic response of expansion, cessation and contraction. Previous studies have revealed that population-level reproducibility is a consequence of multiple clones exhibiting considerable disparity in burst size, highlighting the requirement for single-cell information in understanding T-cell fate regulation. Here we show that individual T-cell clones resulting from controlled stimulation in vitro are strongly lineage imprinted with highly correlated expansion fates. Progeny from clonal families cease dividing in the same or adjacent generations, with inter-clonal variation producing burst-size diversity. The effects of costimulatory signals on individual clones sum together with stochastic independence; therefore, the net effect across multiple clones produces consistent, but heterogeneous population responses. These data demonstrate that substantial clonal heterogeneity arises through differences in experience of clonal progenitors, either through stochastic antigen interaction or by differences in initial receptor sensitivities. PMID:27869196

Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

PubMed Central

Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M.; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W. Y.; Marass, Francesco; Gale, Davina; Ali, H. Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P.; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

2015-01-01

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID:26530965

Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

PubMed

Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W Y; Marass, Francesco; Gale, Davina; Ali, H Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

2015-11-04

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.

Epigenetic Memory as a Basis for Intelligent Behavior in Clonal Plants.

PubMed

Latzel, Vít; Rendina González, Alejandra P; Rosenthal, Jonathan

2016-01-01

Environmentally induced epigenetic change enables plants to remember past environmental interactions. If this memory capability is exploited to prepare plants for future challenges, it can provide a basis for highly sophisticated behavior, considered intelligent by some. Against the backdrop of an overview of plant intelligence, we hypothesize: (1) that the capability of plants to engage in such intelligent behavior increases with the additional level of complexity afforded by clonality, and; (2) that more faithful inheritance of epigenetic information in clonal plants, in conjunction with information exchange and coordination between connected ramets, is likely to enable especially advanced intelligent behavior in this group. We therefore further hypothesize that this behavior provides ecological and evolutionary advantages to clonal plants, possibly explaining, at least in part, their widespread success. Finally, we suggest avenues of inquiry to enable assessing intelligent behavior and the role of epigenetic memory in clonal species.

Clonal diversity of extended-spectrum beta-lactamase producing Escherichia coli isolates in fecal samples of wild animals.

PubMed

Cristóvão, Filipe; Alonso, Carla Andrea; Igrejas, Gilberto; Sousa, Margarida; Silva, Vanessa; Pereira, José Eduardo; Lozano, Carmen; Cortés-Cortés, Gerardo; Torres, Carmen; Poeta, Patrícia

2017-03-01

The clonal diversity of extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli isolates from nine different species of wild animals from distinct regions of Portugal and Spain and their content in replicon plasmids were analyzed. Among the initial 53 ESBL-producing E. coli isolates that were studied (from previous studies), 28 were selected, corresponding to different animal origins with distinct ESBL types and pulsed-field gel electrophoresis (PFGE) patterns. These 28 isolates produced different ESBLs ascribed to the following families: CTX-M, SHV and TEM. The isolates were classified into three phylogenetic groups: B1 (n = 11), A (n = 10) and D (n = 7). The seven E. coli of phylogroup D were then typed by multilocus sequence typing and ascribed to four distinct sequence types: ST117, ST115, ST2001 and ST69. The clonal diversity and relationship between isolates was studied by PFGE. Lastly, the plasmids were analyzed according to their incompatibility group using the PCR-based-replicon-typing scheme. A great diversity of replicon types was identified, with up to five per isolate. Most of the CTX-M-1 and SHV-12 producing E. coli isolates carried IncI1 or IncN replicons. The diversity of ESBL-producing E. coli isolates in wild animals, which can be disseminated in the environment, emphasizes the environmental and health problems that we face nowadays. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Antimicrobial Susceptibility and Clonality of Clinical Ureaplasma Isolates in the United States

PubMed Central

Fernández, Javier; Karau, Melissa J.; Cunningham, Scott A.; Greenwood-Quaintance, Kerryl E.

2016-01-01

Ureaplasma urealyticum and Ureaplasma parvum are pathogens involved in urogenital tract and intrauterine infections and also in systemic diseases in newborns and immunosuppressed patients. There is limited information on the antimicrobial susceptibility and clonality of these species. In this study, we report the susceptibility of 250 contemporary isolates of Ureaplasma (202 U. parvum and 48 U. urealyticum isolates) recovered at Mayo Clinic, Rochester, MN. MICs of doxycycline, azithromycin, ciprofloxacin, tetracycline, erythromycin, and levofloxacin were determined by broth microdilution, with MICS of the last three interpreted according to CLSI guidelines. Levofloxacin resistance was found in 6.4% and 5.2% of U. parvum and U. urealyticum isolates, respectively, while 27.2% and 68.8% of isolates, respectively, showed ciprofloxacin MICs of ≥4 μg/ml. The resistance mechanism of levofloxacin-resistant isolates was due to mutations in parC, with the Ser83Leu substitution being most frequent, followed by Glu87Lys. No macrolide resistance was found among the 250 isolates studied; a single U. parvum isolate was tetracycline resistant. tet(M) was found in 10 U. parvum isolates, including the single tetracycline-resistant isolate, as well as in 9 isolates which had low tetracycline and doxycycline MICs. Multilocus sequence typing (MLST) performed on a selection of 46 isolates showed high diversity within the clinical Ureaplasma isolates studied, regardless of antimicrobial susceptibility. The present work extends previous knowledge regarding susceptibility to antimicrobial agents, resistance mechanisms, and clonality of Ureaplasma species in the United States. PMID:27246773

Cone consumption by southeastern fox squirrels: A potential basis for clonal preferences in a loblolly and slash pine seed orchard

Treesearch

Christopher Asaro; Susan C. Loeb; James L. Hanula

2003-01-01

Southeastern fox squirrels were observed feeding preferentially on seeds of certain clones of loblolly pine in a central Georgia seed orchard in the early 1990s and, similarly, on slash pine seed in an orchard in central Florida in the late 1990s. In each orchard, the degree of feeding preference and avoidance among selected clones was documented and quantified. We...

Influence of the Tumor Microenvironment on Genomic Changes Conferring Chemoresistance in Breast Cancer

DTIC Science & Technology

2013-04-01

tumor microenvironment on clonal selection using intravital microscopy Jae-Hyun Park 1 , Miriam R. Fein 1 , Mikala Egeblad 1 1 Cold Spring Harbor...used surgically implanted mammary imaging windows in immunocompetent mice and injected “brainbow” expressing, syngeneic 4T1 breast carcinoma cells...under the windows. This allowed us to acquire multiple time- lapse imaging series by spinning disk confocal microscopy of the same tumor, done about 3

Virulence, sporulation, and elicitin production in three clonal lineages of Phytophthora ramorum

Treesearch

Daniel Manter; Everett Hansen; Jennifer. Parke

2010-01-01

Phytophthora ramorum populations are clonal and consist of three clonal lineages: EU1 is the only lineage found in Europe with a few isolated nursery infections in the USA; NA1 is associated with natural infestations in California and Oregon as well as some nursery infections in North America, and NA2 has a limited distribution and has only...

An affine projection algorithm using grouping selection of input vectors

NASA Astrophysics Data System (ADS)

Shin, JaeWook; Kong, NamWoong; Park, PooGyeon

2011-10-01

This paper present an affine projection algorithm (APA) using grouping selection of input vectors. To improve the performance of conventional APA, the proposed algorithm adjusts the number of the input vectors using two procedures: grouping procedure and selection procedure. In grouping procedure, the some input vectors that have overlapping information for update is grouped using normalized inner product. Then, few input vectors that have enough information for for coefficient update is selected using steady-state mean square error (MSE) in selection procedure. Finally, the filter coefficients update using selected input vectors. The experimental results show that the proposed algorithm has small steady-state estimation errors comparing with the existing algorithms.

A genotyping protocol for multiple tissue types from the polyploid tree species Sequoia sempervirens (Cupressaceae)1

PubMed Central

Narayan, Lakshmi; Dodd, Richard S.; O’Hara, Kevin L.

2015-01-01

Premise of the study: Identifying clonal lineages in asexually reproducing plants using microsatellite markers is complicated by the possibility of nonidentical genotypes from the same clonal lineage due to somatic mutations, null alleles, and scoring errors. We developed and tested a clonal identification protocol that is robust to these issues for the asexually reproducing hexaploid tree species coast redwood (Sequoia sempervirens). Methods: Microsatellite data from four previously published and two newly developed primers were scored using a modified protocol, and clones were identified using Bruvo genetic distances. The effectiveness of this clonal identification protocol was assessed using simulations and by genotyping a test set of paired samples of different tissue types from the same trees. Results: Data from simulations showed that our protocol allowed us to accurately identify clonal lineages. Multiple test samples from the same trees were identified correctly, although certain tissue type pairs had larger genetic distances on average. Discussion: The methods described in this paper will allow for the accurate identification of coast redwood clones, facilitating future studies of the reproductive ecology of this species. The techniques used in this paper can be applied to studies of other clonal organisms as well. PMID:25798341

A genotyping protocol for multiple tissue types from the polyploid tree species Sequoia sempervirens (Cupressaceae).

PubMed

Narayan, Lakshmi; Dodd, Richard S; O'Hara, Kevin L

2015-03-01

Identifying clonal lineages in asexually reproducing plants using microsatellite markers is complicated by the possibility of nonidentical genotypes from the same clonal lineage due to somatic mutations, null alleles, and scoring errors. We developed and tested a clonal identification protocol that is robust to these issues for the asexually reproducing hexaploid tree species coast redwood (Sequoia sempervirens). Microsatellite data from four previously published and two newly developed primers were scored using a modified protocol, and clones were identified using Bruvo genetic distances. The effectiveness of this clonal identification protocol was assessed using simulations and by genotyping a test set of paired samples of different tissue types from the same trees. Data from simulations showed that our protocol allowed us to accurately identify clonal lineages. Multiple test samples from the same trees were identified correctly, although certain tissue type pairs had larger genetic distances on average. The methods described in this paper will allow for the accurate identification of coast redwood clones, facilitating future studies of the reproductive ecology of this species. The techniques used in this paper can be applied to studies of other clonal organisms as well.

Advances for Studying Clonal Evolution in Cancer

PubMed Central

Raphael, Benjamin J.; Chen, Feng; Wendl, Michael C.

2013-01-01

The “clonal evolution” model of cancer emerged and “evolved” amid ongoing advances in technology, especially in recent years during which next generation sequencing instruments have provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors. It has become increasingly clear that clonal evolution is not a single sequential process, but instead frequently involves simultaneous evolution of multiple subclones that co-exist because they are of similar fitness or are spatially separated. Co-evolution of subclones also occurs when they complement each other’s survival advantages. Recent studies have also shown that clonal evolution is highly heterogeneous: different individual tumors of the same type may undergo very different paths of clonal evolution. New methodological advancements, including deep digital sequencing of a mixed tumor population, single cell sequencing, and the development of more sophisticated computational tools, will continue to shape and reshape the models of clonal evolution. In turn, these will provide both an improved framework for the understanding of cancer progression and a guide for treatment strategies aimed at the elimination of all, rather than just some, of the cancer cells within a patient. PMID:23353056

Advances for studying clonal evolution in cancer.

PubMed

Ding, Li; Raphael, Benjamin J; Chen, Feng; Wendl, Michael C

2013-11-01

The "clonal evolution" model of cancer emerged and "evolved" amid ongoing advances in technology, especially in recent years during which next generation sequencing instruments have provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors. It has become increasingly clear that clonal evolution is not a single sequential process, but instead frequently involves simultaneous evolution of multiple subclones that co-exist because they are of similar fitness or are spatially separated. Co-evolution of subclones also occurs when they complement each other's survival advantages. Recent studies have also shown that clonal evolution is highly heterogeneous: different individual tumors of the same type may undergo very different paths of clonal evolution. New methodological advancements, including deep digital sequencing of a mixed tumor population, single cell sequencing, and the development of more sophisticated computational tools, will continue to shape and reshape the models of clonal evolution. In turn, these will provide both an improved framework for the understanding of cancer progression and a guide for treatment strategies aimed at the elimination of all, rather than just some, of the cancer cells within a patient. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Clonal integration supports the expansion from terrestrial to aquatic environments of the amphibious stoloniferous herb Alternanthera philoxeroides.

PubMed

Wang, N; Yu, F-H; Li, P-X; He, W-M; Liu, J; Yu, G-L; Song, Y-B; Dong, M

2009-05-01

Effects of clonal integration on land plants have been extensively studied, but little is known about the role in amphibious plants that expand from terrestrial to aquatic conditions. We simulated expansion from terrestrial to aquatic habitats in the amphibious stoloniferous alien invasive alligator weed (Alternanthera philoxeroides) by growing basal ramets of clonal fragments in soils connected (allowing integration) or disconnected (preventing integration) to the apical ramets of the same fragments submerged in water to a depth of 0, 5, 10 or 15 cm. Clonal integration significantly increased growth and clonal reproduction of the apical ramets, but decreased both of these characteristics in basal ramets. Consequently, integration did not affect the performance of whole clonal fragments. We propose that alligator weed possesses a double-edged mechanism during population expansion: apical ramets in aquatic habitats can increase growth through connected basal parts in terrestrial habitats; however, once stolon connections with apical ramets are lost by external disturbance, the basal ramets in terrestrial habitats increase stolon and ramet production for rapid spreading. This may contribute greatly to the invasiveness of alligator weed and also make it very adaptable to habitats with heavy disturbance and/or highly heterogeneous resource supply.

Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus.

PubMed

Lavery, Danielle L; Martinez, Pierre; Gay, Laura J; Cereser, Biancastella; Novelli, Marco R; Rodriguez-Justo, Manuel; Meijer, Sybren L; Graham, Trevor A; McDonald, Stuart A C; Wright, Nicholas A; Jansen, Marnix

2016-06-01

Barrett's oesophagus commonly presents as a patchwork of columnar metaplasia with and without goblet cells in the distal oesophagus. The presence of metaplastic columnar epithelium with goblet cells on oesophageal biopsy is a marker of cancer progression risk, but it is unclear whether clonal expansion and progression in Barrett's oesophagus is exclusive to columnar epithelium with goblet cells. We developed a novel method to trace the clonal ancestry of an oesophageal adenocarcinoma across an entire Barrett's segment. Clonal expansions in Barrett's mucosa were identified using cytochrome c oxidase enzyme histochemistry. Somatic mutations were identified through mitochondrial DNA sequencing and single gland whole exome sequencing. By tracing the clonal origin of an oesophageal adenocarcinoma across an entire Barrett's segment through a combination of histopathological spatial mapping and clonal ordering, we find that this cancer developed from a premalignant clonal expansion in non-dysplastic ('cardia-type') columnar metaplasia without goblet cells. Our data demonstrate the premalignant potential of metaplastic columnar epithelium without goblet cells in the context of Barrett's oesophagus. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Genetic Dissection of Clonally Inherited Genomes of Poeciliopsis. I. Linkage Analysis and Preliminary Assessment of Deleterious Gene Loads

PubMed Central

Leslie, James F.; Vrijenhoek, Robert C.

1978-01-01

Theoretical considerations suggest that a high load of deleterious mutations should accumulate in asexual genomes. An ideal system for testing this hypothesis occurs in the hybrid all-female fish Poeciliopsis monacha-lucida. The hybrid genotype is retained between generations by an oogenetic process that transmits only a nonrecombinant haploid monacha genome to their ova. The hybrid genotype is re-established in nature by fertilization of these monacha eggs with sperm from a sexual species, P. lucida. The unique reproductive mechanism of these hybrids allows the genetic dissection of the clonal monacha genome by forced matings with males of P. monacha. The resultant F1 hybrids and their backcross progeny were examined to determine the amount and kinds of genetic changes that might have occurred in two clonal monacha genomes.—Using six allozyme markers, four similar linkage groups were identified in each clonal genome. Segregation and assortment at these loci revealed no apparent differences between monacha genomes from sexually and clonally reproducing species. Mortality of F1 and backcross progeny revealed differences between the two clonal genomes, suggesting that deleterious genes may accumulate in genomes sheltered from recombination. PMID:17248875

A study of metaheuristic algorithms for high dimensional feature selection on microarray data

NASA Astrophysics Data System (ADS)

Dankolo, Muhammad Nasiru; Radzi, Nor Haizan Mohamed; Sallehuddin, Roselina; Mustaffa, Noorfa Haszlinna

2017-11-01

Microarray systems enable experts to examine gene profile at molecular level using machine learning algorithms. It increases the potentials of classification and diagnosis of many diseases at gene expression level. Though, numerous difficulties may affect the efficiency of machine learning algorithms which includes vast number of genes features comprised in the original data. Many of these features may be unrelated to the intended analysis. Therefore, feature selection is necessary to be performed in the data pre-processing. Many feature selection algorithms are developed and applied on microarray which including the metaheuristic optimization algorithms. This paper discusses the application of the metaheuristics algorithms for feature selection in microarray dataset. This study reveals that, the algorithms have yield an interesting result with limited resources thereby saving computational expenses of machine learning algorithms.

Sequential and Mixed Genetic Algorithm and Learning Automata (SGALA, MGALA) for Feature Selection in QSAR

PubMed Central

MotieGhader, Habib; Gharaghani, Sajjad; Masoudi-Sobhanzadeh, Yosef; Masoudi-Nejad, Ali

2017-01-01

Feature selection is of great importance in Quantitative Structure-Activity Relationship (QSAR) analysis. This problem has been solved using some meta-heuristic algorithms such as GA, PSO, ACO and so on. In this work two novel hybrid meta-heuristic algorithms i.e. Sequential GA and LA (SGALA) and Mixed GA and LA (MGALA), which are based on Genetic algorithm and learning automata for QSAR feature selection are proposed. SGALA algorithm uses advantages of Genetic algorithm and Learning Automata sequentially and the MGALA algorithm uses advantages of Genetic Algorithm and Learning Automata simultaneously. We applied our proposed algorithms to select the minimum possible number of features from three different datasets and also we observed that the MGALA and SGALA algorithms had the best outcome independently and in average compared to other feature selection algorithms. Through comparison of our proposed algorithms, we deduced that the rate of convergence to optimal result in MGALA and SGALA algorithms were better than the rate of GA, ACO, PSO and LA algorithms. In the end, the results of GA, ACO, PSO, LA, SGALA, and MGALA algorithms were applied as the input of LS-SVR model and the results from LS-SVR models showed that the LS-SVR model had more predictive ability with the input from SGALA and MGALA algorithms than the input from all other mentioned algorithms. Therefore, the results have corroborated that not only is the predictive efficiency of proposed algorithms better, but their rate of convergence is also superior to the all other mentioned algorithms. PMID:28979308

Sequential and Mixed Genetic Algorithm and Learning Automata (SGALA, MGALA) for Feature Selection in QSAR.

PubMed

MotieGhader, Habib; Gharaghani, Sajjad; Masoudi-Sobhanzadeh, Yosef; Masoudi-Nejad, Ali

2017-01-01

Feature selection is of great importance in Quantitative Structure-Activity Relationship (QSAR) analysis. This problem has been solved using some meta-heuristic algorithms such as GA, PSO, ACO and so on. In this work two novel hybrid meta-heuristic algorithms i.e. Sequential GA and LA (SGALA) and Mixed GA and LA (MGALA), which are based on Genetic algorithm and learning automata for QSAR feature selection are proposed. SGALA algorithm uses advantages of Genetic algorithm and Learning Automata sequentially and the MGALA algorithm uses advantages of Genetic Algorithm and Learning Automata simultaneously. We applied our proposed algorithms to select the minimum possible number of features from three different datasets and also we observed that the MGALA and SGALA algorithms had the best outcome independently and in average compared to other feature selection algorithms. Through comparison of our proposed algorithms, we deduced that the rate of convergence to optimal result in MGALA and SGALA algorithms were better than the rate of GA, ACO, PSO and LA algorithms. In the end, the results of GA, ACO, PSO, LA, SGALA, and MGALA algorithms were applied as the input of LS-SVR model and the results from LS-SVR models showed that the LS-SVR model had more predictive ability with the input from SGALA and MGALA algorithms than the input from all other mentioned algorithms. Therefore, the results have corroborated that not only is the predictive efficiency of proposed algorithms better, but their rate of convergence is also superior to the all other mentioned algorithms.

The clonal and mutational evolution spectrum of primary triple-negative breast cancers.

PubMed

Shah, Sohrab P; Roth, Andrew; Goya, Rodrigo; Oloumi, Arusha; Ha, Gavin; Zhao, Yongjun; Turashvili, Gulisa; Ding, Jiarui; Tse, Kane; Haffari, Gholamreza; Bashashati, Ali; Prentice, Leah M; Khattra, Jaswinder; Burleigh, Angela; Yap, Damian; Bernard, Virginie; McPherson, Andrew; Shumansky, Karey; Crisan, Anamaria; Giuliany, Ryan; Heravi-Moussavi, Alireza; Rosner, Jamie; Lai, Daniel; Birol, Inanc; Varhol, Richard; Tam, Angela; Dhalla, Noreen; Zeng, Thomas; Ma, Kevin; Chan, Simon K; Griffith, Malachi; Moradian, Annie; Cheng, S-W Grace; Morin, Gregg B; Watson, Peter; Gelmon, Karen; Chia, Stephen; Chin, Suet-Feung; Curtis, Christina; Rueda, Oscar M; Pharoah, Paul D; Damaraju, Sambasivarao; Mackey, John; Hoon, Kelly; Harkins, Timothy; Tadigotla, Vasisht; Sigaroudinia, Mahvash; Gascard, Philippe; Tlsty, Thea; Costello, Joseph F; Meyer, Irmtraud M; Eaves, Connie J; Wasserman, Wyeth W; Jones, Steven; Huntsman, David; Hirst, Martin; Caldas, Carlos; Marra, Marco A; Aparicio, Samuel

2012-04-04

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.

Improved clonality detection in B-cell lymphoma using a semi-nested modification of the BIOMED-2 PCR assay for IGH rearrangement: A paraffin-embedded tissue study.

PubMed

Sakamoto, Yuma; Masaki, Ayako; Aoyama, Satsuki; Han, Shusen; Saida, Kosuke; Fujii, Kana; Takino, Hisashi; Murase, Takayuki; Iida, Shinsuke; Inagaki, Hiroshi

2017-09-01

The BIOMED-2 PCR protocol for targeting the IGH gene is widely employed for detecting clonality in B-cell malignancies. Unfortunately, the detection of clonality with this method is not very sensitive when paraffin sections are used as a DNA source. To increase the sensitivity, we devised a semi-nested modification of a JH consensus primer. The clonality detection rates of three assays were compared: the standard BIOMED-2, BIOMED-2 assay followed by BIOMED-2 re-amplification, and BIOMED-2 assay followed by semi-nested BIOMED-2. We tested more than 100 cases using paraffin-embedded tissues of various B-cell lymphomas, and found that the clonality detection rates with the above three assays were 63.9%, 79.6%, and 88.0%, respectively. While BIOMED-2 re-amplification was significantly more sensitive than the standard BIOMED-2, the semi-nested BIOMED-2 was significantly more sensitive than both the standard BIOMED-2 and BIOMED-2 re-amplification. An increase in sensitivity was observed in all lymphoma subtypes examined. In conclusion, tumor clonality may be detected in nearly 90% of B-cell lymphoma cases with semi-nested BIOMED-2. This ancillary assay may be useful when the standard BIOMED-2 fails to detect clonality in histopathologically suspected B-cell lymphomas. © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Purification of Bone Marrow Clonal Cells from Patients with Myelodysplastic Syndrome via IGF-IR

PubMed Central

He, Qi; Chang, Chun-Kang; Xu, Feng; Zhang, Qing-Xia; Shi, Wen-Hui; Li, Xiao

2015-01-01

Malignant clonal cells purification can greatly benefit basic and clinical studies in myelodysplastic syndrome (MDS). In this study, we investigated the potential of using type 1 insulin-like growth factor receptor (IGF-IR) as a marker for purification of malignant bone marrow clonal cells from patients with MDS. The average percentage of IGF-IR expression in CD34+ bone marrow cells among 15 normal controls was 4.5%, 70% of which also express the erythroid lineage marker CD235a. This indicates that IGF-IR mainly express in erythropoiesis. The expression of IGF-IR in CD34+ cells of 55 MDS patients was significantly higher than that of cells from the normal controls (54.0 vs. 4.5%). Based on the pattern of IGF-IR expression in MDS patients and normal controls, sorting of IGF-IR-positive and removal of CD235a-positive erythroid lineage cells with combination of FISH detection were performed on MDS samples with chromosomal abnormalities. The percentage of malignant clonal cells significantly increased after sorting. The enrichment effect was more significant in clonal cells with a previous percentage lower than 50%. This enrichment effect was present in samples from patients with +8, 5q-/-5, 20q-/-20 or 7q-/-7 chromosomal abnormalities. These data suggest that IGF-IR can be used as a marker for MDS bone marrow clonal cells and using flow cytometry for positive IGF-IR sorting may effectively purify MDS clonal cells. PMID:26469401

Optimum location of external markers using feature selection algorithms for real‐time tumor tracking in external‐beam radiotherapy: a virtual phantom study

PubMed Central

Nankali, Saber; Miandoab, Payam Samadi; Baghizadeh, Amin

2016-01-01

In external‐beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation‐based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two “Genetic” and “Ranker” searching procedures. The performance of these algorithms has been evaluated using four‐dimensional extended cardiac‐torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro‐fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F‐test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation‐based feature selection algorithm, in combination with a genetic search algorithm, proved to yield best performance accuracy for selecting optimum markers. PACS numbers: 87.55.km, 87.56.Fc PMID:26894358

Optimum location of external markers using feature selection algorithms for real-time tumor tracking in external-beam radiotherapy: a virtual phantom study.

PubMed

Nankali, Saber; Torshabi, Ahmad Esmaili; Miandoab, Payam Samadi; Baghizadeh, Amin

2016-01-08

In external-beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation-based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two "Genetic" and "Ranker" searching procedures. The performance of these algorithms has been evaluated using four-dimensional extended cardiac-torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro-fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F-test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation-based feature selection algorithm, in combination with a genetic search algorithm, proved to yield best performance accuracy for selecting optimum markers.

PyClone: statistical inference of clonal population structure in cancer.

PubMed

Roth, Andrew; Khattra, Jaswinder; Yap, Damian; Wan, Adrian; Laks, Emma; Biele, Justina; Ha, Gavin; Aparicio, Samuel; Bouchard-Côté, Alexandre; Shah, Sohrab P

2014-04-01

We introduce PyClone, a statistical model for inference of clonal population structures in cancers. PyClone is a Bayesian clustering method for grouping sets of deeply sequenced somatic mutations into putative clonal clusters while estimating their cellular prevalences and accounting for allelic imbalances introduced by segmental copy-number changes and normal-cell contamination. Single-cell sequencing validation demonstrates PyClone's accuracy.

Height-age and height-diameter relationships for monocultures and mixtures of eastern cottonwood clones

Treesearch

Steven A. Knowe; G. Sam Foster; Randall J. Rousseau; Warren L Nance

1998-01-01

Data from an eastern cottonwood clonal mixing study in Mississippi and Kentucky, USA, were used to test the effects of planting locations and genetics (clonal proportions) on height-age and height-d.b.h. functions. Planting locations, which accounted for 5.6 percent of the variation in observed dominant height growth (p = 0.0001), were more important than clonal...

Standardizing the nomenclature for clonal lineages of the sudden oak death pathogen, Phytophthora ramorum

Treesearch

N.J. Grünwald; E.M. Goss; K. Ivors; M. Garbelotto; F.N. Martin; S. Prospero; E. Hansen; P.J.M. Bonants; R.C. Hamelin; G. Chastagner; S. Werres; D.M. Rizzo; G. Abad; P. Beales; G.J. Bilodeau; C.L. Blomquist; C. Brasier; S.C. Brière; A. Chandelier; J.M. Davidson; S. Denman; M. Elliott; S.J. Frankel; E.M. Goheen; H. de Gruyter; K. Heungens; D. James; A. Kanaskie; M.G. McWilliams; W. Man in ' t Veld; E. Moralejo; N.K. Osterbauer; M.E. Palm; J.L. Parke; A.M. Perez Sierra; S.F. Shamoun; N. Shishkoff; P.W. Tooley; A.M. Vettraino; J. Webber; T.L. Widmer

2009-01-01

Phytophthora ramorum, the causal agent of sudden oak death and ramorum blight, is known to exist as three distinct clonal lineages which can only be distinguished by performing molecular marker-based analyses. However, in the recent literature there exists no consensus on naming of these lineages. Here we propose a system for naming clonal lineages of P. ramorum based...

Clonal hematopoiesis as determined by the HUMARA assay is a marker for acquired mutations in epigenetic regulators in older women.

PubMed

Wiedmeier, Julia Erin; Kato, Catherine; Zhang, Zhenzhen; Lee, Hyunjung; Dunlap, Jennifer; Nutt, Eric; Rattray, Rogan; McKay, Sarah; Eide, Christopher; Press, Richard; Mori, Motomi; Druker, Brian; Dao, Kim-Hien

2016-09-01

Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that increase their risk for hematologic malignancy and all-cause cardiovascular deaths. The majority of these mutations are in chromatin and epigenetic regulatory genes (CERGs). CERGs play a key role in regulation of DNA methylation (DNMT3A and TET2) and histone function (ASXL1) and in clonal proliferation of hematopoietic stem cells. We hypothesize that older women manifesting clonal hematopoiesis, defined here as a functional phenomenon in which a hematopoietic stem cell has acquired a survival and proliferative advantage, harbor a higher frequency of somatic mutations in CERGs. The human androgen receptor gene (HUMARA) assay was used in our study to detect the presence of nonrandom X inactivation in women, a marker for clonal hematopoiesis. In our pilot study, we tested 127 blood samples from women ≥65 years old without a history of invasive cancer or hematologic malignancies. Applying stringent qualitative criteria, we found that 26% displayed clonal hematopoiesis; 52.8% displayed polyclonal hematopoiesis; and 21.3% had indeterminate patterns (too close to call by qualitative assessment). Using Illumina MiSeq next-generation sequencing, we identified somatic mutations in CERGs in 15.2% of subjects displaying clonal hematopoiesis (three ASXL1 and two DNMT3A mutations with an average variant allele frequency of 15.7%, range: 6.3%-23.3%). In a more limited sequencing analysis, we evaluated the frequency of ASXL1 mutations by Sanger sequencing and found mutations in 9.7% of the clonal samples and 0% of the polyclonal samples. By comparing several recent studies (with some caveats as described), we determined the fold enrichment of detecting CERG mutations by using the HUMARA assay as a functional screen for clonal hematopoiesis. We conclude that a functional assay of clonal hematopoiesis is enriching for older women with somatic mutations in CERGs, particularly for ASXL1 and TET2 mutations and less so for DNMT3A mutations. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

[Molecular mechanisms of thymocyte differentiation].

PubMed

Kuklina, E M

2003-01-01

A review of the main molecular events occurring during differentiation of T-lymphocytes in the thymus: T-cell specialization of early intrathymic precursors, formation and expression of antigen receptor, formation of antigen recognizing cell repertoire, and alpha beta/gamma beta- and CD4/CD8-commitment. The mechanisms of glucocorticoid-induced apoptosis of thymocytes and its blockade during antigen-dependent activation are considered. A special attention is paid to the analysis of intracellular signals underlying the clonal selection of thymocytes.

Clonal Evaluation of Prostate Cancer by ERG/SPINK1 Status to Improve Prognosis Prediction

DTIC Science & Technology

2015-10-01

waiting for case numbers to increase. Significant changes in use or care of human subjects, vertebrate animals , biohazards, and/or select agents...IHC at UM is no longer with the University. He has been replaced by Connie Brenke, who is now performing the staining which is ongoing (as shown in...and genomics. Institutional partners include the FHCRC and the UW Institute of Stem Cell Sciences. Core A: Tissues/ Sera /Models The major function

TALEN mediated targeted editing of GM2/GD2-synthase gene modulates anchorage independent growth by reducing anoikis resistance in mouse tumor cells

PubMed Central

Mahata, Barun; Banerjee, Avisek; Kundu, Manjari; Bandyopadhyay, Uday; Biswas, Kaushik

2015-01-01

Complex ganglioside expression is highly deregulated in several tumors which is further dependent on specific ganglioside synthase genes. Here, we designed and constructed a pair of highly specific transcription-activator like effector endonuclease (TALENs) to disrupt a particular genomic locus of mouse GM2-synthase, a region conserved in coding sequence of all four transcript variants of mouse GM2-synthase. Our designed TALENs effectively work in different mouse cell lines and TALEN induced mutation rate is over 45%. Clonal selection strategy is undertaken to generate stable GM2-synthase knockout cell line. We have also demonstrated non-homologous end joining (NHEJ) mediated integration of neomycin cassette into the TALEN targeted GM2-synthase locus. Functionally, clonally selected GM2-synthase knockout clones show reduced anchorage-independent growth (AIG), reduction in tumor growth and higher cellular adhesion as compared to wild type Renca-v cells. Insight into the mechanism shows that, reduced AIG is due to loss in anoikis resistance, as both knockout clones show increased sensitivity to detachment induced apoptosis. Therefore, TALEN mediated precise genome editing at GM2-synthase locus not only helps us in understanding the function of GM2-synthase gene and complex gangliosides in tumorigenicity but also holds tremendous potential to use TALENs in translational cancer research and therapeutics. PMID:25762467

TALEN mediated targeted editing of GM2/GD2-synthase gene modulates anchorage independent growth by reducing anoikis resistance in mouse tumor cells.

PubMed

Mahata, Barun; Banerjee, Avisek; Kundu, Manjari; Bandyopadhyay, Uday; Biswas, Kaushik

2015-03-12

Complex ganglioside expression is highly deregulated in several tumors which is further dependent on specific ganglioside synthase genes. Here, we designed and constructed a pair of highly specific transcription-activator like effector endonuclease (TALENs) to disrupt a particular genomic locus of mouse GM2-synthase, a region conserved in coding sequence of all four transcript variants of mouse GM2-synthase. Our designed TALENs effectively work in different mouse cell lines and TALEN induced mutation rate is over 45%. Clonal selection strategy is undertaken to generate stable GM2-synthase knockout cell line. We have also demonstrated non-homologous end joining (NHEJ) mediated integration of neomycin cassette into the TALEN targeted GM2-synthase locus. Functionally, clonally selected GM2-synthase knockout clones show reduced anchorage-independent growth (AIG), reduction in tumor growth and higher cellular adhesion as compared to wild type Renca-v cells. Insight into the mechanism shows that, reduced AIG is due to loss in anoikis resistance, as both knockout clones show increased sensitivity to detachment induced apoptosis. Therefore, TALEN mediated precise genome editing at GM2-synthase locus not only helps us in understanding the function of GM2-synthase gene and complex gangliosides in tumorigenicity but also holds tremendous potential to use TALENs in translational cancer research and therapeutics.

Selection on overdominant genes maintains heterozygosity along multiple chromosomes in a clonal lineage of honey bee.

PubMed

Goudie, Frances; Allsopp, Michael H; Oldroyd, Benjamin P

2014-01-01

Correlations between fitness and genome-wide heterozygosity (heterozygosity-fitness correlations, HFCs) have been reported across a wide range of taxa. The genetic basis of these correlations is controversial: do they arise from genome-wide inbreeding ("general effects") or the "local effects" of overdominant loci acting in linkage disequilibrium with neutral loci? In an asexual thelytokous lineage of the Cape honey bee (Apis mellifera capensis), the effects of inbreeding have been homogenized across the population, making this an ideal system in which to detect overdominant loci, and to make inferences about the importance of overdominance on HFCs in general. Here we investigate the pattern of zygosity along two chromosomes in 42 workers from the clonal Cape honey bee population. On chromosome III (which contains the sex-locus, a gene that is homozygous-lethal) and chromosome IV we show that the pattern of zygosity is characterized by loss of heterozygosity in short regions followed by the telomeric restoration of heterozygosity. We infer that at least four selectively overdominant genes maintain heterozygosity on chromosome III and three on chromosome IV via local effects acting on neutral markers in linkage disequilibrium. We conclude that heterozygote advantage and local effects may be more common and evolutionarily significant than is generally appreciated. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Regional gene mapping using mixed radiation hybrids and reverse chromosome painting.

PubMed

Lin, J Y; Bedford, J S

1997-11-01

We describe a new approach for low-resolution physical mapping using pooled DNA probe from mixed (non-clonal) populations of human-CHO cell hybrids and reverse chromosome painting. This mapping method is based on a process in which the human chromosome fragments bearing a complementing gene were selectively retained in a large non-clonal population of CHO-human hybrid cells during a series of 12- to 15-Gy gamma irradiations each followed by continuous growth selection. The location of the gene could then be identified by reverse chromosome painting on normal human metaphase spreads using biotinylated DNA from this population of "enriched" hybrid cells. We tested the validity of this method by correctly mapping the complementing human HPRT gene, whose location is well established. We then demonstrated the method's usefulness by mapping the chromosome location of a human gene which complemented the defect responsible for the hypersensitivity to ionizing radiation in CHO irs-20 cells. This method represents an efficient alternative to conventional concordance analysis in somatic cell hybrids where detailed chromosome analysis of numerous hybrid clones is necessary. Using this approach, it is possible to localize a gene for which there is no prior sequence or linkage information to a subchromosomal region, thus facilitating association with known mapping landmarks (e.g. RFLP, YAC or STS contigs) for higher-resolution mapping.

Clonal Outbreak of Plasmodium falciparum Infection in Eastern Panama

PubMed Central

Obaldia, Nicanor; Baro, Nicholas K.; Calzada, Jose E.; Santamaria, Ana M.; Daniels, Rachel; Wong, Wesley; Chang, Hsiao-Han; Hamilton, Elizabeth J.; Arevalo-Herrera, Myriam; Herrera, Socrates; Wirth, Dyann F.; Hartl, Daniel L.; Marti, Matthias; Volkman, Sarah K.

2015-01-01

Identifying the source of resurgent parasites is paramount to a strategic, successful intervention for malaria elimination. Although the malaria incidence in Panama is low, a recent outbreak resulted in a 6-fold increase in reported cases. We hypothesized that parasites sampled from this epidemic might be related and exhibit a clonal population structure. We tested the genetic relatedness of parasites, using informative single-nucleotide polymorphisms and drug resistance loci. We found that parasites were clustered into 3 clonal subpopulations and were related to parasites from Colombia. Two clusters of Panamanian parasites shared identical drug resistance haplotypes, and all clusters shared a chloroquine-resistance genotype matching the pfcrt haplotype of Colombian origin. Our findings suggest these resurgent parasite populations are highly clonal and that the high clonality likely resulted from epidemic expansion of imported or vestigial cases. Malaria outbreak investigations that use genetic tools can illuminate potential sources of epidemic malaria and guide strategies to prevent further resurgence in areas where malaria has been eliminated. PMID:25336725

Clonal Evaluation of Prostate Cancer by ERG/SPINK1 Status to Improve Prognosis Prediction

DTIC Science & Technology

2017-12-01

meaning that most men with prostate cancer have multiple, genetically distinct cancers. Pathologists cannot assess clonality by routine microscopic...Hence, in this proposal we utilized dual ERG/SPINK1 immunohistochemistry (IHC)—as a readout of clonal, mutually exclusive molecular subtypes—to assess...multiclonal (also referred to as multifocal), meaning that more than 80% of men with prostate cancer actually have multiple, genetically distinct

Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia.

PubMed

Engle, E K; Fisher, D A C; Miller, C A; McLellan, M D; Fulton, R S; Moore, D M; Wilson, R K; Ley, T J; Oh, S T

2015-04-01

Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

Modified Bat Algorithm for Feature Selection with the Wisconsin Diagnosis Breast Cancer (WDBC) Dataset

PubMed

Jeyasingh, Suganthi; Veluchamy, Malathi

2017-05-01

Early diagnosis of breast cancer is essential to save lives of patients. Usually, medical datasets include a large variety of data that can lead to confusion during diagnosis. The Knowledge Discovery on Database (KDD) process helps to improve efficiency. It requires elimination of inappropriate and repeated data from the dataset before final diagnosis. This can be done using any of the feature selection algorithms available in data mining. Feature selection is considered as a vital step to increase the classification accuracy. This paper proposes a Modified Bat Algorithm (MBA) for feature selection to eliminate irrelevant features from an original dataset. The Bat algorithm was modified using simple random sampling to select the random instances from the dataset. Ranking was with the global best features to recognize the predominant features available in the dataset. The selected features are used to train a Random Forest (RF) classification algorithm. The MBA feature selection algorithm enhanced the classification accuracy of RF in identifying the occurrence of breast cancer. The Wisconsin Diagnosis Breast Cancer Dataset (WDBC) was used for estimating the performance analysis of the proposed MBA feature selection algorithm. The proposed algorithm achieved better performance in terms of Kappa statistic, Mathew’s Correlation Coefficient, Precision, F-measure, Recall, Mean Absolute Error (MAE), Root Mean Square Error (RMSE), Relative Absolute Error (RAE) and Root Relative Squared Error (RRSE). Creative Commons Attribution License

A Monomorphic Haplotype of Chromosome Ia Is Associated with Widespread Success in Clonal and Nonclonal Populations of Toxoplasma gondii

PubMed Central

Khan, Asis; Miller, Natalie; Roos, David S.; Dubey, J. P.; Ajzenberg, Daniel; Dardé, Marie Laure; Ajioka, James W.; Rosenthal, Benjamin; Sibley, L. David

2011-01-01

ABSTRACT Toxoplasma gondii is a common parasite of animals that also causes a zoonotic infection in humans. Previous studies have revealed a strongly clonal population structure that is shared between North America and Europe, while South American strains show greater genetic diversity and evidence of sexual recombination. The common inheritance of a monomorphic version of chromosome Ia (referred to as ChrIa*) among three clonal lineages from North America and Europe suggests that inheritance of this chromosome might underlie their recent clonal expansion. To further examine the diversity and distribution of ChrIa, we have analyzed additional strains with greater geographic diversity. Our findings reveal that the same haplotype of ChrIa* is found in the clonal lineages from North America and Europe and in older lineages in South America, where sexual recombination is more common. Although lineages from all three continents harbor the same conserved ChrIa* haplotype, strains from North America and Europe are genetically separate from those in South America, and these respective geographic regions show limited evidence of recent mixing. Genome-wide, array-based profiling of polymorphisms provided evidence for an ancestral flow from particular older southern lineages that gave rise to the clonal lineages now dominant in the north. Collectively, these data indicate that ChrIa* is widespread among nonclonal strains in South America and has more recently been associated with clonal expansion of specific lineages in North America and Europe. These findings have significant implications for the spread of genetic loci influencing transmission and virulence in pathogen populations. PMID:22068979

Improved clonality detection in Hodgkin lymphoma using a semi-nested modification of the BIOMED-2 PCR assay for IGH and IGK rearrangements: A paraffin-embedded tissue study.

PubMed

Han, Shusen; Masaki, Ayako; Sakamoto, Yuma; Takino, Hisashi; Murase, Takayuki; Iida, Shinsuke; Inagaki, Hiroshi

2018-05-01

The BIOMED-2 PCR protocols targeting IGH and IGK genes may be useful for detecting clonality in Hodgkin lymphoma (HL). The clonality detection rates, however, have not been very high with these methods using paraffin-embedded tumor sections. We previously described the usefulness of the semi-nested BIOMED-2 IGH assay in B-cell malignancies. In this study, we devised a novel semi-nested BIOMED-2 IGK assay. Employing 58 cases of classical HL, we carried out the standard BIOMED-2, BIOMED-2 followed by BIOMED-2 re-amplification, and BIOMED-2 followed by semi-nested BIOMED-2, all targeting IGH and IGK, using paraffin-embedded tissues. In both IGH and IGK assays, semi-nested assays yielded significantly higher clonality detection rates than the standard assays and re-amplification assays. Clonality was detected in 13/58 (22.4%) classical HL cases using the standard IGH/IGK assays while it was detected in 38/58 (65.5%) cases using semi-nested IGH/IGK assays. The detection rates were not associated with the HL subtypes, CD30-positive cell density, CD20-positive cell density, or Epstein-Barr virus (EBV) positivity. In conclusion, tumor clonality was detected in nearly two-thirds of classical HL cases using semi-nested BIOMED-2 IGH/IGK assays using paraffin tumor sections. These semi-nested assays may be useful when the standard IGH/IGK assays fail to detect clonality in histopathologically suspected HLs. © 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Usefullness of IGH/TCR PCR studies in lymphoproliferative disorders with inconclusive clonality by flow cytometry.

PubMed

Ribera, Jordi; Zamora, Lurdes; Juncà, Jordi; Rodríguez, Inés; Marcé, Silvia; Cabezón, Marta; Millá, Fuensanta

2013-07-25

In up to 5-15% of studies of lymphoproliferative disorders (LPD) flow cytometry (FCM) or immunomorphologic methods cannot discriminate malignant from reactive processes. The aim of this work was to determine the usefulness of PCR for solving these diagnostic uncertainties. We analyzed IGH and TCRγ genes by PCR in 106 samples with inconclusive FCM results. A clonal result was registered in 36/106 studies, with a LPD being confirmed in 27 (75%) of these cases. Specifically, 9/9 IGH clonal and 16/25 TCRγ clonal results were finally diagnosed with LPD. Additionally, 2 clonal TCRγ samples with suspicion of undefined LPD were finally diagnosed with T LPD. Although polyclonal results were obtained in 47 of the cases studied (38 IGH and 9 TCRγ), hematologic neoplasms were diagnosed in 4/38 IGH polyclonal and in 1/9 TCRγ polyclonal studies. There were also 14 PCR polyclonal results (4 IGH, 10 TCRγ), albeit non-conclusive. Of these, 2/4 were eventually diagnosed with B-cell lymphoma and 3/10 with T-cell LPD. In 8 IGH samples the results of PCR techniques were non-informative but in 3/8 cases a B lymphoma was finally confirmed. We concluded that PCR is a useful technique to identify LPD when FCM is inconclusive. A PCR clonal B result is indicative of malignancy but IGH polyclonal and non-conclusive results do not exclude lymphoid neoplasms. Interpretation of T-cell clonality should be based on all the available clinical and analytical data. © 2013 Clinical Cytometry Society. Copyright © 2013 Clinical Cytometry Society.

Extensive clonal spread and extreme longevity in saw palmetto, a foundation clonal plant.

PubMed

Takahashi, Mizuki K; Horner, Liana M; Kubota, Toshiro; Keller, Nathan A; Abrahamson, Warren G

2011-09-01

The lack of effective tools has hampered out ability to assess the size, growth and ages of clonal plants. With Serenoa repens (saw palmetto) as a model, we introduce a novel analytical framework that integrates DNA fingerprinting and mathematical modelling to simulate growth and estimate ages of clonal plants. We also demonstrate the application of such life-history information of clonal plants to provide insight into management plans. Serenoa is an ecologically important foundation species in many Southeastern United States ecosystems; yet, many land managers consider Serenoa a troublesome invasive plant. Accordingly, management plans have been developed to reduce or eliminate Serenoa with little understanding of its life history. Using Amplified Fragment Length Polymorphisms, we genotyped 263 Serenoa and 134 Sabal etonia (a sympatric non-clonal palmetto) samples collected from a 20 × 20 m study plot in Florida scrub. Sabal samples were used to assign small field-unidentifiable palmettos to Serenoa or Sabal and also as a negative control for clone detection. We then mathematically modelled clonal networks to estimate genet ages. Our results suggest that Serenoa predominantly propagate via vegetative sprouts and 10,000-year-old genets may be common, while showing no evidence of clone formation by Sabal. The results of this and our previous studies suggest that: (i) Serenoa has been part of scrub associations for thousands of years, (ii) Serenoa invasion are unlikely and (ii) once Serenoa is eliminated from local communities, its restoration will be difficult. Reevaluation of the current management tools and plans is an urgent task. © 2011 Blackwell Publishing Ltd.

Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium

PubMed Central

Lescroart, Fabienne; Hamou, Wissam; Francou, Alexandre; Théveniau-Ruissy, Magali; Kelly, Robert G.; Buckingham, Margaret

2015-01-01

Neck muscles constitute a transition zone between somite-derived skeletal muscles of the trunk and limbs, and muscles of the head, which derive from cranial mesoderm. The trapezius and sternocleidomastoid neck muscles are formed from progenitor cells that have expressed markers of cranial pharyngeal mesoderm, whereas other muscles in the neck arise from Pax3-expressing cells in the somites. Mef2c-AHF-Cre genetic tracing experiments and Tbx1 mutant analysis show that nonsomitic neck muscles share a gene regulatory network with cardiac progenitor cells in pharyngeal mesoderm of the second heart field (SHF) and branchial arch-derived head muscles. Retrospective clonal analysis shows that this group of neck muscles includes laryngeal muscles and a component of the splenius muscle, of mixed somitic and nonsomitic origin. We demonstrate that the trapezius muscle group is clonally related to myocardium at the venous pole of the heart, which derives from the posterior SHF. The left clonal sublineage includes myocardium of the pulmonary trunk at the arterial pole of the heart. Although muscles derived from the first and second branchial arches also share a clonal relationship with different SHF-derived parts of the heart, neck muscles are clonally distinct from these muscles and define a third clonal population of common skeletal and cardiac muscle progenitor cells within cardiopharyngeal mesoderm. By linking neck muscle and heart development, our findings highlight the importance of cardiopharyngeal mesoderm in the evolution of the vertebrate heart and neck and in the pathophysiology of human congenital disease. PMID:25605943

Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium.

PubMed

Lescroart, Fabienne; Hamou, Wissam; Francou, Alexandre; Théveniau-Ruissy, Magali; Kelly, Robert G; Buckingham, Margaret

2015-02-03

Neck muscles constitute a transition zone between somite-derived skeletal muscles of the trunk and limbs, and muscles of the head, which derive from cranial mesoderm. The trapezius and sternocleidomastoid neck muscles are formed from progenitor cells that have expressed markers of cranial pharyngeal mesoderm, whereas other muscles in the neck arise from Pax3-expressing cells in the somites. Mef2c-AHF-Cre genetic tracing experiments and Tbx1 mutant analysis show that nonsomitic neck muscles share a gene regulatory network with cardiac progenitor cells in pharyngeal mesoderm of the second heart field (SHF) and branchial arch-derived head muscles. Retrospective clonal analysis shows that this group of neck muscles includes laryngeal muscles and a component of the splenius muscle, of mixed somitic and nonsomitic origin. We demonstrate that the trapezius muscle group is clonally related to myocardium at the venous pole of the heart, which derives from the posterior SHF. The left clonal sublineage includes myocardium of the pulmonary trunk at the arterial pole of the heart. Although muscles derived from the first and second branchial arches also share a clonal relationship with different SHF-derived parts of the heart, neck muscles are clonally distinct from these muscles and define a third clonal population of common skeletal and cardiac muscle progenitor cells within cardiopharyngeal mesoderm. By linking neck muscle and heart development, our findings highlight the importance of cardiopharyngeal mesoderm in the evolution of the vertebrate heart and neck and in the pathophysiology of human congenital disease.

Environmental and genetic correlates of allocation to sexual reproduction in the circumpolar plant Bistorta vivipara.

PubMed

Bills, John W; Roalson, Eric H; Busch, Jeremiah W; Eidesen, Pernille B

2015-07-01

• Sexual reproduction often requires more energy and time than clonal reproduction. In marginal arctic conditions, species that can reproduce both sexually and clonally dominate. Plants with this capacity may thrive because they can alter reproduction depending on environmental conditions. Bistorta vivipara is a circumpolar herb that predominately reproduces clonally, but certain environmental conditions promote higher investment in flowers (and possible sexual reproduction). Despite largely reproducing clonally, the herb has high levels of genetic variation, and the processes underlying this paradoxical pattern of variation remain unclear. Here we identified environmental factors associated with sexual investment and examined whether sexual reproduction is associated with higher levels of genetic variation.• We sampled 20 populations of B. vivipara across the high Arctic archipelago of Svalbard. In each population, we measured reproductive traits, environmental variables, and collected samples for genetic analyses. These samples permitted hypotheses to be tested regarding sexual investment and ecological and genetic correlates.• Increased soil nitrogen and organic matter content and decreased elevation were positively associated with investment in flowers. Increased investment in flowers significantly correlated with more genotypes per population. Linkage disequilibrium was consistent with predominant clonality, but several populations showed higher genetic variation and lower differentiation than expected. There was no geographical genetic structure.• In B. vivipara, sexual investment is positively associated with habitat quality. Bistorta vivipara predominantly reproduces clonally, but occasional outcrossing, efficient clonal reproduction, and dispersal by bulbils can explain the considerable genetic variation and weak genetic structure in B. vivipara. © 2015 Botanical Society of America, Inc.

Statistical analysis for validating ACO-KNN algorithm as feature selection in sentiment analysis

NASA Astrophysics Data System (ADS)

Ahmad, Siti Rohaidah; Yusop, Nurhafizah Moziyana Mohd; Bakar, Azuraliza Abu; Yaakub, Mohd Ridzwan

2017-10-01

This research paper aims to propose a hybrid of ant colony optimization (ACO) and k-nearest neighbor (KNN) algorithms as feature selections for selecting and choosing relevant features from customer review datasets. Information gain (IG), genetic algorithm (GA), and rough set attribute reduction (RSAR) were used as baseline algorithms in a performance comparison with the proposed algorithm. This paper will also discuss the significance test, which was used to evaluate the performance differences between the ACO-KNN, IG-GA, and IG-RSAR algorithms. This study evaluated the performance of the ACO-KNN algorithm using precision, recall, and F-score, which were validated using the parametric statistical significance tests. The evaluation process has statistically proven that this ACO-KNN algorithm has been significantly improved compared to the baseline algorithms. The evaluation process has statistically proven that this ACO-KNN algorithm has been significantly improved compared to the baseline algorithms. In addition, the experimental results have proven that the ACO-KNN can be used as a feature selection technique in sentiment analysis to obtain quality, optimal feature subset that can represent the actual data in customer review data.

Spatial genetic structure reflects extensive clonality, low genotypic diversity and habitat fragmentation in Grevillea renwickiana (Proteaceae), a rare, sterile shrub from south-eastern Australia

PubMed Central

James, Elizabeth A.; McDougall, Keith L.

2014-01-01

Background and Aims The association of clonality, polyploidy and reduced fecundity has been identified as an extinction risk for clonal plants. Compromised sexual reproduction limits both their ability to adapt to new conditions and their capacity to disperse to more favourable environments. Grevillea renwickiana is a prostrate, putatively sterile shrub reliant on asexual reproduction. Dispersal is most likely limited by the rate of clonal expansion via rhizomes. The nine localized populations constituting this species provide an opportunity to examine the extent of clonality and spatial genotypic diversity to evaluate its evolutionary prospects. Methods Ten microsatellite loci were used to compare genetic and genotypic diversity across all sites with more intensive sampling at four locations (n = 185). The spatial distribution of genotypes and chloroplast DNA haplotypes based on the trnQ–rps16 intergenic spacer region were compared. Chromosome counts provided a basis for examining genetic profiles inconsistent with diploidy. Key Results Microsatellite analysis identified 46 multilocus genotypes (MLGs) in eight multilocus clonal lineages (MLLs). MLLs are not shared among sites, with two exceptions. Spatial autocorrelation was significant to 1·6 km. Genotypic richness ranged from 0 to 0·33. Somatic mutation is likely to contribute to minor variation between MLGs within clonal lineages. The eight chloroplast haplotypes identified were correlated with eight MLLs defined by ordination and generally restricted to single populations. Triploidy is the most likely reason for tri-allelic patterns. Conclusions Grevillea renwickiana comprises few genetic individuals. Sterility has most likely been induced by triploidy. Extensive lateral suckering in long-lived sterile clones facilitates the accumulation of somatic mutations, which contribute to the measured genetic diversity. Genetic conservation value may not be a function of population size. Despite facing evolutionary stagnation, sterile clonal species can play a vital role in mitigating ecological instability as floras respond to rapid environmental change. PMID:24737718

A GPU-Based Implementation of the Firefly Algorithm for Variable Selection in Multivariate Calibration Problems

PubMed Central

de Paula, Lauro C. M.; Soares, Anderson S.; de Lima, Telma W.; Delbem, Alexandre C. B.; Coelho, Clarimar J.; Filho, Arlindo R. G.

2014-01-01

Several variable selection algorithms in multivariate calibration can be accelerated using Graphics Processing Units (GPU). Among these algorithms, the Firefly Algorithm (FA) is a recent proposed metaheuristic that may be used for variable selection. This paper presents a GPU-based FA (FA-MLR) with multiobjective formulation for variable selection in multivariate calibration problems and compares it with some traditional sequential algorithms in the literature. The advantage of the proposed implementation is demonstrated in an example involving a relatively large number of variables. The results showed that the FA-MLR, in comparison with the traditional algorithms is a more suitable choice and a relevant contribution for the variable selection problem. Additionally, the results also demonstrated that the FA-MLR performed in a GPU can be five times faster than its sequential implementation. PMID:25493625

A GPU-Based Implementation of the Firefly Algorithm for Variable Selection in Multivariate Calibration Problems.

PubMed

de Paula, Lauro C M; Soares, Anderson S; de Lima, Telma W; Delbem, Alexandre C B; Coelho, Clarimar J; Filho, Arlindo R G

2014-01-01

Several variable selection algorithms in multivariate calibration can be accelerated using Graphics Processing Units (GPU). Among these algorithms, the Firefly Algorithm (FA) is a recent proposed metaheuristic that may be used for variable selection. This paper presents a GPU-based FA (FA-MLR) with multiobjective formulation for variable selection in multivariate calibration problems and compares it with some traditional sequential algorithms in the literature. The advantage of the proposed implementation is demonstrated in an example involving a relatively large number of variables. The results showed that the FA-MLR, in comparison with the traditional algorithms is a more suitable choice and a relevant contribution for the variable selection problem. Additionally, the results also demonstrated that the FA-MLR performed in a GPU can be five times faster than its sequential implementation.

Molecular Characterization and Antimicrobial Susceptibility of Staphylococcus aureus Isolates from Clinical Infection and Asymptomatic Carriers in Southwest Nigeria

PubMed Central

Olasupo, Nurudeen A.; Egwari, Louis O.; Becker, Karsten

2015-01-01

Few reports from Africa suggest that resistance pattern, virulence factors and genotypes differ between Staphylococcus aureus from nasal carriage and clinical infection. We therefore compared antimicrobial resistance, selected virulence factors and genotypes of S. aureus from nasal carriage and clinical infection in Southwest Nigeria. Non-duplicate S. aureus isolates were obtained from infection (n = 217) and asymptomatic carriers (n = 73) during a cross sectional study in Lagos and Ogun States, Nigeria from 2010–2011. Susceptibility testing was performed using Vitek automated systems. Selected virulence factors were detected by PCR. The population structure was assessed using spa typing. The spa clonal complexes (spa-CC) were deduced using the Based Upon Repeat Pattern algorithm (BURP). Resistance was higher for aminoglycosides in clinical isolates while resistances to quinolones and tetracycline were more prevalent in carrier isolates. The Panton-Valentine leukocidin (PVL) was more frequently detected in isolates from infection compared to carriage (80.2 vs 53.4%; p<0.001, chi2-test). Seven methicillin resistant S. aureus isolates were associated with spa types t002, t008, t064, t194, t8439, t8440 and t8441. The predominant spa types among the methicillin-susceptible S. aureus isolates were t084 (65.5%), t2304 (4.4%) and t8435 (4.1%). spa-CC 084 was predominant among isolates from infection (80.3%, n = 167) and was significantly associated with PVL (OR = 7.1, 95%CI: 3.9–13.2, p<0.001, chi2- test). In conclusion, PVL positive isolates were more frequently detected among isolates from infection compared to carriage and are associated with spa-CC 084. PMID:26348037

Selecting materialized views using random algorithm

NASA Astrophysics Data System (ADS)

Zhou, Lijuan; Hao, Zhongxiao; Liu, Chi

2007-04-01

The data warehouse is a repository of information collected from multiple possibly heterogeneous autonomous distributed databases. The information stored at the data warehouse is in form of views referred to as materialized views. The selection of the materialized views is one of the most important decisions in designing a data warehouse. Materialized views are stored in the data warehouse for the purpose of efficiently implementing on-line analytical processing queries. The first issue for the user to consider is query response time. So in this paper, we develop algorithms to select a set of views to materialize in data warehouse in order to minimize the total view maintenance cost under the constraint of a given query response time. We call it query_cost view_ selection problem. First, cost graph and cost model of query_cost view_ selection problem are presented. Second, the methods for selecting materialized views by using random algorithms are presented. The genetic algorithm is applied to the materialized views selection problem. But with the development of genetic process, the legal solution produced become more and more difficult, so a lot of solutions are eliminated and producing time of the solutions is lengthened in genetic algorithm. Therefore, improved algorithm has been presented in this paper, which is the combination of simulated annealing algorithm and genetic algorithm for the purpose of solving the query cost view selection problem. Finally, in order to test the function and efficiency of our algorithms experiment simulation is adopted. The experiments show that the given methods can provide near-optimal solutions in limited time and works better in practical cases. Randomized algorithms will become invaluable tools for data warehouse evolution.

Genetic Particle Swarm Optimization-Based Feature Selection for Very-High-Resolution Remotely Sensed Imagery Object Change Detection.

PubMed

Chen, Qiang; Chen, Yunhao; Jiang, Weiguo

2016-07-30

In the field of multiple features Object-Based Change Detection (OBCD) for very-high-resolution remotely sensed images, image objects have abundant features and feature selection affects the precision and efficiency of OBCD. Through object-based image analysis, this paper proposes a Genetic Particle Swarm Optimization (GPSO)-based feature selection algorithm to solve the optimization problem of feature selection in multiple features OBCD. We select the Ratio of Mean to Variance (RMV) as the fitness function of GPSO, and apply the proposed algorithm to the object-based hybrid multivariate alternative detection model. Two experiment cases on Worldview-2/3 images confirm that GPSO can significantly improve the speed of convergence, and effectively avoid the problem of premature convergence, relative to other feature selection algorithms. According to the accuracy evaluation of OBCD, GPSO is superior at overall accuracy (84.17% and 83.59%) and Kappa coefficient (0.6771 and 0.6314) than other algorithms. Moreover, the sensitivity analysis results show that the proposed algorithm is not easily influenced by the initial parameters, but the number of features to be selected and the size of the particle swarm would affect the algorithm. The comparison experiment results reveal that RMV is more suitable than other functions as the fitness function of GPSO-based feature selection algorithm.

Affine Projection Algorithm with Improved Data-Selective Method Using the Condition Number

NASA Astrophysics Data System (ADS)

Ban, Sung Jun; Lee, Chang Woo; Kim, Sang Woo

Recently, a data-selective method has been proposed to achieve low misalignment in affine projection algorithm (APA) by keeping the condition number of an input data matrix small. We present an improved method, and a complexity reduction algorithm for the APA with the data-selective method. Experimental results show that the proposed algorithm has lower misalignment and a lower condition number for an input data matrix than both the conventional APA and the APA with the previous data-selective method.

A selective-update affine projection algorithm with selective input vectors

NASA Astrophysics Data System (ADS)

Kong, NamWoong; Shin, JaeWook; Park, PooGyeon

2011-10-01

This paper proposes an affine projection algorithm (APA) with selective input vectors, which based on the concept of selective-update in order to reduce estimation errors and computations. The algorithm consists of two procedures: input- vector-selection and state-decision. The input-vector-selection procedure determines the number of input vectors by checking with mean square error (MSE) whether the input vectors have enough information for update. The state-decision procedure determines the current state of the adaptive filter by using the state-decision criterion. As the adaptive filter is in transient state, the algorithm updates the filter coefficients with the selected input vectors. On the other hand, as soon as the adaptive filter reaches the steady state, the update procedure is not performed. Through these two procedures, the proposed algorithm achieves small steady-state estimation errors, low computational complexity and low update complexity for colored input signals.

Occurrence of the Plasmid-Mediated Fluoroquinolone Resistance qepA1 Gene in Two Clonal Clinical Isolates of CTX-M-15-Producing Escherichia coli from Algeria.

PubMed

Yanat, Betitera; Dali Yahia, Radia; Yazi, Leila; Machuca, Jesús; Díaz-De-Alba, Paula; Touati, Abdelaziz; Pascual, Álvaro; Rodríguez-Martínez, José-Manuel

2017-06-01

QepA is a plasmid-mediated quinolone resistance determinant of low prevalence described worldwide, mainly in Enterobacteriaceae. This study describes, for the first time in Algeria, two clonally related, QepA-producing Escherichia coli clinical isolates positive for CTX-M-15. The clonal spread of these multidrug-resistant isolates is a major public health concern.

Successful Immunosuppressive Therapy for Severe Infectious Mononucleosis in a Patient with Clonal Proliferation of EBV-infected CD8-positive Cells.

PubMed

Hosoi, Hiroki; Sonoki, Takashi; Murata, Shogo; Mushino, Toshiki; Kuriyama, Kodai; Nishikawa, Akinori; Hanaoka, Nobuyoshi; Ohshima, Koichi; Imadome, Ken-Ichi; Nakakuma, Hideki

2015-01-01

A 30-year-old woman was diagnosed with severe infectious mononucleosis (IM). The Epstein-Barr virus (EBV) had infected both CD19- and CD8-positive cells, and clonal proliferation of EBV-infected cells and T-cells was detected. Although we suspected malignant lymphoma, her condition improved following immunosuppressive therapy. A similar case was recently reported; therefore, this case is the second case of IM with EBV-infected CD8-positive cells and clonal proliferation of EBV-infected cells. Our results demonstrate that the clonal proliferation of EBV-infected cells is not always an indication for chemotherapy in the primary infection phase and that monitoring the EBV viral load is useful for therapeutic decision-making.

Recombinant transfer in the basic genome of E. coli

DOE PAGES

Dixit, Purushottam; Studier, F. William; Pang, Tin Yau; ...

2015-07-07

An approximation to the ~4-Mbp basic genome shared by 32 strains of E. coli representing six evolutionary groups has been derived and analyzed computationally. A multiple-alignment of the 32 complete genome sequences was filtered to remove mobile elements and identify the most reliable ~90% of the aligned length of each of the resulting 496 basic-genome pairs. Patterns of single bp mutations (SNPs) in aligned pairs distinguish clonally inherited regions from regions where either genome has acquired DNA fragments from diverged genomes by homologous recombination since their last common ancestor. Such recombinant transfer is pervasive across the basic genome, mostly betweenmore » genomes in the same evolutionary group, and generates many unique mosaic patterns. The six least-diverged genome-pairs have one or two recombinant transfers of length ~40–115 kbp (and few if any other transfers), each containing one or more gene clusters known to confer strong selective advantage in some environments. Moderately diverged genome pairs (0.4–1% SNPs) show mosaic patterns of interspersed clonal and recombinant regions of varying lengths throughout the basic genome, whereas more highly diverged pairs within an evolutionary group or pairs between evolutionary groups having >1.3% SNPs have few clonal matches longer than a few kbp. Many recombinant transfers appear to incorporate fragments of the entering DNA produced by restriction systems of the recipient cell. A simple computational model can closely fit the data. As a result, most recombinant transfers seem likely to be due to generalized transduction by co-evolving populations of phages, which could efficiently distribute variability throughout bacterial genomes.« less

Recombinant transfer in the basic genome of E. coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dixit, Purushottam; Studier, F. William; Pang, Tin Yau

An approximation to the ~4-Mbp basic genome shared by 32 strains of E. coli representing six evolutionary groups has been derived and analyzed computationally. A multiple-alignment of the 32 complete genome sequences was filtered to remove mobile elements and identify the most reliable ~90% of the aligned length of each of the resulting 496 basic-genome pairs. Patterns of single bp mutations (SNPs) in aligned pairs distinguish clonally inherited regions from regions where either genome has acquired DNA fragments from diverged genomes by homologous recombination since their last common ancestor. Such recombinant transfer is pervasive across the basic genome, mostly betweenmore » genomes in the same evolutionary group, and generates many unique mosaic patterns. The six least-diverged genome-pairs have one or two recombinant transfers of length ~40–115 kbp (and few if any other transfers), each containing one or more gene clusters known to confer strong selective advantage in some environments. Moderately diverged genome pairs (0.4–1% SNPs) show mosaic patterns of interspersed clonal and recombinant regions of varying lengths throughout the basic genome, whereas more highly diverged pairs within an evolutionary group or pairs between evolutionary groups having >1.3% SNPs have few clonal matches longer than a few kbp. Many recombinant transfers appear to incorporate fragments of the entering DNA produced by restriction systems of the recipient cell. A simple computational model can closely fit the data. As a result, most recombinant transfers seem likely to be due to generalized transduction by co-evolving populations of phages, which could efficiently distribute variability throughout bacterial genomes.« less

Genomic Structural Variations Affecting Virulence During Clonal Expansion of Pseudomonas syringae pv. actinidiae Biovar 3 in Europe.

PubMed

Firrao, Giuseppe; Torelli, Emanuela; Polano, Cesare; Ferrante, Patrizia; Ferrini, Francesca; Martini, Marta; Marcelletti, Simone; Scortichini, Marco; Ermacora, Paolo

2018-01-01

Pseudomonas syringae pv. actinidiae (Psa) biovar 3 caused pandemic bacterial canker of Actinidia chinensis and Actinidia deliciosa since 2008. In Europe, the disease spread rapidly in the kiwifruit cultivation areas from a single introduction. In this study, we investigated the genomic diversity of Psa biovar 3 strains during the primary clonal expansion in Europe using single molecule real-time (SMRT), Illumina and Sanger sequencing technologies. We recorded evidences of frequent mobilization and loss of transposon Tn6212, large chromosome inversions, and ectopic integration of IS sequences (remarkably ISPsy31, ISPsy36, and ISPsy37). While no phenotype change associated with Tn6212 mobilization could be detected, strains CRAFRU 12.29 and CRAFRU 12.50 did not elicit the hypersensitivity response (HR) on tobacco and eggplant leaves and were limited in their growth in kiwifruit leaves due to insertion of ISPsy31 and ISPsy36 in the hrpS and hrpR genes, respectively, interrupting the hrp cluster. Both strains had been isolated from symptomatic plants, suggesting coexistence of variant strains with reduced virulence together with virulent strains in mixed populations. The structural differences caused by rearrangements of self-genetic elements within European and New Zealand strains were comparable in number and type to those occurring among the European strains, in contrast with the significant difference in terms of nucleotide polymorphisms. We hypothesize a relaxation, during clonal expansion, of the selection limiting the accumulation of deleterious mutations associated with genome structural variation due to transposition of mobile elements. This consideration may be relevant when evaluating strategies to be adopted for epidemics management.

Dynamic Patterns of Clonal Evolution in Tumor Vasculature Underlie Alterations in Lymphocyte-Endothelial Recognition to Foster Tumor Immune Escape.

PubMed

Corey, Daniel M; Rinkevich, Yuval; Weissman, Irving L

2016-03-15

Although tumor blood vessels have been a major therapeutic target for cancer chemotherapy, little is known regarding the stepwise development of the tumor microenvironment. Here, we use a multicolor Cre-dependent marker system to trace clonality within the tumor microenvironment to show that tumor blood vessels follow a pattern of dynamic clonal evolution. In an advanced melanoma tumor microenvironment, the vast majority of tumor vasculature clones are derived from a common precursor. Quantitative lineage analysis reveals founder clones diminish in frequency and are replaced by subclones as tumors evolve. These tumor-specific blood vessels are characterized by a developmental switch to a more invasive and immunologically silent phenotype. Gene expression profiling and pathway analysis reveals selection for traits promoting upregulation of alternative angiogenic programs such as unregulated HGF-MET signaling and enhanced autocrine signaling through VEGF and PDGF. Furthermore, we show a developmental switch in the expression of functionally significant primary lymphocyte adhesion molecules on tumor endothelium, such as the loss in expression of the mucosal addressin MAdCAM-1, whose counter receptor a4β7 on lymphocytes controls lymphocyte homing. Changes in adhesive properties on tumor endothelial subclones are accompanied by decreases in expression of lymphocyte chemokines CXCL16, CXCL13, CXCL12, CXCL9, CXCL10, and CCL19. These evolutionary patterns in the expressed genetic program within tumor endothelium will have both a quantitative and functional impact on lymphocyte distribution that may well influence tumor immune function and underlie escape mechanisms from current antiangiogenic pharmacotherapies. ©2015 American Association for Cancer Research.

Minimal Residual Disease Monitoring of Acute Myeloid Leukemia by Massively Multiplex Digital PCR in Patients with NPM1 Mutations.

PubMed

Mencia-Trinchant, Nuria; Hu, Yang; Alas, Maria Antonina; Ali, Fatima; Wouters, Bas J; Lee, Sangmin; Ritchie, Ellen K; Desai, Pinkal; Guzman, Monica L; Roboz, Gail J; Hassane, Duane C

2017-07-01

The presence of minimal residual disease (MRD) is widely recognized as a powerful predictor of therapeutic outcome in acute myeloid leukemia (AML), but methods of measurement and quantification of MRD in AML are not yet standardized in clinical practice. There is an urgent, unmet need for robust and sensitive assays that can be readily adopted as real-time tools for disease monitoring. NPM1 frameshift mutations are an established MRD marker present in half of patients with cytogenetically normal AML. However, detection is complicated by the existence of hundreds of potential frameshift insertions, clonal heterogeneity, and absence of sequence information when the NPM1 mutation is identified using capillary electrophoresis. Thus, some patients are ineligible for NPM1 MRD monitoring. Furthermore, a subset of patients with NPM1-mutated AML will have false-negative MRD results because of clonal evolution. To simplify and improve MRD testing for NPM1, we present a novel digital PCR technique composed of massively multiplex pools of insertion-specific primers that selectively detect mutated but not wild-type NPM1. By measuring reaction end points using digital PCR technology, the resulting single assay enables sensitive and specific quantification of most NPM1 exon 12 mutations in a manner that is robust to clonal heterogeneity, does not require NPM1 sequence information, and obviates the need for maintenance of hundreds of type-specific assays and associated plasmid standards. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Antimicrobial Susceptibility and Clonality of Clinical Ureaplasma Isolates in the United States.

PubMed

Fernández, Javier; Karau, Melissa J; Cunningham, Scott A; Greenwood-Quaintance, Kerryl E; Patel, Robin

2016-08-01

Ureaplasma urealyticum and Ureaplasma parvum are pathogens involved in urogenital tract and intrauterine infections and also in systemic diseases in newborns and immunosuppressed patients. There is limited information on the antimicrobial susceptibility and clonality of these species. In this study, we report the susceptibility of 250 contemporary isolates of Ureaplasma (202 U. parvum and 48 U. urealyticum isolates) recovered at Mayo Clinic, Rochester, MN. MICs of doxycycline, azithromycin, ciprofloxacin, tetracycline, erythromycin, and levofloxacin were determined by broth microdilution, with MICS of the last three interpreted according to CLSI guidelines. Levofloxacin resistance was found in 6.4% and 5.2% of U. parvum and U. urealyticum isolates, respectively, while 27.2% and 68.8% of isolates, respectively, showed ciprofloxacin MICs of ≥4 μg/ml. The resistance mechanism of levofloxacin-resistant isolates was due to mutations in parC, with the Ser83Leu substitution being most frequent, followed by Glu87Lys. No macrolide resistance was found among the 250 isolates studied; a single U. parvum isolate was tetracycline resistant. tet(M) was found in 10 U. parvum isolates, including the single tetracycline-resistant isolate, as well as in 9 isolates which had low tetracycline and doxycycline MICs. Multilocus sequence typing (MLST) performed on a selection of 46 isolates showed high diversity within the clinical Ureaplasma isolates studied, regardless of antimicrobial susceptibility. The present work extends previous knowledge regarding susceptibility to antimicrobial agents, resistance mechanisms, and clonality of Ureaplasma species in the United States. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Murine glomerulotropic monoclonal antibodies are highly oligoclonal and exhibit distinctive molecular features.

PubMed

Lefkowith, J B; Di Valerio, R; Norris, J; Glick, G D; Alexander, A L; Jackson, L; Gilkeson, G S

1996-08-01

We recently produced a panel of seven glomerular-binding mAbs from a nephritic MRL-lpr mouse that bind to histones/nucleosomes (group I) or DNA (group II) adherent to glomerular basement membrane. To elucidate the molecular basis of their binding and ontogeny, we sequenced their variable (V) regions, analyzed the apparent somatic mutations, and predicted their three-dimensional structures. There were two clonally related sets (3 of 4 in group I, 3 of 3 in group II) both of the VHJ1558 family, and one mAb of the VH 7183 family. V region somatic mutations within clonally related sets had little effect on glomerular binding and did not appear to be selected for based on glomerular binding. The VH regions were most homologous with those from autoantibodies to histones, DNA, or IgG (i.e., rheumatoid factors), the Vkappa regions, with those from autoantibodies to small nuclear ribonucleoproteins (snRNP). The VH regions also exhibited an unusual VD junction (in the group I clonally related set) and an overall high content of charged amino acids (arginine, aspartic acid) in complementarity-determining regions (CDRs), particularly in CDR3. Molecular modeling studies suggested that the Fv regions of these mAbs converge to form a flat, open surface with a net positive charge. The CDR arginines in group I mAbs; appear to be located in Ag contact regions of the binding cleft. In sum, these data suggest that glomerulotropic mAbs are a highly restricted set of Abs with distinctive molecular features that may mediate their binding to glomeruli.

Clonal diversity and detection of carbapenem resistance encoding genes among multidrug-resistant Acinetobacter baumannii isolates recovered from patients and environment in two intensive care units in a Moroccan hospital.

PubMed

Uwingabiye, Jean; Lemnouer, Abdelhay; Roca, Ignasi; Alouane, Tarek; Frikh, Mohammed; Belefquih, Bouchra; Bssaibis, Fatna; Maleb, Adil; Benlahlou, Yassine; Kassouati, Jalal; Doghmi, Nawfal; Bait, Abdelouahed; Haimeur, Charki; Louzi, Lhoussain; Ibrahimi, Azeddine; Vila, Jordi; Elouennass, Mostafa

2017-01-01

Carbapenem-resistant Acinetobacter baumannii has recently been defined by the World Health Organization as a critical pathogen. The aim of this study was to compare clonal diversity and carbapenemase-encoding genes of A. baumannii isolates collected from colonized or infected patients and hospital environment in two intensive care units (ICUs) in Morocco. The patient and environmental sampling was carried out in the medical and surgical ICUs of Mohammed V Military teaching hospital from March to August 2015. All A. baumannii isolates recovered from clinical and environmental samples, were identified using routine microbiological techniques and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Antimicrobial susceptibility testing was performed using disc diffusion method. The carbapenemase-encoding genes were screened for by PCR. Clonal relatedness was analyzed by digestion of the DNA with low frequency restriction enzymes and pulsed field gel electrophoresis (PFGE) and the multi locus sequence typing (MLST) was performed on two selected isolates from two major pulsotypes. A total of 83 multidrug-resistant A. baumannii isolates were collected: 47 clinical isolates and 36 environmental isolates. All isolates were positive for the bla OXA51-like and bla OXA23-like genes. The coexistence of bla NDM-1 /bla OXA-23-like and bla OXA 24-like /bla OXA-23-like were detected in 27 (32.5%) and 2 (2.4%) of A. baumannii isolates, respectively. The environmental samples and the fecally-colonized patients were significantly identified ( p  < 0.05) as the most common sites of isolation of NDM-1-harboring isolates. PFGE grouped all isolates into 9 distinct clusters with two major groups (0007 and 0008) containing up to 59% of the isolates. The pulsotype 0008 corresponds to sequence type (ST) 195 while pulsotype 0007 corresponds to ST 1089.The genetic similarity between the clinical and environmental isolates was observed in 80/83 = 96.4% of all isolates, belonging to 7 pulsotypes. This study shows that the clonal spread of environmental A. baumannii isolates is related to that of clinical isolates recovered from colonized or infected patients, being both associated with a high prevalence of the bla OXA23-like and bla NDM-1 genes. These findings emphasize the need for prioritizing the bio-cleaning of the hospital environment to control and prevent the dissemination of A. baumannii clonal lineages.

Revisiting negative selection algorithms.

PubMed

Ji, Zhou; Dasgupta, Dipankar

2007-01-01

This paper reviews the progress of negative selection algorithms, an anomaly/change detection approach in Artificial Immune Systems (AIS). Following its initial model, we try to identify the fundamental characteristics of this family of algorithms and summarize their diversities. There exist various elements in this method, including data representation, coverage estimate, affinity measure, and matching rules, which are discussed for different variations. The various negative selection algorithms are categorized by different criteria as well. The relationship and possible combinations with other AIS or other machine learning methods are discussed. Prospective development and applicability of negative selection algorithms and their influence on related areas are then speculated based on the discussion.

An avirulent Micropterus salmoides rhabdovirus vaccine candidate protects Chinese perch against rhabdovirus infection.

PubMed

Lijuan, Zhang; Ningqiu, Li; Qiang, Lin; Lihui, Liu; Hongru, Liang; Zhibin, Huang; Xiaozhe, Fu

2018-06-01

In order to develop live vaccine against Siniperca chuatsi rhabdovirus (SCRV) disease, an avirulent virus strain, designed as Micropterus salmoides rhabdovirus Sanshui (MSRV-SS), was selected from six fish rhabdovirus isolates (SCRV-QY、SCRV-SS、SCRV-GM、CMRV-FS、OMBRV-JM、MSRV-SS) by fish challenge assay. When Chinese perch (Siniperca chuatsi) were intraperitoneally injected live virus strain MSRV-SS, they were completely protected from virulent SCRV-GM challenge with a relative percent survival (RPS) of 100% on 18th day post vaccination. Then, the wild type MSRV-SS was purified by plaque clone assays, and the biological characteristics of the clonal strain designed as MSRV-SS-7 were investigated. The MSRV-SS-7 was avirulent to Chinese perch and its growth characteristic was similar to the MSRV-SS. The immune protection effects of clonal MSRV-SS-7 against virulent SCRV-GM were evaluated by intraperitoneal injection (IP) vaccination and immersion (IM) vaccination, their RPSs were all 100%. Altogether, these results indicate that MSRV-SS-7 is a potential live vaccine candidate against SCRV disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Changes of heterogeneous cell populations in the Ishikawa cell line during long-term culture: Proposal for an in vitro clonal evolution model of tumor cells.

PubMed

Kasai, Fumio; Hirayama, Noriko; Ozawa, Midori; Iemura, Masashi; Kohara, Arihiro

2016-06-01

Genomic changes in tumor cell lines can occur during culture, leading to differences between cell lines carrying the same name. In this study, genome profiles between low and high passages were investigated in the Ishikawa 3-H-12 cell line (JCRB1505). Cells contained between 43 and 46 chromosomes and the modal number changed from 46 to 45 during culture. Cytogenetic analysis revealed that a translocation t(9;14), observed in all metaphases, is a robust marker for this cell line. Single-nucleotide polymorphism microarrays showed a heterogeneous copy number in the early passages and distinct profiles at late passages. These results demonstrate that cell culture can lead to elimination of ancestral clones by sequential selection, resulting in extensive replacement with a novel clone. Our observations on Ishikawa cells in vitro are different from the in vivo heterogeneity in which ancestral clones are often retained during tumor evolution and suggest a model for in vitro clonal evolution. Copyright © 2016 Elsevier Inc. All rights reserved.

Dissimilar Fitness Associated with Resistance to Fluoroquinolones Influences Clonal Dynamics of Various Multiresistant Bacteria

PubMed Central

Fuzi, Miklos

2016-01-01

Fitness cost associated with resistance to fluoroquinolones was recently shown to vary across clones of methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing Klebsiella pneumoniae. The resulting dissimilar fitness should have influenced the clonal dynamics and thereby the rates of resistance for these pathogens. Moreover, a similar mechanism was recently proposed for the emergence of the H30 and H30R lineages of ESBL-producing E. coli and the major international clone (ribotype 027) of Clostridium difficile. Furthermore, several additional international clones of various multiresistant bacteria are suspect to have been selected by an analogous process. An ability to develop favorable mutations in the gyrase and topoisomerase IV genes seems to be a prerequisite for pathogens to retain fitness while showing high-level resistance to fluoroquinolones. Since, the consumption of other “non-fluoroquinolone” groups of antibiotics have also contributed to the rise in resistance rates a more judicious use of antibiotics in general and of fluoroquinolones in particular could ameliorate the international resistance situation. PMID:27458434

Detection of clonal evolution in hematopoietic malignancies by combining comparative genomic hybridization and single nucleotide polymorphism arrays.

PubMed

Hartmann, Luise; Stephenson, Christine F; Verkamp, Stephanie R; Johnson, Krystal R; Burnworth, Bettina; Hammock, Kelle; Brodersen, Lisa Eidenschink; de Baca, Monica E; Wells, Denise A; Loken, Michael R; Zehentner, Barbara K

2014-12-01

Array comparative genomic hybridization (aCGH) has become a powerful tool for analyzing hematopoietic neoplasms and identifying genome-wide copy number changes in a single assay. aCGH also has superior resolution compared with fluorescence in situ hybridization (FISH) or conventional cytogenetics. Integration of single nucleotide polymorphism (SNP) probes with microarray analysis allows additional identification of acquired uniparental disomy, a copy neutral aberration with known potential to contribute to tumor pathogenesis. However, a limitation of microarray analysis has been the inability to detect clonal heterogeneity in a sample. This study comprised 16 samples (acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, plasma cell neoplasm) with complex cytogenetic features and evidence of clonal evolution. We used an integrated manual peak reassignment approach combining analysis of aCGH and SNP microarray data for characterization of subclonal abnormalities. We compared array findings with results obtained from conventional cytogenetic and FISH studies. Clonal heterogeneity was detected in 13 of 16 samples by microarray on the basis of log2 values. Use of the manual peak reassignment analysis approach improved resolution of the sample's clonal composition and genetic heterogeneity in 10 of 13 (77%) patients. Moreover, in 3 patients, clonal disease progression was revealed by array analysis that was not evident by cytogenetic or FISH studies. Genetic abnormalities originating from separate clonal subpopulations can be identified and further characterized by combining aCGH and SNP hybridization results from 1 integrated microarray chip by use of the manual peak reassignment technique. Its clinical utility in comparison to conventional cytogenetic or FISH studies is demonstrated. © 2014 American Association for Clinical Chemistry.

Facilitation of amphibious habit by physiological integration in the clonal, perennial, climbing herb Ipomoea aquatica.

PubMed

Lin, Hui-Feng; Alpert, Peter; Zhang, Qian; Yu, Fei-Hai

2018-03-15

Physiological integration of connected ramets of clonal plants can increase clonal performance when ramets grow in contrasting microenvironments within a habitat. In amphibious clonal species, integration of ramets in different habitats, terrestrial and aquatic, is possible. This may increase performance of amphibious clones, especially under eutrophic conditions. To test this, clonal fragments consisting of two ramets of the amphibious, perennial, climbing herb Ipomoea aquatica connected by a stem were placed such that the proximal ramet was rooted in a simulated riparian community of four other species, while the distal ramet extended into a simulated aquatic habitat with open water and sediment. The connection between ramets was either left intact or severed, and 0, 5, or 25mg N L -1 was added to the aquatic habitat to simulate different degrees of eutrophication. Without added N, fragments in which the original ramets were left connected accumulated two times more total mass than fragments in which the ramets were disconnected from one another. The positive effect of connection increased two-fold with increasing N. These results were consistent with the hypotheses that physiological integration between connected terrestrial and aquatic ramets can increase clonal performance in plants and that this effect can be greater when the aquatic ramet is richer in nutrients. Connection reduced root to shoot ratio in terrestrial ramets, but increased it in aquatic ones, suggesting that physiological integration induced a division of labor in which terrestrial ramets specialized for light acquisition and aquatic ramets specialized for acquisition of nutrients. This provides the first report of increase in clonal performance and induction of division of labor due to physiological integration between ramets in different habitats. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Cu Pollution on the Expansion of an Amphibious Clonal Herb in Aquatic-Terrestrial Ecotones.

PubMed

Xu, Liang; Zhou, Zhen-Feng

2016-01-01

Physiological integration can enhance the performance of clonal plants in aquatic and terrestrial heterogeneous habitats and associated ecotones. Similar to nutrients, pollutants may be transported among connected ramets via physiological integration. Few studies have examined the expansion of amphibious clonal plants from terrestrial to aquatic environments, particularly when the local water supply is polluted with heavy metals. A greenhouse experiment was conducted using the amphibious plant Alternanthera philoxeroides to determine whether Cu can spread among clonal plants and examine the corresponding effects of this pollution on the expansion of clonal plants in aquatic-terrestrial ecotones. Ramets from the same clonal fragments were rooted in unpolluted soil and polluted water at five different levels. The responses of the ramets in terrestrial and aquatic habitats were quantified via traits associated with growth, morphology and Cu accumulation. The results indicated that ramets in soil and water significantly differed in nearly all of these traits. The expansion of populations from terrestrial to polluted aquatic habitats was facilitated by stem elongation rather than new ramet production. The accumulated Cu in polluted ramets can be horizontally transported to other ramets in soil via connected stolons. In terms of clonal growth patterns, variations in Cu pollution intensity were negatively correlated with variations in the morphological and growth traits of ramets in polluted aquatic habitats and unpolluted soil. We concluded that Cu ions are distributed among the clones and accumulated in different ramet tissues in heterogeneous habitats. Therefore, we suggest that Cu pollution of aquatic-terrestrial ecotones, especially at high levels, can affect the growth and expansion of the whole clones because Cu ions are shared between integrated ramets.

Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life.

PubMed

Acuna-Hidalgo, Rocio; Sengul, Hilal; Steehouwer, Marloes; van de Vorst, Maartje; Vermeulen, Sita H; Kiemeney, Lambertus A L M; Veltman, Joris A; Gilissen, Christian; Hoischen, Alexander

2017-07-06

Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

The human urothelium consists of multiple clonal units, each maintained by a stem cell.

PubMed

Gaisa, Nadine T; Graham, Trevor A; McDonald, Stuart A C; Cañadillas-Lopez, Sagrario; Poulsom, Richard; Heidenreich, Axel; Jakse, Gerhard; Tadrous, Paul J; Knuechel, Ruth; Wright, Nicholas A

2011-10-01

Little is known about the clonal architecture of human urothelium. It is likely that urothelial stem cells reside within the basal epithelial layer, yet lineage tracing from a single stem cell as a means to show the presence of a urothelial stem cell has never been performed. Here, we identify clonally related cell areas within human bladder mucosa in order to visualize epithelial fields maintained by a single founder/stem cell. Sixteen frozen cystectomy specimens were serially sectioned. Patches of cells deficient for the mitochondrially encoded enzyme cytochrome c oxidase (CCO) were identified using dual-colour enzyme histochemistry. To show that these patches represent clonal proliferations, small CCO-proficient and -deficient areas were individually laser-capture microdissected and the entire mitochondrial genome (mtDNA) in each area was PCR amplified and sequenced to identify mtDNA mutations. Immunohistochemistry was performed for the different cell layers of the urothelium and adjacent mesenchyme. CCO-deficient patches could be observed in normal urothelium of all cystectomy specimens. The two-dimensional length of these negative patches varied from 2-3 cells (about 30 µm) to 4.7 mm. Each cell area within a CCO-deficient patch contained an identical somatic mtDNA mutation, indicating that the patch was a clonal unit. Patches contained all the mature cell differentiation stages present in the urothelium, suggesting the presence of a stem cell. Our results demonstrate that the normal mucosa of human bladder contains stem cell-derived clonal units that actively replenish the urothelium during ageing. The size of the clonal unit attributable to each stem cell was broadly distributed, suggesting replacement of one stem cell clone by another. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genet-specific DNA methylation probabilities detected in a spatial epigenetic analysis of a clonal plant population.

PubMed

Araki, Kiwako S; Kubo, Takuya; Kudoh, Hiroshi

2017-01-01

In sessile organisms such as plants, spatial genetic structures of populations show long-lasting patterns. These structures have been analyzed across diverse taxa to understand the processes that determine the genetic makeup of organismal populations. For many sessile organisms that mainly propagate via clonal spread, epigenetic status can vary between clonal individuals in the absence of genetic changes. However, fewer previous studies have explored the epigenetic properties in comparison to the genetic properties of natural plant populations. Here, we report the simultaneous evaluation of the spatial structure of genetic and epigenetic variation in a natural population of the clonal plant Cardamine leucantha. We applied a hierarchical Bayesian model to evaluate the effects of membership of a genet (a group of individuals clonally derived from a single seed) and vegetation cover on the epigenetic variation between ramets (clonal plants that are physiologically independent individuals). We sampled 332 ramets in a 20 m × 20 m study plot that contained 137 genets (identified using eight SSR markers). We detected epigenetic variation in DNA methylation at 24 methylation-sensitive amplified fragment length polymorphism (MS-AFLP) loci. There were significant genet effects at all 24 MS-AFLP loci in the distribution of subepiloci. Vegetation cover had no statistically significant effect on variation in the majority of MS-AFLP loci. The spatial aggregation of epigenetic variation is therefore largely explained by the aggregation of ramets that belong to the same genets. By applying hierarchical Bayesian analyses, we successfully identified a number of genet-specific changes in epigenetic status within a natural plant population in a complex context, where genotypes and environmental factors are unevenly distributed. This finding suggests that it requires further studies on the spatial epigenetic structure of natural populations of diverse organisms, particularly for sessile clonal species.

Effects of Cu Pollution on the Expansion of an Amphibious Clonal Herb in Aquatic-Terrestrial Ecotones

PubMed Central

Zhou, Zhen-Feng

2016-01-01

Physiological integration can enhance the performance of clonal plants in aquatic and terrestrial heterogeneous habitats and associated ecotones. Similar to nutrients, pollutants may be transported among connected ramets via physiological integration. Few studies have examined the expansion of amphibious clonal plants from terrestrial to aquatic environments, particularly when the local water supply is polluted with heavy metals. A greenhouse experiment was conducted using the amphibious plant Alternanthera philoxeroides to determine whether Cu can spread among clonal plants and examine the corresponding effects of this pollution on the expansion of clonal plants in aquatic-terrestrial ecotones. Ramets from the same clonal fragments were rooted in unpolluted soil and polluted water at five different levels. The responses of the ramets in terrestrial and aquatic habitats were quantified via traits associated with growth, morphology and Cu accumulation. The results indicated that ramets in soil and water significantly differed in nearly all of these traits. The expansion of populations from terrestrial to polluted aquatic habitats was facilitated by stem elongation rather than new ramet production. The accumulated Cu in polluted ramets can be horizontally transported to other ramets in soil via connected stolons. In terms of clonal growth patterns, variations in Cu pollution intensity were negatively correlated with variations in the morphological and growth traits of ramets in polluted aquatic habitats and unpolluted soil. We concluded that Cu ions are distributed among the clones and accumulated in different ramet tissues in heterogeneous habitats. Therefore, we suggest that Cu pollution of aquatic-terrestrial ecotones, especially at high levels, can affect the growth and expansion of the whole clones because Cu ions are shared between integrated ramets. PMID:27736932

De Novo Chromosome Copy Number Variation in Fanconi Anemia-Associated Hematopoietic Defects

DTIC Science & Technology

2012-04-01

Appendix 1. Expansion of monoclonal populations of FA-A hTERT and FA-A + FANCA hTERT cells Appendix 2. Expansion of monoclonal populations of FA...marrow failure (BMF) and pronounced cancer susceptibility. The FA proteins and the major breast cancer susceptibility gene products BRCA1 and BRCA2...Correction of FA-A, FA-C, and FA-D2 hTERT cells with pLenti6.2/V5- FANCA , -FANCC, and FANCD2, respectively. Sub-task 1. Selection and expansion of clonal

Examining applying high performance genetic data feature selection and classification algorithms for colon cancer diagnosis.

PubMed

Al-Rajab, Murad; Lu, Joan; Xu, Qiang

2017-07-01

This paper examines the accuracy and efficiency (time complexity) of high performance genetic data feature selection and classification algorithms for colon cancer diagnosis. The need for this research derives from the urgent and increasing need for accurate and efficient algorithms. Colon cancer is a leading cause of death worldwide, hence it is vitally important for the cancer tissues to be expertly identified and classified in a rapid and timely manner, to assure both a fast detection of the disease and to expedite the drug discovery process. In this research, a three-phase approach was proposed and implemented: Phases One and Two examined the feature selection algorithms and classification algorithms employed separately, and Phase Three examined the performance of the combination of these. It was found from Phase One that the Particle Swarm Optimization (PSO) algorithm performed best with the colon dataset as a feature selection (29 genes selected) and from Phase Two that the Support Vector Machine (SVM) algorithm outperformed other classifications, with an accuracy of almost 86%. It was also found from Phase Three that the combined use of PSO and SVM surpassed other algorithms in accuracy and performance, and was faster in terms of time analysis (94%). It is concluded that applying feature selection algorithms prior to classification algorithms results in better accuracy than when the latter are applied alone. This conclusion is important and significant to industry and society. Copyright © 2017 Elsevier B.V. All rights reserved.

SamSelect: a sample sequence selection algorithm for quorum planted motif search on large DNA datasets.

PubMed

Yu, Qiang; Wei, Dingbang; Huo, Hongwei

2018-06-18

Given a set of t n-length DNA sequences, q satisfying 0 < q ≤ 1, and l and d satisfying 0 ≤ d < l < n, the quorum planted motif search (qPMS) finds l-length strings that occur in at least qt input sequences with up to d mismatches and is mainly used to locate transcription factor binding sites in DNA sequences. Existing qPMS algorithms have been able to efficiently process small standard datasets (e.g., t = 20 and n = 600), but they are too time consuming to process large DNA datasets, such as ChIP-seq datasets that contain thousands of sequences or more. We analyze the effects of t and q on the time performance of qPMS algorithms and find that a large t or a small q causes a longer computation time. Based on this information, we improve the time performance of existing qPMS algorithms by selecting a sample sequence set D' with a small t and a large q from the large input dataset D and then executing qPMS algorithms on D'. A sample sequence selection algorithm named SamSelect is proposed. The experimental results on both simulated and real data show (1) that SamSelect can select D' efficiently and (2) that the qPMS algorithms executed on D' can find implanted or real motifs in a significantly shorter time than when executed on D. We improve the ability of existing qPMS algorithms to process large DNA datasets from the perspective of selecting high-quality sample sequence sets so that the qPMS algorithms can find motifs in a short time in the selected sample sequence set D', rather than take an unfeasibly long time to search the original sequence set D. Our motif discovery method is an approximate algorithm.

Genomic analyses of dominant U.S. clonal lineages of Phytophthora infestans reveals a shared common ancestry for clonal lineages US11 and US18 and a lack of recently shared ancestry among all other U.S. lineages

USDA-ARS?s Scientific Manuscript database

The populations of the potato and tomato late blight pathogen, Phytophthora infestans, in the US are well known for emerging repeatedly as novel clonal lineages. These successions of dominant clones have historically been named US1-US24, in order of appearance, since their first characterization usi...

Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma.

PubMed

Kim, Tae-Min; An, Chang Hyeok; Rhee, Je-Keun; Jung, Seung-Hyun; Lee, Sung Hak; Baek, In-Pyo; Kim, Min Sung; Lee, Sug Hyung; Chung, Yeun-Jun

2015-09-29

Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model, the evolution of the mutational landscape underlying this model is not fully understood. In this study, we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas, four microsatellite-unstable (MSU) and four-stable (MSS) pairs, using whole-exome sequencing. In the MSU adenoma-carcinoma pairs, we observed no subclonal mutations in adenomas that became fixed in paired carcinomas, suggesting a 'parallel' evolution of synchronous adenoma-to-carcinoma, rather than a 'stepwise' evolution. The abundance of indel (in MSU and MSS pairs) and microsatellite instability (in MSU pairs) was noted in the later adenoma- or carcinoma-specific mutations, indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different. All MSU cases exhibited clonal, truncating mutations in ACVR2A, TGFBR2, and DNA mismatch repair genes, but none were present in APC or KRAS. In three MSS pairs, both APC and KRAS mutations were identified as both early and clonal events, often accompanying clonal copy number changes. An MSS case uniquely exhibited clonal ERBB2 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent.

[Lymphocytic Clonal Expansion in Adult Patients with Epstein-Barr Virus-Associated Lymphoproliferative Disease].

PubMed

Zhong, Feng-Luan; Zhang, Hong-Yu; Zhang, Qian; Feng, Jia; Zhang, Wen-Li; Xu, Lei; Xu, Hai-Chan; Wen, Juan-Juan; Meng, Qing-Xiang

2017-12-01

To explore the lymphocytic clonal expansion in adult patients with Epstein-Barr virus-associated lymphoproliferative diseases (EBV+LPD), and to investigate the experimental methods for EBV+LPD cells so as to provide a more objective measure for the diagnosis, classification and prognosis in the early stage of this disease. Peripheral blood samples from 5 patients with EBV+LPD, 4 patients with adult infectious mononucleosis(IM) as negative control and 3 patients with acute NK-cell leukemia(ANKL) as positive control were collected. Prior to immunochemotherapy, viral loads and clonality were analysed by flow cytometry (FCM), T cell receptor gene rearrangement (TCR) was detected by real-time polymerase chain reaction (RT-PCR), and diversity of EB virus terminal repeat (EBV-TR) was detected by Southern blot. FCM showed only 1 case with clonal TCRVβ in 5 patients with EBV+LPD, TCR clonal expansion could be detected both in patients with IM(4 of 4) and 4 patients with EBV+LPD(4 of 5), Out of patients with EBV+LPD, 1 patient displayed a monoclonal band and 2 patients showed oligoclonal bands when detecting EBV-TR by southen blot. Detecting the diversity of EBV-TR by Southern blot may be the most objective way to reflex clonal transformation of EBV+LPD, which is of great benefit to the diagnosis, classification and prognosis in the early stage of this disease.

Emergence of Clonal Hematopoiesis in the Majority of Patients with Acquired Aplastic Anemia

PubMed Central

Babushok, Daria V.; Perdigones, Nieves; Perin, Juan C.; Olson, Timothy S.; Ye, Wenda; Roth, Jacquelyn J.; Lind, Curt; Cattier, Carine; Li, Yimei; Hartung, Helge; Paessler, Michele E.; Frank, Dale M.; Xie, Hongbo M.; Cross, Shanna; Cockroft, Joshua D.; Podsakoff, Gregory M.; Monos, Dimitrios; Biegel, Jaclyn A.; Mason, Philip J.; Bessler, Monica

2015-01-01

Acquired aplastic anemia (aAA) is a non-malignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20–25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin in 22 patients. We found somatic mutations in sixteen patients (72.7%) with a median disease duration of 1 year; twelve (66.7%) were patients with pediatriconset aAA. Fifty-eight mutations in 51 unique genes were primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with 7 mutations. Only two mutations were in genes recurrently-mutated in MDS. Two patients had oligoclonal loss of HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B(p.N642H), CAMK2G(p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging― immune escape and increased proliferation. Our findings expand conceptual understanding of this non-neoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes, and for designing personalized treatment strategies. PMID:25800665

Aldosterone induces clonal β-cell failure through glucocorticoid receptor

PubMed Central

Chen, Fang; Liu, Jia; Wang, Yanyang; Wu, Tijun; Shan, Wei; Zhu, Yunxia; Han, Xiao

2015-01-01

Aldosterone excess causes insulin resistance in peripheral tissues and directly impairs the function of clonal β-cell. The aim of this study was to investigate the molecular mechanisms involved in the aldosterone-induced impairment of clonal β-cells. As expected, aldosterone induced apoptosis and β-cell dysfunction, including impairment of insulin synthesis and secretion, which were reversed by Glucocorticoid receptor (GR) antagonists or GR-specific siRNA. However, mineralocorticoid receptor (MR) antagonists or MR-specific siRNA had no effect on impairment of clonal β-cells induced by aldosterone. Besides, aldosterone significantly decreased expression and activity of MafA, while activated JNK and p38 MAPK in a GR-dependent manner. In addition, JNK inhibitors (SP600125) and/or p38 inhibitors (SB203580) could abolish the effect of aldosterone on MafA expression and activity. Importantly, overexpression of JNK1 or p38 reversed the protective effect of a GR antagonist on the decrease of MafA expression and activity. Furthermore, aldosterone inhibits MafA expression at the transcriptional and post-transcriptional level through activation of JNK and p38, respectively. Consequently, overexpression of MafA increased synthesis and secretion of insulin, and decreased apoptosis in clonal β-cells exposed to aldosterone. These findings identified aldosterone as an inducer of clonal β-cell failure that operates through the GR-MAPK-MafA signaling pathway. PMID:26287126

A Longitudinal 6-Year Study of the Molecular Epidemiology of Clinical Campylobacter Isolates in Oxfordshire, United Kingdom

PubMed Central

McCarthy, Noel M.; Wimalarathna, Helen L.; Colles, Frances M.; Clark, Lorraine; Bowler, Ian C. J. W.; Maiden, Martin C. J.; Dingle, Kate E.

2012-01-01

Temporal and seasonal trends in Campylobacter genotypes causing human gastroenteritis were investigated in a 6-year study of 3,300 recent isolates from Oxfordshire, United Kingdom. Genotypes (sequence types [ST]) were defined using multilocus sequence typing and assigned to a clonal complex (a cluster of related strains that share four or more identical alleles with a previously defined central genotype). A previously undescribed clonal complex (ST-464) was identified which, together with ST-42, ST-45, and ST-52 complexes, showed increasing incidence. Concurrently, the incidence of ST-574, ST-607, and ST-658 complexes declined. The relative frequencies of three clonal complexes (ST-45, ST-283, and ST-42) peaked during summer and those of two (ST-353 and ST-403) peaked during winter. Nine clonal complexes (ST-22, ST-45, ST-48, ST-61, ST-257, ST-283, ST-403, ST-658, and ST-677) were significantly associated with ciprofloxacin sensitivity (P < 0.05). Seven clonal complexes (ST-49, ST-206, ST-354, ST-446, ST-460, ST-464, and ST-607) were associated with ciprofloxacin resistance (P < 0.05). Clonal complexes exhibited changing incidence and differences in seasonality and antibiotic resistance phenotype. These data also demonstrated that detailed surveillance at a single site captures information which reflects that observed nationally. PMID:22814466

Clonal reproduction in fungi

PubMed Central

Taylor, John W.; Hann-Soden, Christopher; Branco, Sara; Sylvain, Iman; Ellison, Christopher E.

2015-01-01

Research over the past two decades shows that both recombination and clonality are likely to contribute to the reproduction of all fungi. This view of fungi is different from the historical and still commonly held view that a large fraction of fungi are exclusively clonal and that some fungi have been exclusively clonal for hundreds of millions of years. Here, we first will consider how these two historical views have changed. Then we will examine the impact on fungal research of the concept of restrained recombination [Tibayrenc M, Ayala FJ (2012) Proc Natl Acad Sci USA 109 (48):E3305–E3313]. Using animal and human pathogenic fungi, we examine extrinsic restraints on recombination associated with bottlenecks in genetic variation caused by geographic dispersal and extrinsic restraints caused by shifts in reproductive mode associated with either disease transmission or hybridization. Using species of the model yeast Saccharomyces and the model filamentous fungus Neurospora, we examine intrinsic restraints on recombination associated with mating systems that range from strictly clonal at one extreme to fully outbreeding at the other and those that lie between, including selfing and inbreeding. We also consider the effect of nomenclature on perception of reproductive mode and a means of comparing the relative impact of clonality and recombination on fungal populations. Last, we consider a recent hypothesis suggesting that fungi thought to have the most severe intrinsic constraints on recombination actually may have the fewest. PMID:26195774

Concurrent Effects of Sediment Accretion and Nutrient Availability on the Clonal Growth Strategy of Carex brevicuspis-A Wetland Sedge That Produces Both Spreading and Clumping Ramets

PubMed Central

Chen, Xinsheng; Liao, Yulin; Xie, Yonghong; Li, Feng; Deng, Zhengmiao; Hou, Zhiyong; Wu, Chao

2017-01-01

Clonal plants producing both clumping and spreading ramets can adjust their growth forms in response to resource heterogeneity or environmental stress. They might produce clumping ramets to retain favorable patches, or produce spreading ramets to escape from stress-affected patches. This study aimed to investigate the rarely reported concurrent effects of sediment accretion and nutrient enrichment, which often occur simultaneously in lacustrine wetlands, on the vegetative propagation and clonal growth forms of Carex brevicuspis C.B. Clarke by conducting a factorial experiment of sediment burial and nutrient addition. Biomass accumulation, new ramet and rhizome numbers, and ramet length of C. brevicuspis were not affected at moderate burial, but were significantly lower after deep burial. Similarly, nutrient enrichment increased the growth and vegetative propagation of C. brevicuspis up to moderate sediment burial, but not after deep burial. Sediment accretion increased the proportion of spreading ramets produced by C. brevicuspis, whereas nutrient addition had no effect on the clonal growth forms. Our results indicated that the plasticity of clonal growth forms is an effective strategy used by plants to acclimate to moderate sediment accretion. Nutrient enrichment did not influence the clonal growth forms of C. brevicuspis and could not facilitate its acclimation to heavy sedimentation condition. PMID:29021805

Molecular Characteristics of Mantle Cell Lymphoma Presenting with Clonal Plasma Cell Component

PubMed Central

Visco, Carlo; Hoeller, Sylvia; Malik, Jeffrey T.; Xu-Monette, Zijun Y.; Wiggins, Michele L.; Liu, Jessica; Sanger, Warren G.; Liu, Zhongfeng; Chang, Julie; Ranheim, Erik A.; Gradowski, Joel F.; Serrrano, Sergio; Wang, Huan-You; Liu, Qingquan; Dave, Sandeep; Olsen, Brian; Gascoyne, Randy D.; Campo, Elias; Swerdlow, Steven H.; Chan, Wing C.; Tzankov, Alexander; Young, Ken H.

2011-01-01

The normal counterparts of mantle cell lymphoma (MCL) are naïve quiescent B-cells that have not been processed through the germinal center (GC). For this reason, while lymphomas arising from GC or post-GC B-cells often exhibit plasmacytic differentiation, MCL rarely presents with plasmacytic features. Seven cases of MCL with a monotypic plasma cell (PC) population were collected from six centers and studied by immunohistochemistry, FICTION (Fluorescence immunophenotyping and Interphase Cytogenetics as a Tool for the Investigation of Neoplasms), capillary gel electrophoresis, and restriction fragment length polymorphism of immunoglobulin heavy chain analysis (RFLP/IgH) of microdissections of each of the MCL and PC populations to assess their clonal relationship. Clinical presentation was rather unusual compared to typical MCL, with two cases arising from extranodal soft-tissues of the head. All MCL cases were morphologically and immunohistochemically typical, bearing the t(11;14)(q13;q32). In all cases PC populations were clonal. In 5 of the 7 cases, the MCL and PC clones showed identical restriction fragments, indicating a common clonal origin of the neoplastic populations. The two cases with clonal diversity denoted the coexistence of two different tumors in a composite lymphoma/plasma cell neoplasm. Our findings suggest that MCL can present with a PC component that is often clonally related to the lymphoma, representing a rare but unique biological variant of this tumor. PMID:21263238

ICUS/CCUS/CHIP: basics & beyond.

PubMed

Jain, Mili; Tripathi, Anil

2017-10-01

Patients presenting with idiopathic cytopenia with non-diagnostic marrow morphology and a normal karyotype pose a diagnostic and therapeutic challenge. Additional diagnostic information from mutation analysis could provide important clinical insights. However, one has to be cautious during such diagnostic interpretations in view of the recent documentation of clonal somatic mutations in healthy elder individuals. Whether to regard clonality synonymous with malignant proliferation or a manifestation of ageing process is to be judged carefully. Areas covered: The review covers defining criteria and diagnostic work up for Idiopathic cytopenia of undetermined significance (ICUS), Clonal cytopenia of undetermined significance (CCUS), Clonal hematopoiesis of indeterminate potential (CHIP). It also presents the results from previous reports on this subject. In addition the evolution and potential impact of these entities is discussed. Expert commentary: Current evidence does not support the use of somatic mutations as presumptive evidence of myelodysplastic syndrome (MDS). Including CCUS under the category of MDS requires further insight on natural disease course. Longitudinal follow up study on ICUS, CCUS, CHIP may eventually identify the pathological significance of the clonal mutations. An absence of mutation however may still be useful as good predictor of not having MDS.

Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

PubMed Central

Niederer, Heather A.; Bangham, Charles R. M.

2014-01-01

Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety. PMID:25365582

Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential in HLA-Matched and -Mismatched Donor-Recipient Pairs.

PubMed

Abdul Razzaq, Badar; Scalora, Allison; Koparde, Vishal N; Meier, Jeremy; Mahmood, Musa; Salman, Salman; Jameson-Lee, Max; Serrano, Myrna G; Sheth, Nihar; Voelkner, Mark; Kobulnicky, David J; Roberts, Catherine H; Ferreira-Gonzalez, Andrea; Manjili, Masoud H; Buck, Gregory A; Neale, Michael C; Toor, Amir A

2016-05-01

Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA-matched SCT donor-recipient pairs (DRPs) and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance with the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady-state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire, including sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity, and alteration of clonal dominance when a different antigen array is encountered, such as in SCT. The simulated, alloreactive T cell repertoire was markedly different in HLA-matched DRPs. The patterns were differentiated by rate of growth and steady-state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRPs may allow simulation of donor alloreactive T cell response to recipient antigens and may provide a quantitative basis for refining donor selection and titration of immunosuppression after SCT. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Temporal Changes in BEXSERO® Antigen Sequence Type Associated with Genetic Lineages of Neisseria meningitidis over a 15-Year Period in Western Australia

PubMed Central

Mowlaboccus, Shakeel; Perkins, Timothy T.; Smith, Helen; Sloots, Theo; Tozer, Sarah; Prempeh, Lydia-Jessica; Tay, Chin Yen; Peters, Fanny; Speers, David; Keil, Anthony D.; Kahler, Charlene M.

2016-01-01

Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD). The BEXSERO® vaccine which is used to prevent serogroup B disease is composed of four sub-capsular protein antigens supplemented with an outer membrane vesicle. Since the sub-capsular protein antigens are variably expressed and antigenically variable amongst meningococcal isolates, vaccine coverage can be estimated by the meningococcal antigen typing system (MATS) which measures the propensity of the strain to be killed by vaccinated sera. Whole genome sequencing (WGS) which identifies the alleles of the antigens that may be recognised by the antibody response could represent, in future, an alternative estimate of coverage. In this study, WGS of 278 meningococcal isolates responsible for 62% of IMD in Western Australia from 2000–2014 were analysed for association of genetic lineage (sequence type [ST], clonal complex [cc]) with BEXSERO® antigen sequence type (BAST) and MATS to predict the annual vaccine coverage. A hyper-endemic period of IMD between 2000–05 was caused by cc41/44 with the major sequence type of ST-146 which was not predicted by MATS or BAST to be covered by the vaccine. An increase in serogroup diversity was observed between 2010–14 with the emergence of cc11 serogroup W in the adolescent population and cc23 serogroup Y in the elderly. BASTs were statistically associated with clonal complex although individual antigens underwent antigenic drift from the major type. BAST and MATS predicted an annual range of 44–91% vaccine coverage. Periods of low vaccine coverage in years post-2005 were not a result of the resurgence of cc41/44:ST-146 but were characterised by increased diversity of clonal complexes expressing BASTs which were not predicted by MATS to be covered by the vaccine. The driving force behind the diversity of the clonal complex and BAST during these periods of low vaccine coverage is unknown, but could be due to immune selection and inter-strain competition with carriage of non-disease causing meningococci. PMID:27355628

Fast object detection algorithm based on HOG and CNN

NASA Astrophysics Data System (ADS)

Lu, Tongwei; Wang, Dandan; Zhang, Yanduo

2018-04-01

In the field of computer vision, object classification and object detection are widely used in many fields. The traditional object detection have two main problems:one is that sliding window of the regional selection strategy is high time complexity and have window redundancy. And the other one is that Robustness of the feature is not well. In order to solve those problems, Regional Proposal Network (RPN) is used to select candidate regions instead of selective search algorithm. Compared with traditional algorithms and selective search algorithms, RPN has higher efficiency and accuracy. We combine HOG feature and convolution neural network (CNN) to extract features. And we use SVM to classify. For TorontoNet, our algorithm's mAP is 1.6 percentage points higher. For OxfordNet, our algorithm's mAP is 1.3 percentage higher.

Novel and efficient tag SNPs selection algorithms.

PubMed

Chen, Wen-Pei; Hung, Che-Lun; Tsai, Suh-Jen Jane; Lin, Yaw-Ling

2014-01-01

SNPs are the most abundant forms of genetic variations amongst species; the association studies between complex diseases and SNPs or haplotypes have received great attention. However, these studies are restricted by the cost of genotyping all SNPs; thus, it is necessary to find smaller subsets, or tag SNPs, representing the rest of the SNPs. In fact, the existing tag SNP selection algorithms are notoriously time-consuming. An efficient algorithm for tag SNP selection was presented, which was applied to analyze the HapMap YRI data. The experimental results show that the proposed algorithm can achieve better performance than the existing tag SNP selection algorithms; in most cases, this proposed algorithm is at least ten times faster than the existing methods. In many cases, when the redundant ratio of the block is high, the proposed algorithm can even be thousands times faster than the previously known methods. Tools and web services for haplotype block analysis integrated by hadoop MapReduce framework are also developed using the proposed algorithm as computation kernels.

Collective Functionality through Bacterial Individuality

NASA Astrophysics Data System (ADS)

Ackermann, Martin

According to the conventional view, the properties of an organism are a product of nature and nurture - of its genes and the environment it lives in. Recent experiments with unicellular organisms have challenged this view: several molecular mechanisms generate phenotypic variation independently of environmental signals, leading to variation in clonal groups. My presentation will focus on the causes and consequences of this microbial individuality. Using examples from bacterial genetic model systems, I will first discuss different molecular and cellular mechanisms that give rise to bacterial individuality. Then, I will discuss the consequences of individuality, and focus on how phenotypic variation in clonal populations of bacteria can promote interactions between individuals, lead to the division of labor, and allow clonal groups of bacteria to cope with environmental uncertainty. Variation between individuals thus provides clonal groups with collective functionality.

Genetic Particle Swarm Optimization–Based Feature Selection for Very-High-Resolution Remotely Sensed Imagery Object Change Detection

PubMed Central

Chen, Qiang; Chen, Yunhao; Jiang, Weiguo

2016-01-01

In the field of multiple features Object-Based Change Detection (OBCD) for very-high-resolution remotely sensed images, image objects have abundant features and feature selection affects the precision and efficiency of OBCD. Through object-based image analysis, this paper proposes a Genetic Particle Swarm Optimization (GPSO)-based feature selection algorithm to solve the optimization problem of feature selection in multiple features OBCD. We select the Ratio of Mean to Variance (RMV) as the fitness function of GPSO, and apply the proposed algorithm to the object-based hybrid multivariate alternative detection model. Two experiment cases on Worldview-2/3 images confirm that GPSO can significantly improve the speed of convergence, and effectively avoid the problem of premature convergence, relative to other feature selection algorithms. According to the accuracy evaluation of OBCD, GPSO is superior at overall accuracy (84.17% and 83.59%) and Kappa coefficient (0.6771 and 0.6314) than other algorithms. Moreover, the sensitivity analysis results show that the proposed algorithm is not easily influenced by the initial parameters, but the number of features to be selected and the size of the particle swarm would affect the algorithm. The comparison experiment results reveal that RMV is more suitable than other functions as the fitness function of GPSO-based feature selection algorithm. PMID:27483285

Online selective kernel-based temporal difference learning.

PubMed

Chen, Xingguo; Gao, Yang; Wang, Ruili

2013-12-01

In this paper, an online selective kernel-based temporal difference (OSKTD) learning algorithm is proposed to deal with large scale and/or continuous reinforcement learning problems. OSKTD includes two online procedures: online sparsification and parameter updating for the selective kernel-based value function. A new sparsification method (i.e., a kernel distance-based online sparsification method) is proposed based on selective ensemble learning, which is computationally less complex compared with other sparsification methods. With the proposed sparsification method, the sparsified dictionary of samples is constructed online by checking if a sample needs to be added to the sparsified dictionary. In addition, based on local validity, a selective kernel-based value function is proposed to select the best samples from the sample dictionary for the selective kernel-based value function approximator. The parameters of the selective kernel-based value function are iteratively updated by using the temporal difference (TD) learning algorithm combined with the gradient descent technique. The complexity of the online sparsification procedure in the OSKTD algorithm is O(n). In addition, two typical experiments (Maze and Mountain Car) are used to compare with both traditional and up-to-date O(n) algorithms (GTD, GTD2, and TDC using the kernel-based value function), and the results demonstrate the effectiveness of our proposed algorithm. In the Maze problem, OSKTD converges to an optimal policy and converges faster than both traditional and up-to-date algorithms. In the Mountain Car problem, OSKTD converges, requires less computation time compared with other sparsification methods, gets a better local optima than the traditional algorithms, and converges much faster than the up-to-date algorithms. In addition, OSKTD can reach a competitive ultimate optima compared with the up-to-date algorithms.

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

PubMed

Anderson, Alexander R A; Weaver, Alissa M; Cummings, Peter T; Quaranta, Vito

2006-12-01

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Low complexity adaptive equalizers for underwater acoustic communications

NASA Astrophysics Data System (ADS)

Soflaei, Masoumeh; Azmi, Paeiz

2014-08-01

Interference signals due to scattering from surface and reflecting from bottom is one of the most important problems of reliable communications in shallow water channels. To solve this problem, one of the best suggested ways is to use adaptive equalizers. Convergence rate and misadjustment error in adaptive algorithms play important roles in adaptive equalizer performance. In this paper, affine projection algorithm (APA), selective regressor APA(SR-APA), family of selective partial update (SPU) algorithms, family of set-membership (SM) algorithms and selective partial update selective regressor APA (SPU-SR-APA) are compared with conventional algorithms such as the least mean square (LMS) in underwater acoustic communications. We apply experimental data from the Strait of Hormuz for demonstrating the efficiency of the proposed methods over shallow water channel. We observe that the values of the steady-state mean square error (MSE) of SR-APA, SPU-APA, SPU-normalized least mean square (SPU-NLMS), SPU-SR-APA, SM-APA and SM-NLMS algorithms decrease in comparison with the LMS algorithm. Also these algorithms have better convergence rates than LMS type algorithm.

spa Typing and Multilocus Sequence Typing Show Comparable Performance in a Macroepidemiologic Study of Staphylococcus aureus in the United States

PubMed Central

O'Hara, F. Patrick; Suaya, Jose A.; Ray, G. Thomas; Baxter, Roger; Brown, Megan L.; Mera, Robertino M.; Close, Nicole M.; Thomas, Elizabeth

2016-01-01

A number of molecular typing methods have been developed for characterization of Staphylococcus aureus isolates. The utility of these systems depends on the nature of the investigation for which they are used. We compared two commonly used methods of molecular typing, multilocus sequence typing (MLST) (and its clustering algorithm, Based Upon Related Sequence Type [BURST]) with the staphylococcal protein A (spa) typing (and its clustering algorithm, Based Upon Repeat Pattern [BURP]), to assess the utility of these methods for macroepidemiology and evolutionary studies of S. aureus in the United States. We typed a total of 366 clinical isolates of S. aureus by these methods and evaluated indices of diversity and concordance values. Our results show that, when combined with the BURP clustering algorithm to delineate clonal lineages, spa typing produces results that are highly comparable with those produced by MLST/BURST. Therefore, spa typing is appropriate for use in macroepidemiology and evolutionary studies and, given its lower implementation cost, this method appears to be more efficient. The findings are robust and are consistent across different settings, patient ages, and specimen sources. Our results also support a model in which the methicillin-resistant S. aureus (MRSA) population in the United States comprises two major lineages (USA300 and USA100), which each consist of closely related variants. PMID:26669861

spa Typing and Multilocus Sequence Typing Show Comparable Performance in a Macroepidemiologic Study of Staphylococcus aureus in the United States.

PubMed

O'Hara, F Patrick; Suaya, Jose A; Ray, G Thomas; Baxter, Roger; Brown, Megan L; Mera, Robertino M; Close, Nicole M; Thomas, Elizabeth; Amrine-Madsen, Heather

2016-01-01

A number of molecular typing methods have been developed for characterization of Staphylococcus aureus isolates. The utility of these systems depends on the nature of the investigation for which they are used. We compared two commonly used methods of molecular typing, multilocus sequence typing (MLST) (and its clustering algorithm, Based Upon Related Sequence Type [BURST]) with the staphylococcal protein A (spa) typing (and its clustering algorithm, Based Upon Repeat Pattern [BURP]), to assess the utility of these methods for macroepidemiology and evolutionary studies of S. aureus in the United States. We typed a total of 366 clinical isolates of S. aureus by these methods and evaluated indices of diversity and concordance values. Our results show that, when combined with the BURP clustering algorithm to delineate clonal lineages, spa typing produces results that are highly comparable with those produced by MLST/BURST. Therefore, spa typing is appropriate for use in macroepidemiology and evolutionary studies and, given its lower implementation cost, this method appears to be more efficient. The findings are robust and are consistent across different settings, patient ages, and specimen sources. Our results also support a model in which the methicillin-resistant S. aureus (MRSA) population in the United States comprises two major lineages (USA300 and USA100), which each consist of closely related variants.

Primary cutaneous B-cell lymphoma is associated with somatically hypermutated immunoglobulin variable genes and frequent use of VH1-69 and VH4-59 segments.

PubMed

Perez, M; Pacchiarotti, A; Frontani, M; Pescarmona, E; Caprini, E; Lombardo, G A; Russo, G; Faraggiana, T

2010-03-01

Accurate assessment of the somatic mutational status of clonal immunoglobulin variable region (IgV) genes is relevant in elucidating tumour cell origin in B-cell lymphoma; virgin B cells bear unmutated IgV genes, while germinal centre and postfollicular B cells carry mutated IgV genes. Furthermore, biases in the IgV repertoire and distribution pattern of somatic mutations indicate a possible antigen role in the pathogenesis of B-cell malignancies. This work investigates the cellular origin and antigenic selection in primary cutaneous B-cell lymphoma (PCBCL). We analysed the nucleotide sequence of clonal IgV heavy-chain gene (IgVH) rearrangements in 51 cases of PCBCL (25 follicle centre, 19 marginal zone and seven diffuse large B-cell lymphoma, leg-type) and compared IgVH sequences with their closest germline segment in the GenBank database. Molecular data were then correlated with histopathological features. We showed that all but one of the 51 IgVH sequences analysed exhibited extensive somatic hypermutations. The detected mutation rate ranged from 1.6% to 21%, with a median rate of 9.8% and was independent of PCBCL histotype. Calculation of antigen-selection pressure showed that 39% of the mutated IgVH genes displayed a number of replacement mutations and silent mutations in a pattern consistent with antigenic selection. Furthermore, two segments, VH1-69 (12%) and VH4-59 (14%), were preferentially used in our case series. Data indicate that neoplastic B cells of PBCBL have experienced germinal centre reaction and also suggest that the involvement of IgVH genes is not entirely random in PCBCL and that common antigen epitopes could be pathologically relevant in cutaneous lymphomagenesis.

Gene selection in cancer classification using sparse logistic regression with Bayesian regularization.

PubMed

Cawley, Gavin C; Talbot, Nicola L C

2006-10-01

Gene selection algorithms for cancer classification, based on the expression of a small number of biomarker genes, have been the subject of considerable research in recent years. Shevade and Keerthi propose a gene selection algorithm based on sparse logistic regression (SLogReg) incorporating a Laplace prior to promote sparsity in the model parameters, and provide a simple but efficient training procedure. The degree of sparsity obtained is determined by the value of a regularization parameter, which must be carefully tuned in order to optimize performance. This normally involves a model selection stage, based on a computationally intensive search for the minimizer of the cross-validation error. In this paper, we demonstrate that a simple Bayesian approach can be taken to eliminate this regularization parameter entirely, by integrating it out analytically using an uninformative Jeffrey's prior. The improved algorithm (BLogReg) is then typically two or three orders of magnitude faster than the original algorithm, as there is no longer a need for a model selection step. The BLogReg algorithm is also free from selection bias in performance estimation, a common pitfall in the application of machine learning algorithms in cancer classification. The SLogReg, BLogReg and Relevance Vector Machine (RVM) gene selection algorithms are evaluated over the well-studied colon cancer and leukaemia benchmark datasets. The leave-one-out estimates of the probability of test error and cross-entropy of the BLogReg and SLogReg algorithms are very similar, however the BlogReg algorithm is found to be considerably faster than the original SLogReg algorithm. Using nested cross-validation to avoid selection bias, performance estimation for SLogReg on the leukaemia dataset takes almost 48 h, whereas the corresponding result for BLogReg is obtained in only 1 min 24 s, making BLogReg by far the more practical algorithm. BLogReg also demonstrates better estimates of conditional probability than the RVM, which are of great importance in medical applications, with similar computational expense. A MATLAB implementation of the sparse logistic regression algorithm with Bayesian regularization (BLogReg) is available from http://theoval.cmp.uea.ac.uk/~gcc/cbl/blogreg/

Compact cancer biomarkers discovery using a swarm intelligence feature selection algorithm.

PubMed

Martinez, Emmanuel; Alvarez, Mario Moises; Trevino, Victor

2010-08-01

Biomarker discovery is a typical application from functional genomics. Due to the large number of genes studied simultaneously in microarray data, feature selection is a key step. Swarm intelligence has emerged as a solution for the feature selection problem. However, swarm intelligence settings for feature selection fail to select small features subsets. We have proposed a swarm intelligence feature selection algorithm based on the initialization and update of only a subset of particles in the swarm. In this study, we tested our algorithm in 11 microarray datasets for brain, leukemia, lung, prostate, and others. We show that the proposed swarm intelligence algorithm successfully increase the classification accuracy and decrease the number of selected features compared to other swarm intelligence methods. Copyright © 2010 Elsevier Ltd. All rights reserved.

Multi-task feature selection in microarray data by binary integer programming.

PubMed

Lan, Liang; Vucetic, Slobodan

2013-12-20

A major challenge in microarray classification is that the number of features is typically orders of magnitude larger than the number of examples. In this paper, we propose a novel feature filter algorithm to select the feature subset with maximal discriminative power and minimal redundancy by solving a quadratic objective function with binary integer constraints. To improve the computational efficiency, the binary integer constraints are relaxed and a low-rank approximation to the quadratic term is applied. The proposed feature selection algorithm was extended to solve multi-task microarray classification problems. We compared the single-task version of the proposed feature selection algorithm with 9 existing feature selection methods on 4 benchmark microarray data sets. The empirical results show that the proposed method achieved the most accurate predictions overall. We also evaluated the multi-task version of the proposed algorithm on 8 multi-task microarray datasets. The multi-task feature selection algorithm resulted in significantly higher accuracy than when using the single-task feature selection methods.

mRMR-ABC: A Hybrid Gene Selection Algorithm for Cancer Classification Using Microarray Gene Expression Profiling

PubMed Central

Alshamlan, Hala; Badr, Ghada; Alohali, Yousef

2015-01-01

An artificial bee colony (ABC) is a relatively recent swarm intelligence optimization approach. In this paper, we propose the first attempt at applying ABC algorithm in analyzing a microarray gene expression profile. In addition, we propose an innovative feature selection algorithm, minimum redundancy maximum relevance (mRMR), and combine it with an ABC algorithm, mRMR-ABC, to select informative genes from microarray profile. The new approach is based on a support vector machine (SVM) algorithm to measure the classification accuracy for selected genes. We evaluate the performance of the proposed mRMR-ABC algorithm by conducting extensive experiments on six binary and multiclass gene expression microarray datasets. Furthermore, we compare our proposed mRMR-ABC algorithm with previously known techniques. We reimplemented two of these techniques for the sake of a fair comparison using the same parameters. These two techniques are mRMR when combined with a genetic algorithm (mRMR-GA) and mRMR when combined with a particle swarm optimization algorithm (mRMR-PSO). The experimental results prove that the proposed mRMR-ABC algorithm achieves accurate classification performance using small number of predictive genes when tested using both datasets and compared to previously suggested methods. This shows that mRMR-ABC is a promising approach for solving gene selection and cancer classification problems. PMID:25961028

mRMR-ABC: A Hybrid Gene Selection Algorithm for Cancer Classification Using Microarray Gene Expression Profiling.

PubMed

Alshamlan, Hala; Badr, Ghada; Alohali, Yousef

2015-01-01

An artificial bee colony (ABC) is a relatively recent swarm intelligence optimization approach. In this paper, we propose the first attempt at applying ABC algorithm in analyzing a microarray gene expression profile. In addition, we propose an innovative feature selection algorithm, minimum redundancy maximum relevance (mRMR), and combine it with an ABC algorithm, mRMR-ABC, to select informative genes from microarray profile. The new approach is based on a support vector machine (SVM) algorithm to measure the classification accuracy for selected genes. We evaluate the performance of the proposed mRMR-ABC algorithm by conducting extensive experiments on six binary and multiclass gene expression microarray datasets. Furthermore, we compare our proposed mRMR-ABC algorithm with previously known techniques. We reimplemented two of these techniques for the sake of a fair comparison using the same parameters. These two techniques are mRMR when combined with a genetic algorithm (mRMR-GA) and mRMR when combined with a particle swarm optimization algorithm (mRMR-PSO). The experimental results prove that the proposed mRMR-ABC algorithm achieves accurate classification performance using small number of predictive genes when tested using both datasets and compared to previously suggested methods. This shows that mRMR-ABC is a promising approach for solving gene selection and cancer classification problems.

Genetic Considerations for the Restoration of Smooth Cordgrass (Spartina alterniflora) Within Its Native Range

USGS Publications Warehouse

Travis, Steven E.; Proffitt, C. Edward; Edwards, Keith R.

2006-01-01

In order to remain viable over many generations, plant populations require the ability to respond adaptively to a changing environment. Such adaptive potential is directly controlled by underlying genetic variation, which can be measured in terms of both heterozygosity at the individual level and clonal, or genotypic diversity at the population level. This report summarizes research relating to the importance of genetic diversity in the restoration of salt marsh smooth cordgrass, Spartina alterniflora, a dominant member of low elevation intertidal marshes throughout the northern Gulf of Mexico and Atlantic Coasts of North America. Recent research has indicated that S. alterniflora is a partially clonal species characterized by the recruitment of seedlings exclusively during the initial colonization phase of population establishment. A major consequence of this finding is that clonal diversity generally peaks rather early in the development of a restored marsh, depending on the rate of natural immigration and/or the clonal diversity of planting units, and then undergoes a steady decline over geological time spans because of stochastic mortality and intraspecific competition. Low levels of clonal diversity resulting from restricted immigration or clonally depauperate planting materials in turn places strict limits on opportunities for outcrossing in a species known to suffer from severe inbreeding depression. Low clonal diversity may further lead to declining levels of heterozyosity of individual clones, which directly affects competitive ability. In addition, the planting of genetically diverse plant materials should take into account the genetic and adaptive differentiation that takes place when plant populations are widely separated in space and/or dwell under varying sets of environmental conditions. Thus, steps should be taken to ensure that S. alterniflora clones developed for restorative plantings are both genetically diverse and sufficiently pre-adapted to environmental conditions at the proposed restoration site. This can be achieved by growing plant materials collected from local sources and by either taking care to maintain relatively high levels of clonal diversity or by planting clones at sufficiently low densities that they will not quickly grow to monopolize a restoration site without first producing several generations of sexual recruits through crosses with nearby native populations.

Threshold automatic selection hybrid phase unwrapping algorithm for digital holographic microscopy

NASA Astrophysics Data System (ADS)

Zhou, Meiling; Min, Junwei; Yao, Baoli; Yu, Xianghua; Lei, Ming; Yan, Shaohui; Yang, Yanlong; Dan, Dan

2015-01-01

Conventional quality-guided (QG) phase unwrapping algorithm is hard to be applied to digital holographic microscopy because of the long execution time. In this paper, we present a threshold automatic selection hybrid phase unwrapping algorithm that combines the existing QG algorithm and the flood-filled (FF) algorithm to solve this problem. The original wrapped phase map is divided into high- and low-quality sub-maps by selecting a threshold automatically, and then the FF and QG unwrapping algorithms are used in each level to unwrap the phase, respectively. The feasibility of the proposed method is proved by experimental results, and the execution speed is shown to be much faster than that of the original QG unwrapping algorithm.

Intra-Species Genetic Diversity and Clonal Structure of Cryptosporidium parvum in Sheep Farms in a Confined Geographical Area in Northeastern Spain

PubMed Central

Ramo, Ana; Monteagudo, Luis V.; Del Cacho, Emilio; Sánchez-Acedo, Caridad

2016-01-01

A multilocus fragment typing approach including eleven variable-number tandem-repeat (VNTR) loci and the GP60 gene was used to investigate the intra-farm and intra-host genetic diversity of Cryptosporidium parvum in sheep farms in a confined area in northeastern Spain. Genomic DNA samples of 113 C. parvum isolates from diarrheic pre-weaned lambs collected in 49 meat-type sheep farms were analyzed. Loci exhibited various degrees of polymorphism, the finding of 7–9 alleles in the four most variable and discriminatory markers (ML2, Cgd6_5400, Cgd6_3940, and GP60) being remarkable. The combination of alleles at the twelve loci identified a total of 74 multilocus subtypes (MLTs) and provided a Hunter-Gaston discriminatory index of 0.988 (95% CI, 0.979−0.996). The finding that most MLTs (n = 64) were unique to individual farms evidenced that cryptosporidial infection is mainly transmitted within sheep flocks, with herd-to-herd transmission playing a secondary role. Limited intra- host variability was found, since only five isolates were genotypically mixed. In contrast, a significant intra-farm genetic diversity was seen, with the presence of multiple MLTs on more than a half of the farms (28/46), suggesting frequent mutations or genetic exchange through recombination. Comparison with a previous study in calves in northern Spain using the same 12-loci typing approach showed differences in the identity of major alleles at most loci, with a single MLT being shared between lambs and calves. Analysis of evolutionary descent by the algorithm eBURST indicated a high degree of genetic divergence, with over 41% MLTs appearing as singletons along with a high number of clonal complexes, most of them linking only two MLTs. Bayesian Structure analysis and F statistics also revealed the genetic remoteness of most C. parvum isolates and no ancestral population size was chosen. Linkage analysis evidenced a prevalent pattern of clonality within the parasite population. PMID:27176718

Multilocus sequence typing of Lactococcus lactis from naturally fermented milk foods in ethnic minority areas of China.

PubMed

Xu, Haiyan; Sun, Zhihong; Liu, Wenjun; Yu, Jie; Song, Yuqin; Lv, Qiang; Zhang, Jiachao; Shao, Yuyu; Menghe, Bilige; Zhang, Heping

2014-05-01

To determine the genetic diversity and phylogenetic relationships among Lactococcus lactis isolates, 197 strains isolated from naturally homemade yogurt in 9 ethnic minority areas of 6 provinces of China were subjected to multilocus sequence typing (MLST). The MLST analysis was performed using internal fragment sequences of 12 housekeeping genes (carB, clpX, dnaA, groEL, murC, murE, pepN, pepX, pyrG, recA, rpoB, and pheS). Six (dnaA) to 8 (murC) different alleles were detected for these genes, which ranged from 33.62 (clpX) to 41.95% (recA) GC (guanine-cytosine) content. The nucleotide diversity (π) ranged from 0.00362 (murE) to 0.08439 (carB). Despite this limited allelic diversity, the allele combinations of each strain revealed 72 different sequence types, which denoted significant genotypic diversity. The dN/dS ratios (where dS is the number of synonymous substitutions per synonymous site, and dN is the number of nonsynonymous substitutions per nonsynonymous site) were lower than 1, suggesting potential negative selection for these genes. The standardized index of association of the alleles IA(S)=0.3038 supported the clonality of Lc. lactis, but the presence of network structure revealed by the split decomposition analysis of the concatenated sequence was strong evidence for intraspecies recombination. Therefore, this suggests that recombination contributed to the evolution of Lc. lactis. A minimum spanning tree analysis of the 197 isolates identified 14 clonal complexes and 23 singletons. Phylogenetic trees were constructed based on the sequence types, using the minimum evolution algorithm, and on the concatenated sequence (6,192 bp), using the unweighted pair-group method with arithmetic mean, and these trees indicated that the evolution of our Lc. lactis population was correlated with geographic origin. Taken together, our results demonstrated that MLST could provide a better understanding of Lc. lactis genome evolution, as well as useful information for future studies on global Lc. lactis structure and genetic evolution, which will lay the foundation for screening Lc. lactis as starter cultures in fermented dairy products. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Genetic Heterogeneity and Clonal Evolution of Tumor Cells and their Impact on Precision Cancer Medicine.

PubMed

Sabaawy, Hatem E

2013-11-18

The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells. Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors. Moreover, drug-resistant subclones present at initiation of therapy or emerging as a result of targeted therapies represent major challenges for achieving success of personalized therapies in providing meaningful improvement in cancer survival rates. Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine.

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia.

PubMed

Sperling, Adam S; Gibson, Christopher J; Ebert, Benjamin L

2017-01-01

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate.

PubMed

Polski, Jacek M; Galambos, Csaba; Gale, Gordon B; Dunphy, Cherie H; Evans, H Lance; Batanian, Jacqueline R

2002-01-01

We report a case of transient myeloproliferative disorder (TMD) in a neonate without features of Down syndrome (DS) with clonal karyotype evolution, after apparent spontaneous resolution of TMD, but eventually progressing to acute megakaryoblastic leukemia (AMKL). The patient had petechiae, thrombocytopenia, and blastemia. Trisomy 21 with a satellited Y chromosome (Yqs) was found in proliferating blasts. A stimulated peripheral blood culture confirmed the constitutional origin of the Yqs, but did not reveal the presence of any trisomic 21 cell. By the age of 3 months, clonal chromosome evolution in the form of an interstitial deletion of the long-arm of chromosome 13 [del(13)(q13q31)] was detected along with trisomy 21 in unstimulated bone marrow cultures. However, remission was achieved without treatment at the age of 4 months. Trisomy 21 and del(13)(q13q31) were not identified in either cytogenetics or fluorescence in situ hybridization studies at that time. The child was asymptomatic until the age of 20 months when anemia and thrombocytopenia prompted a bone marrow biopsy, revealing changes consistent with AMKL. The remission proceeded by clonal karyotype evolution in a neonate with TMD demonstrates that clonal karyotype evolution does not indicate an immediately progressive disease. However, the development of AMKL after TMD in this case illustrates the increased risk for leukemia in TMD cases, even without DS. The gradual clonal evolution of the blasts in our patient suggests that "multiple hits" oncogenesis applies to TMD progression to acute leukemia.

Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.

PubMed

Babushok, Daria V; Perdigones, Nieves; Perin, Juan C; Olson, Timothy S; Ye, Wenda; Roth, Jacquelyn J; Lind, Curt; Cattier, Carine; Li, Yimei; Hartung, Helge; Paessler, Michele E; Frank, Dale M; Xie, Hongbo M; Cross, Shanna; Cockroft, Joshua D; Podsakoff, Gregory M; Monos, Dimitrios; Biegel, Jaclyn A; Mason, Philip J; Bessler, Monica

2015-04-01

Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20-25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric-onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging-immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

Spatial Genetic Structure and Clonal Diversity in an Alpine Population of Salix herbacea (Salicaceae)

PubMed Central

Reisch, Christoph; Schurm, Sophia; Poschlod, Peter

2007-01-01

Background and Aims Many alpine plant species combine clonal and sexual reproduction to minimize the risks of flowering and seed production in high mountain regions. The spatial genetic structure and diversity of these alpine species is strongly affected by different clonal strategies (phalanx or guerrilla) and the proportion of generative and vegetative reproduction. Methods The clonal structure of the alpine plant species Salix herbacea was investigated in a 3 × 3 m plot of an alpine meadow using microsatellite (simple sequence repeat; SSR) analysis. The data obtained were compared with the results of a random amplified polymorphic DNA (RAPD) analysis. Key Results SSR analysis, based on three loci and 16 alleles, revealed 24 different genotypes and a proportion of distinguishable genotypes of 0·18. Six SSR clones were found consisting of at least five samples, 17 clones consisting of more than two samples and seven single genotypes. Mean clone size comprising at least five samples was 0·96 m2, and spatial autocorrelation analysis showed strong similarity of samples up to 130 cm. RAPD analysis revealed a higher level of clonal diversity but a comparable number of larger clones and a similar spatial structure. Conclusions The spatial genetic structure as well as the occurrence of single genotypes revealed in this study suggests both clonal and sexual propagation and repeated seedling recruitment in established populations of S. herbacea and is thus suggestive of a relaxed phalanx strategy. PMID:17242040

Fire coral clones demonstrate phenotypic plasticity among reef habitats.

PubMed

Dubé, Caroline E; Boissin, Emilie; Maynard, Jeffrey A; Planes, Serge

2017-08-01

Clonal populations are often characterized by reduced levels of genotypic diversity, which can translate into lower numbers of functional phenotypes, both of which impede adaptation. Study of partially clonal animals enables examination of the environmental settings under which clonal reproduction is favoured. Here, we gathered genotypic and phenotypic information from 3,651 georeferenced colonies of the fire coral Millepora platyphylla in five habitats with different hydrodynamic regimes in Moorea, French Polynesia. In the upper slope where waves break, most colonies grew as vertical sheets ("sheet tree") making them more vulnerable to fragmentation. Nearly all fire corals in the other habitats are encrusting or massive. The M. platyphylla population is highly clonal (80% of the colonies are clones), while characterized by the highest genotype diversity ever documented for terrestrial or marine populations (1,064 genotypes). The proportion of clones varies greatly among habitats (≥58%-97%) and clones (328 clonal lineages) are distributed perpendicularly from the reef crest, perfectly aligned with wave energy. There are six clonal lineages with clones dispersed in at least two adjacent habitats that strongly demonstrate phenotypic plasticity. Eighty per cent of the colonies in these lineages are "sheet tree" on the upper slope, while 80%-100% are encrusting or massive on the mid slope and back reef. This is a unique example of phenotypic plasticity among reef-building coral clones as corals typically have wave-tolerant growth forms in high-energy reef areas. © 2017 John Wiley & Sons Ltd.

Feature selection method based on multi-fractal dimension and harmony search algorithm and its application

NASA Astrophysics Data System (ADS)

Zhang, Chen; Ni, Zhiwei; Ni, Liping; Tang, Na

2016-10-01

Feature selection is an important method of data preprocessing in data mining. In this paper, a novel feature selection method based on multi-fractal dimension and harmony search algorithm is proposed. Multi-fractal dimension is adopted as the evaluation criterion of feature subset, which can determine the number of selected features. An improved harmony search algorithm is used as the search strategy to improve the efficiency of feature selection. The performance of the proposed method is compared with that of other feature selection algorithms on UCI data-sets. Besides, the proposed method is also used to predict the daily average concentration of PM2.5 in China. Experimental results show that the proposed method can obtain competitive results in terms of both prediction accuracy and the number of selected features.

Clonal selection prevents tragedy of the commons when neighbors compete in a rock-paper-scissors game

NASA Astrophysics Data System (ADS)

Juul, Jeppe; Sneppen, Kim; Mathiesen, Joachim

2012-06-01

The rock-paper-scissors game is a model example of the ongoing cyclic turnover typical of many ecosystems, ranging from the terrestrial and aquatic to the microbial. Here we explore the evolution of a rock-paper-scissors system where three species compete for space. The species are allowed to mutate and change the speed by which they invade one another. In the case when all species have similar mutation rates, we observe a perpetual arms race where no single species prevails. When only two species mutate, their aggressions increase indefinitely until the ecosystem collapses and only the nonmutating species survives. Finally we show that when only one species mutates, group selection removes individual predators with the fastest growth rates, causing the growth rate of the species to stabilize. We explain this group selection quantitatively.

Classification of Medical Datasets Using SVMs with Hybrid Evolutionary Algorithms Based on Endocrine-Based Particle Swarm Optimization and Artificial Bee Colony Algorithms.

PubMed

Lin, Kuan-Cheng; Hsieh, Yi-Hsiu

2015-10-01

The classification and analysis of data is an important issue in today's research. Selecting a suitable set of features makes it possible to classify an enormous quantity of data quickly and efficiently. Feature selection is generally viewed as a problem of feature subset selection, such as combination optimization problems. Evolutionary algorithms using random search methods have proven highly effective in obtaining solutions to problems of optimization in a diversity of applications. In this study, we developed a hybrid evolutionary algorithm based on endocrine-based particle swarm optimization (EPSO) and artificial bee colony (ABC) algorithms in conjunction with a support vector machine (SVM) for the selection of optimal feature subsets for the classification of datasets. The results of experiments using specific UCI medical datasets demonstrate that the accuracy of the proposed hybrid evolutionary algorithm is superior to that of basic PSO, EPSO and ABC algorithms, with regard to classification accuracy using subsets with a reduced number of features.

[Chronologic analysis of clonal evolution in acquired aplastic anemia and sMDS].

PubMed

Yoshizato, Tetsuichi

2016-04-01

Acquired aplastic anemia (AA) is a prototype of idiopathic bone marrow failure, which is caused by immune-mediated destruction of hematopoietic progenitors but is also characterized by frequent evolution to clonal myeloid disorders, such as myelodysplastic syndromes or acute myeloid leukemia. However, the chronological behavior of the clonality and its link to myelodysplastic syndrome or acute myeloid leukemia has not been fully explored. To define the clonality and its chronological behavior in AA, we performed targeted sequencing (N=439) in cases with AA. Somatic mutations were detected in 1/3 of our cases. Mutations were most frequently found in DNMT3A, followed by BCOR, PIGA and ASXL1. The prevalence of mutations increased with age. The clone sizes in DNMT3A and ASXL1 were prone to increase, whereas those of BCOR and PIGA were more likely to decrease or remain stable. Mutations in PIGA, BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and more favorable survival. On the other hand, other mutations were associated with worse outcomes. The chronological dynamics of clonality showed marked variability and were not necessarily associated with prognosis.

[Clonal relationship and detection of blaKPC gene in strains of Klebsiella pneumoniae resistant to carbapenems, at a hospital in Venezuela].

PubMed

Martínez, Dianny; Araque, Yasmina; Roduifo, Hectorina; Caña, Luisa; García, José; Gonzáiez, Diorelis; Rodríguez, Lucy; De Donato, Marcos

2016-10-01

In order to study the clonal relationship and blaKPC gene detection in clinical isolates of Klebsiella pneumoniae resistant to carbapenems, we analyzed 22 clinical isolates of K. pneumoniae with resistance to imipenem and/ or meropenem, isolated in the laboratory of bacteriology at the University Hospital "Antonio Patricio de Alcalá" (HUAPA) from the Cumana city, Sucre state, Venezuela, for a period of five consecutive years. Susceptibility to different antimicrobials was determined, and the presence of carbapenemases was detected by modified Hodge method, phenyl boronic acid synergy and combination discs. blaKPC gene detection was conducted by polymerase chain reaction and the clonal relationship was determined by pulsed field electrophoresis. High rates of antimicrobial resistance were found, five strains were negative, at least one phenotypic method, and all carried the blaKPC gene. Clonal spread was observed only in the intensive care unit (ICU), while in other services, polyclonality was found. We concluded that blaKPC gene is present in K. pneumoniae strains resistant to carbapenems isolated in the HUAPA and clonal spread it was only in the ICU.

Thelytokous parthenogenesis, male clonality and genetic caste determination in the little fire ant: new evidence and insights from the lab.

PubMed

Foucaud, J; Estoup, A; Loiseau, A; Rey, O; Orivel, J

2010-08-01

Previous studies indicate that some populations of the little fire ant, Wasmannia auropunctata, display an unusual reproduction system polymorphism. Although some populations have a classical haplodiploid reproduction system, in other populations queens are produced by thelytokous parthenogenesis, males are produced by a male clonality system and workers are produced sexually. An atypical genetic caste determination system was also suggested. However, these conclusions were indirectly inferred from genetic studies on field population samples. Here we set up experimental laboratory nests that allow the control of the parental relationships between individuals. The queens heading those nests originated from either putatively clonal or sexual populations. We characterized the male, queen and worker offspring they produced at 12 microsatellite loci. Our results unambiguously confirm the unique reproduction system polymorphism mentioned above and that male clonality is strictly associated with thelytokous parthenogenesis. We also observed direct evidence of the rare production of sexual gynes and arrhenotokous males in clonal populations. Finally, we obtained evidence of a genetic basis for caste determination. The evolutionary significance of the reproduction system polymorphism and genetic caste determination as well as future research opportunities are discussed.

Ephemeral clonal integration in Calathea marantifolia (Marantaceae): Evidence of diminished integration over time.

PubMed

Matlaga, David P; da S L Sternberg, Leonel

2009-02-01

A major advantage of clonal growth forms is the intergenerational transfer of resources through vascular connections (clonal integration). Connections linking ramets can be persistent or ephemeral. For species with ephemeral connections, whether the extent of clonal integration changes over time is unclear. To address this issue, we tracked water movement using an isotopic label and assessed the demographic performance of parent and offspring ramets over time in a severing experiment. Our study system was the understory herb Calathea marantifolia, which has parent ramets that produce vegetative bulbils (clonal offspring) that pass through distinct pre- and post-rooting stages. Little water was transported between parents and offspring, and the direction of movement was primarily from parent to pre-rooting offspring. Anatomical observations of inter-ramet connections showed that vascular bundles were twice as abundant in parent stems compared to inter-ramet connections. Severing inter-ramet connections reduced the growth of offspring ramets but not parents. Survival of pre-rooting offspring was reduced by 10% due to severing, but post-rooting offspring were not affected. Our results suggest that offspring ramets of C. marantifolia are weaned from their parent as they progress from pre- to post-rooting stages.

Universality of clone dynamics during tissue development

NASA Astrophysics Data System (ADS)

Rulands, Steffen; Lescroart, Fabienne; Chabab, Samira; Hindley, Christopher J.; Prior, Nicole; Sznurkowska, Magdalena K.; Huch, Meritxell; Philpott, Anna; Blanpain, Cedric; Simons, Benjamin D.

2018-05-01

The emergence of complex organs is driven by the coordinated proliferation, migration and differentiation of precursor cells. The fate behaviour of these cells is reflected in the time evolution of their progeny, termed clones, which serve as a key experimental observable. In adult tissues, where cell dynamics is constrained by the condition of homeostasis, clonal tracing studies based on transgenic animal models have advanced our understanding of cell fate behaviour and its dysregulation in disease1,2. But what can be learnt from clonal dynamics in development, where the spatial cohesiveness of clones is impaired by tissue deformations during tissue growth? Drawing on the results of clonal tracing studies, we show that, despite the complexity of organ development, clonal dynamics may converge to a critical state characterized by universal scaling behaviour of clone sizes. By mapping clonal dynamics onto a generalization of the classical theory of aerosols, we elucidate the origin and range of scaling behaviours and show how the identification of universal scaling dependences may allow lineage-specific information to be distilled from experiments. Our study shows the emergence of core concepts of statistical physics in an unexpected context, identifying cellular systems as a laboratory to study non-equilibrium statistical physics.

Traditional Amerindian cultivators combine directional and ideotypic selection for sustainable management of cassava genetic diversity.

PubMed

Duputié, A; Massol, F; David, P; Haxaire, C; McKey, D

2009-06-01

Plant domestication provides striking examples of rapid evolution. Yet, it involves more complex processes than plain directional selection. Understanding the dynamics of diversity in traditional agroecosystems is both a fundamental goal in evolutionary biology and a practical goal in conservation. We studied how Amerindian cultivators maintain dynamically evolving gene pools in cassava. Farmers purposely maintain diversity in the form of phenotypically distinct, clonally propagated landraces. Landrace gene pools are continuously renewed by incorporating seedlings issued from spontaneous sexual reproduction. This poses two problems: agronomic quality may decrease because some seedlings are inbred, and landrace identity may be progressively lost through the incorporation of unrelated seedlings. Using a large microsatellite dataset, we show that farmers solve these problems by applying two kinds of selection: directional selection against inbred genotypes, and counter-selection of off-type phenotypes, which maintains high intra-landrace relatedness. Thus, cultural elements such as ideotypes (a representation of the ideal phenotype of a landrace) can shape genetic diversity.

Effect of ozone on diverse tall fescue germplasm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnston, W.J.; Dickens, R.; Haaland, R.L.

Six tall fescue (Festuca arundinacea Schreb.) genotypes of diverse origin (Algeria, Australia, France, Netherlands, Morocco, and a Kentucky 31 type) were evaluated for O/sub 3/ tolerance under controlled environmental conditions. In two tests on clonal parent material, (1) O/sub 3/ constant 0.3 ppm and exposure varied 0-12 hr and (2) O/sub 3/ concentration varied 0-0.5 ppm and exposure varied 1-3 hr, the Australian and Kentucky 31 selections were superior to all others in O/sub 3/ tolerance. Sixteen-day old polycross progeny of the six selections were exposed to 0.5 ppm O/sub 3/ for 0, 3, or 6 hr. Progeny of themore » Australian and Kentucky 31 selections were superior to some, but not all other selections. Increased duration of exposure increased damage only slightly. It would appear that O/sub 3/ tolerance is a heritable characteristic that can be easily detected and selected for in tall fescue.« less

Parameter selection in limited data cone-beam CT reconstruction using edge-preserving total variation algorithms

NASA Astrophysics Data System (ADS)

Lohvithee, Manasavee; Biguri, Ander; Soleimani, Manuchehr

2017-12-01

There are a number of powerful total variation (TV) regularization methods that have great promise in limited data cone-beam CT reconstruction with an enhancement of image quality. These promising TV methods require careful selection of the image reconstruction parameters, for which there are no well-established criteria. This paper presents a comprehensive evaluation of parameter selection in a number of major TV-based reconstruction algorithms. An appropriate way of selecting the values for each individual parameter has been suggested. Finally, a new adaptive-weighted projection-controlled steepest descent (AwPCSD) algorithm is presented, which implements the edge-preserving function for CBCT reconstruction with limited data. The proposed algorithm shows significant robustness compared to three other existing algorithms: ASD-POCS, AwASD-POCS and PCSD. The proposed AwPCSD algorithm is able to preserve the edges of the reconstructed images better with fewer sensitive parameters to tune.

CURE-SMOTE algorithm and hybrid algorithm for feature selection and parameter optimization based on random forests.

PubMed

Ma, Li; Fan, Suohai

2017-03-14

The random forests algorithm is a type of classifier with prominent universality, a wide application range, and robustness for avoiding overfitting. But there are still some drawbacks to random forests. Therefore, to improve the performance of random forests, this paper seeks to improve imbalanced data processing, feature selection and parameter optimization. We propose the CURE-SMOTE algorithm for the imbalanced data classification problem. Experiments on imbalanced UCI data reveal that the combination of Clustering Using Representatives (CURE) enhances the original synthetic minority oversampling technique (SMOTE) algorithms effectively compared with the classification results on the original data using random sampling, Borderline-SMOTE1, safe-level SMOTE, C-SMOTE, and k-means-SMOTE. Additionally, the hybrid RF (random forests) algorithm has been proposed for feature selection and parameter optimization, which uses the minimum out of bag (OOB) data error as its objective function. Simulation results on binary and higher-dimensional data indicate that the proposed hybrid RF algorithms, hybrid genetic-random forests algorithm, hybrid particle swarm-random forests algorithm and hybrid fish swarm-random forests algorithm can achieve the minimum OOB error and show the best generalization ability. The training set produced from the proposed CURE-SMOTE algorithm is closer to the original data distribution because it contains minimal noise. Thus, better classification results are produced from this feasible and effective algorithm. Moreover, the hybrid algorithm's F-value, G-mean, AUC and OOB scores demonstrate that they surpass the performance of the original RF algorithm. Hence, this hybrid algorithm provides a new way to perform feature selection and parameter optimization.

Long-Term Colonization of the Cystic Fibrosis Lung by Burkholderia cepacia Complex Bacteria: Epidemiology, Clonal Variation, and Genome-Wide Expression Alterations

PubMed Central

Coutinho, Carla P.; dos Santos, Sandra C.; Madeira, Andreia; Mira, Nuno P.; Moreira, Ana S.; Sá-Correia, Isabel

2011-01-01

Long-term respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) patients generally lead to a more rapid decline in lung function and, in some cases, to a fatal necrotizing pneumonia known as the “cepacia syndrome.” Bcc bacteria are ubiquitous in the environment and are recognized as serious opportunistic pathogens that are virtually impossible to eradicate from the CF lung, posing a serious clinical threat. The epidemiological survey of Bcc bacteria involved in respiratory infections at the major Portuguese CF Treatment Center at Santa Maria Hospital, in Lisbon, has been carried out by our research group for the past 16 years, covering over 500 clinical isolates where B. cepacia and B. cenocepacia are the predominant species, with B. stabilis, B. contaminans, B. dolosa, and B. multivorans also represented. The systematic and longitudinal study of this CF population during such an extended period of time represents a unique case–study, comprehending 41 Bcc-infected patients (29 pediatric and 12 adult) of whom around 70% have been persistently colonized between 7 months and 9 years. During chronic infection, the CF airways represent an evolving ecosystem, with multiple phenotypic variants emerging from the clonal population and becoming established in the patients’ airways as the result of genetic adaptation. Understanding the evolutionary mechanisms involved is crucial for an improved therapeutic outcome of chronic infections in CF. This review focuses on our contribution to the understanding of these adaptive mechanisms based on extensive phenotypic, genotypic, and genome-wide expression approaches of selected Bcc clonal variants obtained during long-term colonization of the CF airways. PMID:22919578

Food-borne pathogens, health and role of dietary phytochemicals.

PubMed

Shetty, K; Labbe, R G

1998-12-01

Infectious diseases transmitted by food have become a major public health concern in recent years. In the USA alone, there are an estimated 6-33 million cases each year. The list of responsible agents continues to grow. In the past 20 years some dozen new pathogens that are primarily food-borne have been identified. Fruits and vegetables, often from the global food market, have been added to the traditional vehicles of food-borne illness; that is, undercooked meat, poultry, seafood, or unpasteurized milk. Such products are minimally processed and have fewer barriers to microbial growth such as salt, sugar or preservatives. The evolution of the epidemiology of food-borne illness requires a rethinking of traditional, though still valid, solutions for their prevention. Among various strategies to prevent food-borne pathogens, use of dietary phytochemicals is promising. The major obstacle in the use of dietary phytochemical is the consistency of phytochemicals in different foods due to their natural genetic variation. We have developed a novel tissue-culture-based selection strategy to isolate elite phenolic phytochemical-producing clonal lines of species belonging to the family Lamiaceae. Among several species we have targeted elite clonal lines of thyme (Thymus vulgaris) and oregano (Origanum vulgare) against Escherichia coli and Clostridium perfrigens in fresh and processed meats. We are also evaluating high phenolic profile-containing clonal lines of basil (Ocimum basilicum) to inhibit gastric ulcer-causing Helicobacter pylori. Other elite lines of the members of the family Lamiaceae, rosemary (Rosmarinus officinalis) and salvia (Salvia officinalis) also hold promise against a wide range of food pathogens such as Salmonella species in poultry products and Vibrio species in seafood.

Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.

PubMed

Sowalsky, Adam G; Kissick, Haydn T; Gerrin, Sean J; Schaefer, Rachel J; Xia, Zheng; Russo, Joshua W; Arredouani, M Simo; Bubley, Glenn J; Sanda, Martin G; Li, Wei; Ye, Huihui; Balk, Steven P

2017-07-15

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Occurrence, species distribution, antimicrobial resistance and clonality of methicillin- and erythromycin-resistant staphylococci in the nasal cavity of domestic animals.

PubMed

Bagcigil, Funda A; Moodley, Arshnee; Baptiste, Keith E; Jensen, Vibeke F; Guardabassi, Luca

2007-04-15

beta-Lactams and macrolides are important antibiotics for treatment of staphylococcal infections in both humans and animals. The aim of the study was to investigate the occurrence, species distribution and clonality of methicillin- and erythromycin-resistant staphylococci in the nasal cavity of dogs, horses, pigs, and cattle in Denmark. Nasal swabs were collected from a total of 400 animals, including 100 individuals of each species. Methicillin- and erythromycin-resistant staphylococci were isolated on selective media, identified by 16S rDNA sequencing, and typed by pulsed field gel electrophoresis (PFGE). Methicillin-resistant coagulase-negative staphylococci (MRCoNS) harbouring mecA were isolated from horses (50%) and dogs (13%), but not from food animals. The species identified were S. haemolyticus (n=21), S. vitulinus (n=19), S. sciuri (n=13), S. epidermidis (n=8), and S. warneri (n=2). mecA-mediated methicillin resistance in S. vitulinus was described for the first time. Methicillin-resistant S. aureus was not detected. PFGE analysis revealed the presence of specific MRCoNS clones in samples originating from the same veterinary hospital or equine farm. Erythromycin-resistant S. aureus (ERSA) was detected in 38% of pigs and all isolates harboured a constitutively expressed erm(C) gene. The vast majority (37/38) of pigs carrying ERSA originated from a farm characterized by frequent use of macrolides. Most ERSA isolates (28/38) displayed indistinguishable or closely related PFGE patterns, indicating clonal distribution within the farm. Based on the analysis of data on antimicrobial consumption, the occurrence of MRCoNS in companion animals and that of ERSA in pigs reflected national and local patterns of antimicrobial usage.

Genomic Structural Variations Affecting Virulence During Clonal Expansion of Pseudomonas syringae pv. actinidiae Biovar 3 in Europe

PubMed Central

Firrao, Giuseppe; Torelli, Emanuela; Polano, Cesare; Ferrante, Patrizia; Ferrini, Francesca; Martini, Marta; Marcelletti, Simone; Scortichini, Marco; Ermacora, Paolo

2018-01-01

Pseudomonas syringae pv. actinidiae (Psa) biovar 3 caused pandemic bacterial canker of Actinidia chinensis and Actinidia deliciosa since 2008. In Europe, the disease spread rapidly in the kiwifruit cultivation areas from a single introduction. In this study, we investigated the genomic diversity of Psa biovar 3 strains during the primary clonal expansion in Europe using single molecule real-time (SMRT), Illumina and Sanger sequencing technologies. We recorded evidences of frequent mobilization and loss of transposon Tn6212, large chromosome inversions, and ectopic integration of IS sequences (remarkably ISPsy31, ISPsy36, and ISPsy37). While no phenotype change associated with Tn6212 mobilization could be detected, strains CRAFRU 12.29 and CRAFRU 12.50 did not elicit the hypersensitivity response (HR) on tobacco and eggplant leaves and were limited in their growth in kiwifruit leaves due to insertion of ISPsy31 and ISPsy36 in the hrpS and hrpR genes, respectively, interrupting the hrp cluster. Both strains had been isolated from symptomatic plants, suggesting coexistence of variant strains with reduced virulence together with virulent strains in mixed populations. The structural differences caused by rearrangements of self-genetic elements within European and New Zealand strains were comparable in number and type to those occurring among the European strains, in contrast with the significant difference in terms of nucleotide polymorphisms. We hypothesize a relaxation, during clonal expansion, of the selection limiting the accumulation of deleterious mutations associated with genome structural variation due to transposition of mobile elements. This consideration may be relevant when evaluating strategies to be adopted for epidemics management. PMID:29675009

Long-term colonization of the cystic fibrosis lung by Burkholderia cepacia complex bacteria: epidemiology, clonal variation, and genome-wide expression alterations.

PubMed

Coutinho, Carla P; Dos Santos, Sandra C; Madeira, Andreia; Mira, Nuno P; Moreira, Ana S; Sá-Correia, Isabel

2011-01-01

Long-term respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) patients generally lead to a more rapid decline in lung function and, in some cases, to a fatal necrotizing pneumonia known as the "cepacia syndrome." Bcc bacteria are ubiquitous in the environment and are recognized as serious opportunistic pathogens that are virtually impossible to eradicate from the CF lung, posing a serious clinical threat. The epidemiological survey of Bcc bacteria involved in respiratory infections at the major Portuguese CF Treatment Center at Santa Maria Hospital, in Lisbon, has been carried out by our research group for the past 16 years, covering over 500 clinical isolates where B. cepacia and B. cenocepacia are the predominant species, with B. stabilis, B. contaminans, B. dolosa, and B. multivorans also represented. The systematic and longitudinal study of this CF population during such an extended period of time represents a unique case-study, comprehending 41 Bcc-infected patients (29 pediatric and 12 adult) of whom around 70% have been persistently colonized between 7 months and 9 years. During chronic infection, the CF airways represent an evolving ecosystem, with multiple phenotypic variants emerging from the clonal population and becoming established in the patients' airways as the result of genetic adaptation. Understanding the evolutionary mechanisms involved is crucial for an improved therapeutic outcome of chronic infections in CF. This review focuses on our contribution to the understanding of these adaptive mechanisms based on extensive phenotypic, genotypic, and genome-wide expression approaches of selected Bcc clonal variants obtained during long-term colonization of the CF airways.

Cell plasticity and heterogeneity in cancer.

PubMed

Marjanovic, Nemanja D; Weinberg, Robert A; Chaffer, Christine L

2013-01-01

Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models. The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity. Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies. © 2012 American Association for Clinical Chemistry

Co-colonization and clonal diversity of methicillin-sensitive and methicillin-resistant Staphylococcus aureus in sows.

PubMed

Fetsch, Alexandra; Roesler, Uwe; Kraushaar, Britta; Friese, Anika

2016-03-15

Methicillin-susceptible Staphylococcus (S.) aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are colonizers of skin and mucosa. In humans, MSSA and MRSA compete for colonization space in the anterior nares of pig farmers; however, it was also shown that MSSA/MRSA co-colonization is common and one clone can be found rather than differing types of MSSA and MRSA. We investigated the colonization and clonality of both, MSSA and MRSA in pigs over a longer time. Eighteen sows were nasally sampled three times every ten weeks. Additionally, environmental samples were taken. Samples were investigated for MSSA and MRSA, respectively. The spa type was defined from up to five MRSA and MSSA isolates found per sample and sampling time; selected isolates were further investigated by microarray. Three sows (16.7%) were completely negative for MSSA and MRSA. Twelve pigs (66.7%) were irregularly positive for both, MSSA and MRSA over the time, whereas seven out of them (38.9%) were simultaneously colonized. CC398 (t034, t011) MRSA and CC9 (t337, t1430, and t13816) MSSA associated spa types were exclusively found. In 44.4% (n=8) of sows up to two different types of MSSA were present at the same time and sample. Strains of the same clonal lineage showed a high genetic identity despite their origin. Highly identic clones were present in sows and their environment. As conclusion, MSSA/MRSA may not exclude each other in the anterior nares of pigs. Pigs may also carry different clones at the same time. Copyright © 2016 Elsevier B.V. All rights reserved.

Establishment and characterization of scleroderma fibroblast clonal cell lines by introduction of the hTERT gene

PubMed Central

Kapanadze, Bagrat; Morris, Erin; Smith, Edwin; Trojanowska, Maria

2010-01-01

Abstract Lack of an adequate experimental model has hindered the ability to fully understand scleroderma (SSc) pathogenesis. Current SSc research is based on the study of cultured fibroblasts from skin biopsies. In depth characterization of the SSc fibroblast phenotype is hindered by the limited lifespan and heterogeneity of these cells. The goal of this study was to isolate high collagen-producing fibroblasts from SSc biopsies and extend their lifespan with hTERT immortalization to enable characterization of their phenotype. Fibroblasts from two pairs of closely matched normal and SSc biopsies were infected with an hTERT lentivirus. Infected colonies were isolated, cultured into clonal cell lines and analysed with respect to profibrotic gene expression. The mRNA levels of nine profibrotic genes were measured by quantitative real-time PCR. Protein levels were assessed by Western blot. The hTERT SSc clones were heterogeneous with regards to expression of the profibrotic genes measured. A subset of the SSc clones showed elevated expression levels of collagen I, connective tissue growth factor and thrombospondin 1 mRNA, while expression of other genes was not significantly changed. Elevated expression of collagen I protein and mRNA was correlative with elevated expression of connective tissue growth factor. Several hTERT clones expressed high levels of pSmad1, Smad1 and TGF-βRI indicative of altered TGF-β signalling. A portion of SSc clones expressed several profibrotic genes. This study demonstrates that select characteristics of the SSc phenotype are expressed in a subset of activated fibroblasts in culture. The clonal SSc cell lines may present a new and useful model to investigate the mechanisms involved in SSc fibrosis. PMID:19432820

Establishment and characterization of scleroderma fibroblast clonal cell lines by introduction of the hTERT gene.

PubMed

Kapanadze, Bagrat; Morris, Erin; Smith, Edwin; Trojanowska, Maria

2010-05-01

Lack of an adequate experimental model has hindered the ability to fully understand scleroderma (SSc) pathogenesis. Current SSc research is based on the study of cultured fibroblasts from skin biopsies. In depth characterization of the SSc fibroblast phenotype is hindered by the limited lifespan and heterogeneity of these cells. The goal of this study was to isolate high collagen-producing fibroblasts from SSc biopsies and extend their lifespan with hTERT immortalization to enable characterization of their phenotype. Fibroblasts from two pairs of closely matched normal and SSc biopsies were infected with an hTERT lentivirus. Infected colonies were isolated, cultured into clonal cell lines and analysed with respect to profibrotic gene expression. The mRNA levels of nine profibrotic genes were measured by quantitative real-time PCR. Protein levels were assessed by Western blot. The hTERT SSc clones were heterogeneous with regards to expression of the profibrotic genes measured. A subset of the SSc clones showed elevated expression levels of collagen I, connective tissue growth factor and thrombospondin 1 mRNA, while expression of other genes was not significantly changed. Elevated expression of collagen I protein and mRNA was correlative with elevated expression of connective tissue growth factor. Several hTERT clones expressed high levels of pSmad1, Smad1 and TGF-betaRI indicative of altered TGF-beta signalling. A portion of SSc clones expressed several profibrotic genes. This study demonstrates that select characteristics of the SSc phenotype are expressed in a subset of activated fibroblasts in culture. The clonal SSc cell lines may present a new and useful model to investigate the mechanisms involved in SSc fibrosis.

A Comparative Study of Optimization Algorithms for Engineering Synthesis.

DTIC Science & Technology

1983-03-01

the ADS program demonstrates the flexibility a design engineer would have in selecting an optimization algorithm best suited to solve a particular...demonstrates the flexibility a design engineer would have in selecting an optimization algorithm best suited to solve a particular problem. 4 TABLE OF...algorithm to suit a particular problem. The ADS library of design optimization algorithms was . developed by Vanderplaats in response to the first

Clonal Expansion (CE) Models in Cancer Risk Assessment

EPA Science Inventory

Cancer arises when cells accumulate sufficient critical mutations. Carcinogens increase the probability of mutation during cell division or promote clonal expansion within stages. Multistage CE models recapitulate this process and provide a framework for incorporating relevant da...

Turning rice meiosis into mitosis

PubMed Central

Mieulet, Delphine; Jolivet, Sylvie; Rivard, Maud; Cromer, Laurence; Vernet, Aurore; Mayonove, Pauline; Pereira, Lucie; Droc, Gaëtan; Courtois, Brigitte; Guiderdoni, Emmanuel; Mercier, Raphael

2016-01-01

Introduction of clonal reproduction through seeds (apomixis) in crops has the potential to revolutionize agriculture by allowing self-propagation of any elite variety, in particular F1 hybrids. In the sexual model plant Arabidopsis thaliana synthetic clonal reproduction through seeds can be artificially implemented by (i) combining three mutations to turn meiosis into mitosis (MiMe) and (ii) crossing the obtained clonal gametes with a line expressing modified CENH3 and whose genome is eliminated in the zygote. Here we show that additional combinations of mutations can turn Arabidopsis meiosis into mitosis and that a combination of three mutations in rice (Oryza sativa) efficiently turns meiosis into mitosis, leading to the production of male and female clonal diploid gametes in this major crop. Successful implementation of the MiMe technology in the phylogenetically distant eudicot Arabidopsis and monocot rice opens doors for its application to any flowering plant and paves the way for introducing apomixis in crop species. PMID:27767093

TEM Derivative-Producing Enterobacter aerogenes Strains: Dissemination of a Prevalent Clone

PubMed Central

Dumarche, P.; De Champs, C.; Sirot, D.; Chanal, C.; Bonnet, R.; Sirot, J.

2002-01-01

TEM-24 (CAZ-6) extended-spectrum β-lactamase (ESBL) was detected in 1988 in Clermont-Ferrand, France, in Klebsiella pneumoniae (blaTEM-24) and Enterobacter aerogenes (blaTEM-24b), and since 1994, a TEM-24-producing E. aerogenes clonal strain has been observed elsewhere in the country. To determine if the spread of this clonal strain was restricted to TEM-24-producing E. aerogenes strains, 84 E. aerogenes strains (non-TEM/SHV-producing strains, TEM-1- or -2-producing strains, and different ESBL-producing strains), isolated from 1988 to 1999 in Clermont-Ferrand (n = 59) and in 11 other French hospitals in 1998 (n = 25), were studied. A clonal strain was found for TEM-24- but also for TEM-3- and TEM-1- or 2-producing isolates. This study shows that there is a clonal strain dependent on acquisition of the TEM-type enzyme (TEM-24 and other TEM types). PMID:11897606

Identifying relevant hyperspectral bands using Boruta: a temporal analysis of water hyacinth biocontrol

NASA Astrophysics Data System (ADS)

Agjee, Na'eem Hoosen; Ismail, Riyad; Mutanga, Onisimo

2016-10-01

Water hyacinth plants (Eichhornia crassipes) are threatening freshwater ecosystems throughout Africa. The Neochetina spp. weevils are seen as an effective solution that can combat the proliferation of the invasive alien plant. We aimed to determine if multitemporal hyperspectral data could be utilized to detect the efficacy of the biocontrol agent. The random forest (RF) algorithm was used to classify variable infestation levels for 6 weeks using: (1) all the hyperspectral bands, (2) bands selected by the recursive feature elimination (RFE) algorithm, and (3) bands selected by the Boruta algorithm. Results showed that the RF model using all the bands successfully produced low-classification errors (12.50% to 32.29%) for all 6 weeks. However, the RF model using Boruta selected bands produced lower classification errors (8.33% to 15.62%) than the RF model using all the bands or bands selected by the RFE algorithm (11.25% to 21.25%) for all 6 weeks, highlighting the utility of Boruta as an all relevant band selection algorithm. All relevant bands selected by Boruta included: 352, 754, 770, 771, 775, 781, 782, 783, 786, and 789 nm. It was concluded that RF coupled with Boruta band-selection algorithm can be utilized to undertake multitemporal monitoring of variable infestation levels on water hyacinth plants.

A genetic algorithm based global search strategy for population pharmacokinetic/pharmacodynamic model selection

PubMed Central

Sale, Mark; Sherer, Eric A

2015-01-01

The current algorithm for selecting a population pharmacokinetic/pharmacodynamic model is based on the well-established forward addition/backward elimination method. A central strength of this approach is the opportunity for a modeller to continuously examine the data and postulate new hypotheses to explain observed biases. This algorithm has served the modelling community well, but the model selection process has essentially remained unchanged for the last 30 years. During this time, more robust approaches to model selection have been made feasible by new technology and dramatic increases in computation speed. We review these methods, with emphasis on genetic algorithm approaches and discuss the role these methods may play in population pharmacokinetic/pharmacodynamic model selection. PMID:23772792

Developing operation algorithms for vision subsystems in autonomous mobile robots

NASA Astrophysics Data System (ADS)

Shikhman, M. V.; Shidlovskiy, S. V.

2018-05-01

The paper analyzes algorithms for selecting keypoints on the image for the subsequent automatic detection of people and obstacles. The algorithm is based on the histogram of oriented gradients and the support vector method. The combination of these methods allows successful selection of dynamic and static objects. The algorithm can be applied in various autonomous mobile robots.

Solving TSP problem with improved genetic algorithm

NASA Astrophysics Data System (ADS)

Fu, Chunhua; Zhang, Lijun; Wang, Xiaojing; Qiao, Liying

2018-05-01

The TSP is a typical NP problem. The optimization of vehicle routing problem (VRP) and city pipeline optimization can use TSP to solve; therefore it is very important to the optimization for solving TSP problem. The genetic algorithm (GA) is one of ideal methods in solving it. The standard genetic algorithm has some limitations. Improving the selection operator of genetic algorithm, and importing elite retention strategy can ensure the select operation of quality, In mutation operation, using the adaptive algorithm selection can improve the quality of search results and variation, after the chromosome evolved one-way evolution reverse operation is added which can make the offspring inherit gene of parental quality improvement opportunities, and improve the ability of searching the optimal solution algorithm.

A Feature Selection Algorithm to Compute Gene Centric Methylation from Probe Level Methylation Data.

PubMed

Baur, Brittany; Bozdag, Serdar

2016-01-01

DNA methylation is an important epigenetic event that effects gene expression during development and various diseases such as cancer. Understanding the mechanism of action of DNA methylation is important for downstream analysis. In the Illumina Infinium HumanMethylation 450K array, there are tens of probes associated with each gene. Given methylation intensities of all these probes, it is necessary to compute which of these probes are most representative of the gene centric methylation level. In this study, we developed a feature selection algorithm based on sequential forward selection that utilized different classification methods to compute gene centric DNA methylation using probe level DNA methylation data. We compared our algorithm to other feature selection algorithms such as support vector machines with recursive feature elimination, genetic algorithms and ReliefF. We evaluated all methods based on the predictive power of selected probes on their mRNA expression levels and found that a K-Nearest Neighbors classification using the sequential forward selection algorithm performed better than other algorithms based on all metrics. We also observed that transcriptional activities of certain genes were more sensitive to DNA methylation changes than transcriptional activities of other genes. Our algorithm was able to predict the expression of those genes with high accuracy using only DNA methylation data. Our results also showed that those DNA methylation-sensitive genes were enriched in Gene Ontology terms related to the regulation of various biological processes.

A polarized low-coherence interferometry demodulation algorithm by recovering the absolute phase of a selected monochromatic frequency.

PubMed

Jiang, Junfeng; Wang, Shaohua; Liu, Tiegen; Liu, Kun; Yin, Jinde; Meng, Xiange; Zhang, Yimo; Wang, Shuang; Qin, Zunqi; Wu, Fan; Li, Dingjie

2012-07-30

A demodulation algorithm based on absolute phase recovery of a selected monochromatic frequency is proposed for optical fiber Fabry-Perot pressure sensing system. The algorithm uses Fourier transform to get the relative phase and intercept of the unwrapped phase-frequency linear fit curve to identify its interference-order, which are then used to recover the absolute phase. A simplified mathematical model of the polarized low-coherence interference fringes was established to illustrate the principle of the proposed algorithm. Phase unwrapping and the selection of monochromatic frequency were discussed in detail. Pressure measurement experiment was carried out to verify the effectiveness of the proposed algorithm. Results showed that the demodulation precision by our algorithm could reach up to 0.15kPa, which has been improved by 13 times comparing with phase slope based algorithm.

Normalizing gene expression by quantitative PCR during somatic embryogenesis in two representative conifer species: Pinus pinaster and Picea abies.

PubMed

de Vega-Bartol, José J; Santos, Raquen Raissa; Simões, Marta; Miguel, Célia M

2013-05-01

Suitable internal control genes to normalize qPCR data from different stages of embryo development and germination were identified in two representative conifer species. Clonal propagation by somatic embryogenesis has a great application potentiality in conifers. Quantitative PCR (qPCR) is widely used for gene expression analysis during somatic embryogenesis and embryo germination. No single reference gene is universal, so a systematic characterization of endogenous genes for concrete conditions is fundamental for accuracy. We identified suitable internal control genes to normalize qPCR data obtained at different steps of somatic embryogenesis (embryonal mass proliferation, embryo maturation and germination) in two representative conifer species, Pinus pinaster and Picea abies. Candidate genes included endogenous genes commonly used in conifers, genes previously tested in model plants, and genes with a lower variation of the expression along embryo development according to genome-wide transcript profiling studies. Three different algorithms were used to evaluate expression stability. The geometric average of the expression values of elongation factor-1α, α-tubulin and histone 3 in P. pinaster, and elongation factor-1α, α-tubulin, adenosine kinase and CAC in P. abies were adequate for expression studies throughout somatic embryogenesis. However, improved accuracy was achieved when using other gene combinations in experiments with samples at a single developmental stage. The importance of studies selecting reference genes to use in different tissues or developmental stages within one or close species, and the instability of commonly used reference genes, is highlighted.

Comparison of the DiversiLab Repetitive Element PCR System with spa Typing and Pulsed-Field Gel Electrophoresis for Clonal Characterization of Methicillin-Resistant Staphylococcus aureus▿

PubMed Central

Babouee, B.; Frei, R.; Schultheiss, E.; Widmer, A. F.; Goldenberger, D.

2011-01-01

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become an increasing problem worldwide in recent decades. Molecular typing methods have been developed to identify clonality of strains and monitor spread of MRSA. We compared a new commercially available DiversiLab (DL) repetitive element PCR system with spa typing, spa clonal cluster analysis, and pulsed-field gel electrophoresis (PFGE) in terms of discriminatory power and concordance. A collection of 106 well-defined MRSA strains from our hospital was analyzed, isolated between 1994 and 2006. In addition, we analyzed 6 USA300 strains collected in our institution. DL typing separated the 106 MRSA isolates in 10 distinct clusters and 8 singleton patterns. Clustering analysis into spa clonal complexes resulted in 3 clusters: spa-CC 067/548, spa-CC 008, and spa-CC 012. The discriminatory powers (Simpson's index of diversity) were 0.982, 0.950, 0.846, and 0.757 for PFGE, spa typing, DL typing, and spa clonal clustering, respectively. DL typing and spa clonal clustering showed the highest concordance, calculated by adjusted Rand's coefficients. The 6 USA300 isolates grouped homogeneously into distinct PFGE and DL clusters, and all belonged to spa type t008 and spa-CC 008. Among the three methods, DL proved to be rapid and easy to perform. DL typing qualifies for initial screening during outbreak investigation. However, compared to PFGE and spa typing, DL typing has limited discriminatory power and therefore should be complemented by more discriminative methods in isolates that share identical DL patterns. PMID:21307215

Significance of clonal rearrangements of lymphocyte antigen receptor genes on the prognosis of chronic enteropathy in 22 Shiba dogs.

PubMed

Ohmi, Aki; Ohno, Koichi; Uchida, Kazuyuki; Goto-Koshino, Yuko; Tomiyasu, Hirotaka; Kanemoto, Hideyuki; Fukushima, Kenjiro; Tsujimoto, Hajime

2017-09-29

Shiba dogs are predisposed to chronic enteropathy (CE) and have poorer prognosis than other dog breeds. The objective of this study was to investigate the significance of polymerase chain reaction for antigen receptor rearrangement (PARR) results on clinical findings and prognosis of Shiba dogs with CE. We retrospectively collected data on 22 Shiba dogs diagnosed as having CE. Fifty-nine percent of the dogs had clonality-positive results on PARR analysis. Furthermore, on histopathology, epitheliotropic behavior of small lymphocytes of the intestinal mucosa was observed significantly more frequently in dogs with clonal rearrangement of antigen receptor genes (P=0.027). The median overall survival time of clonality-positive dogs was 48 days (range, 4-239 days), compared to 271 days (range, 45-1,316+ days) in clonality-negative dogs. The median overall survival time of epitheliotropism-positive dogs was 76 days (range, 30-349 days) compared to 239 days (range, 4-1,316+ days) for epitheliotropism-negative dogs. Statistical analysis revealed that the clonality-positive result was associated with significantly shorter survival time (P=0.036). In contrast, presence or absence of epitheliotropism had no statistically significant effect on survival time (P=0.223). These cases might appropriately be diagnosed as small T-cell intestinal lymphoma; there are some common clinical and pathogenic features with human enteropathy-associated T-cell lymphoma type 2. The pathogenesis and poor prognosis for Shiba dogs with CE seem to be associated with this type of lymphoma, although further investigation is warranted.

Clonality, virulence and antimicrobial resistance of enteroaggregative Escherichia coli from Mirzapur, Bangladesh.

PubMed

Chattaway, Marie Anne; Day, Michaela; Mtwale, Julia; White, Emma; Rogers, James; Day, Martin; Powell, David; Ahmad, Marwa; Harris, Ross; Talukder, Kaisar Ali; Wain, John; Jenkins, Claire; Cravioto, Alejandro

2017-10-01

This study investigates the virulence and antimicrobial resistance in association with common clonal complexes (CCs) of enteroaggregative Escherichia coli (EAEC) isolated from Bangladesh. The aim was to determine whether specific CCs were more likely to be associated with putative virulence genes and/or antimicrobial resistance. The presence of 15 virulence genes (by PCR) and susceptibility to 18 antibiotics were determined for 151 EAEC isolated from cases and controls during an intestinal infectious disease study carried out between 2007-2011 in the rural setting of Mirzapur, Bangladesh (Kotloff KL, Blackwelder WC, Nasrin D, Nataro JP, Farag TH et al.Clin Infect Dis 2012;55:S232-S245). These data were then analysed in the context of previously determined serotypes and clonal complexes defined by multi-locus sequence typing. Overall there was no association between the presence of virulence or antimicrobial resistance genes in isolates of EAEC from cases versus controls. However, when stratified by clonal complex (CC) one CC associated with cases harboured more virulence factors (CC40) and one CC harboured more resistance genes (CC38) than the average. There was no direct link between the virulence gene content and antibiotic resistance. Strains within a single CC had variable virulence and resistance gene content indicating independent and multiple gene acquisitions over time. In Bangladesh, there are multiple clonal complexes of EAEC harbouring a variety of virulence and resistance genes. The emergence of two of the most successful clones appeared to be linked to either increased virulence (CC40) or antimicrobial resistance (CC38), but increased resistance and virulence were not found in the same clonal complexes.

Generation of Stable Knockout Mammalian Cells by TALEN-Mediated Locus-Specific Gene Editing.

PubMed

Mahata, Barun; Biswas, Kaushik

2017-01-01

Precise and targeted genome editing using Transcription Activator-Like Effector Endonucleases (TALENs) has been widely used and proven to be an extremely effective and specific knockout strategy in both cultured cells and animal models. The current chapter describes a protocol for the construction and generation of TALENs using serial and hierarchical digestion and ligation steps, and using the synthesized TALEN pairs to achieve locus-specific targeted gene editing in mammalian cell lines using a modified clonal selection strategy in an easy and cost-efficient manner.

Clonal integration in Ludwigia hexapetala under different light regimes

USDA-ARS?s Scientific Manuscript database

Physiological integration among ramets of invasive plant species may support their colonization and spread in novel aquatic environments where growth-limiting resources are spatially heterogeneous. Under contrasting light conditions, we investigated how clonal integration influences growth, biomass...

HIV genetic information and clonal growth

Cancer.gov

Based on an analysis of blood cells from five HIV-infected individuals, NCI researchers have identified more than 2,400 HIV DNA insertion sites. Analysis of these sites showed that there is extensive clonal expansion (growth) of HIV infected cells.

Microcoppice: a new strategy for red oak clonal propagation

Treesearch

D.E. Harper; B.H. McCown

1991-01-01

The great demand for red oak (Quercus rubra L.) has forced plant propagators to consider viable methods of mass clonal propagation for the species. A process called 'microcoppicing' is presently being developed to help meet such needs.

V2.1.4 L2AS Detailed Release Description September 27, 2001

Atmospheric Science Data Center

2013-03-14

... 27, 2001 Algorithm Changes Change method of selecting radiance pixels to use in aerosol retrieval over ... het. surface retrieval algorithm over areas of 100% dark water. Modify algorithm for selecting a default aerosol model to use in ...

Optimal Parameter Design of Coarse Alignment for Fiber Optic Gyro Inertial Navigation System.

PubMed

Lu, Baofeng; Wang, Qiuying; Yu, Chunmei; Gao, Wei

2015-06-25

Two different coarse alignment algorithms for Fiber Optic Gyro (FOG) Inertial Navigation System (INS) based on inertial reference frame are discussed in this paper. Both of them are based on gravity vector integration, therefore, the performance of these algorithms is determined by integration time. In previous works, integration time is selected by experience. In order to give a criterion for the selection process, and make the selection of the integration time more accurate, optimal parameter design of these algorithms for FOG INS is performed in this paper. The design process is accomplished based on the analysis of the error characteristics of these two coarse alignment algorithms. Moreover, this analysis and optimal parameter design allow us to make an adequate selection of the most accurate algorithm for FOG INS according to the actual operational conditions. The analysis and simulation results show that the parameter provided by this work is the optimal value, and indicate that in different operational conditions, the coarse alignment algorithms adopted for FOG INS are different in order to achieve better performance. Lastly, the experiment results validate the effectiveness of the proposed algorithm.

Log-linear model based behavior selection method for artificial fish swarm algorithm.

PubMed

Huang, Zhehuang; Chen, Yidong

2015-01-01

Artificial fish swarm algorithm (AFSA) is a population based optimization technique inspired by social behavior of fishes. In past several years, AFSA has been successfully applied in many research and application areas. The behavior of fishes has a crucial impact on the performance of AFSA, such as global exploration ability and convergence speed. How to construct and select behaviors of fishes are an important task. To solve these problems, an improved artificial fish swarm algorithm based on log-linear model is proposed and implemented in this paper. There are three main works. Firstly, we proposed a new behavior selection algorithm based on log-linear model which can enhance decision making ability of behavior selection. Secondly, adaptive movement behavior based on adaptive weight is presented, which can dynamically adjust according to the diversity of fishes. Finally, some new behaviors are defined and introduced into artificial fish swarm algorithm at the first time to improve global optimization capability. The experiments on high dimensional function optimization showed that the improved algorithm has more powerful global exploration ability and reasonable convergence speed compared with the standard artificial fish swarm algorithm.

Tissue homeostasis and immunity--more on models.

PubMed

Cunliffe, J

2006-09-01

This article continues the ongoing debate around models of the immune system. Earlier contributors have paid much attention to the various processes that lead to adaptive immune system aggression or tolerance. They have often based their discussions around facts that have been established by experimental investigation. However, both the observation and interpretation of these facts have been influenced by the function--or system goal--that is believed to have generated them. The perception of this function (of all or part of the immune system) is influenced by long established theories in immunology (e.g. horror autotoxicus, clonal deletion in utero, pathogen elimination, clonal selection, auto-immunity and so on) which, for many, have become enshrined as facts. One function that has had less consideration and has not been extensively investigated is the maintenance of tissue homeostasis. When the immune system is viewed from this perspective, the facts invite alternative interpretations. Whilst this perspective may not necessarily be the only valid one, let alone a correct one, viewing things this way--at least briefly--might help to expose hidden assumptions. It also emphasizes that the immune system is a system and, as such, it can by analysed through the principles of general systems theory.

Label retention identifies a multipotent mesenchymal stem cell-like population in the postnatal thymus.

PubMed

Osada, Masako; Singh, Varan J; Wu, Kenmin; Sant'Angelo, Derek B; Pezzano, Mark

2013-01-01

Thymic microenvironments are essential for the proper development and selection of T cells critical for a functional and self-tolerant adaptive immune response. While significant turnover occurs, it is unclear whether populations of adult stem cells contribute to the maintenance of postnatal thymic epithelial microenvironments. Here, the slow cycling characteristic of stem cells and their property of label-retention were used to identify a K5-expressing thymic stromal cell population capable of generating clonal cell lines that retain the capacity to differentiate into a number of mesenchymal lineages including adipocytes, chondrocytes and osteoblasts suggesting a mesenchymal stem cell-like phenotype. Using cell surface analysis both culture expanded LRCs and clonal thymic mesenchymal cell lines were found to express Sca1, PDGFRα, PDGFRβ,CD29, CD44, CD49F, and CD90 similar to MSCs. Sorted GFP-expressing stroma, that give rise to TMSC lines, contribute to thymic architecture when reaggregated with fetal stroma and transplanted under the kidney capsule of nude mice. Together these results show that the postnatal thymus contains a population of mesenchymal stem cells that can be maintained in culture and suggests they may contribute to the maintenance of functional thymic microenvironments.

Aborted fruits of Opuntia microdasys (Cactaceae): insurance against reproductive failure.

PubMed

Palleiro, N; Mandujano, M C; Golubov, J

2006-04-01

New individuals in clonal populations arise through the recruitment of sexual or clonal offspring. The predominance of one type of regeneration over the other has been correlated with different selective environmental pressures. We compared the reproductive mode (sexual through seeds and vegetative through plantlets or detached cladodes) of Opuntia microdasys from three desert habitats of the Chihuahuan Desert: bajada (BH), hill-piedmont (HPH), and an interdune (IDH). Successful establishment and growth of plantlets were determined in two experiments: (1) the effect of light (three levels of photosynthetically active radiation [PAR]: full, low, and medium) and two levels of watering and (2) maternal effects and provenance of plantlets. Adult plant densities did not differ among habitats (639 individuals/ha), but the number of offspring and fruit production increased significantly at BH. Plantlets (94.3%) dominated the form of recruitment for all habitats, followed by cladodes (3.1%) and seedlings (2.6%). A higher proportion of plantlets established in the low and medium PAR treatments (76%) in comparison to full exposure (39%). Maternal factors affected survival and growth, but plantlet provenance did not. The high fruit abortion rate resulting from environmental and maternal effects provided suitable conditions for establishment of plantlets.

Fanconi anemia.

PubMed

Soulier, Jean

2011-01-01

Fanconi anemia (FA) is the most frequent inherited cause of BM failure (BMF). Fifteen FANC genes have been identified to date, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. In addition to classical presentations with progressive BMF during childhood and a positive chromosome breakage test in the blood, atypical clinical and/or biological situations can be seen in which a FA diagnosis has to be confirmed or eliminated. For this, a range of biological tools have been developed, including analysis of skin fibroblasts. FA patients experience a strong selective pressure in the BM that predisposes to clonal evolution and to the emergence in their teens or young adulthood of myelodysplasia syndrome (MDS) and/or acute myeloid leukemia (AML) with a specific pattern of somatic chromosomal lesions. The cellular mechanisms underlying (1) the hematopoietic defect which leads to progressive BMF and (2) somatic clonal evolutions in this background, are still largely elusive. Elucidation of these mechanisms at the molecular and cellular levels should be useful to understand the physiopathology of the disease and to adapt the follow-up and treatment of FA patients. This may also ultimately benefit older, non-FA patients with aplastic anemia, MDS/AML for whom FA represents a model genetic condition.

Differential effects of immunosuppressive drugs on T-cell motility.

PubMed

Datta, A; David, R; Glennie, S; Scott, D; Cernuda-Morollon, E; Lechler, R I; Ridley, A J; Marelli-Berg, F M

2006-12-01

The best-characterized mechanism of the action of immunosuppressive drugs is to prevent T-cell clonal expansion, thus containing the magnitude of the ensuing immune response. As T-cell recruitment to the inflammatory site is another key step in the development of T-cell-mediated inflammation, we analyzed and compared the effects of two commonly used immunosuppressants, cyclosporin A (CsA) and the rapamycin-related compound SDZ-RAD, on the motility of human CD4+ T cells. We show that CsA, but not SDZ-RAD, inhibits T-cell transendothelial migration in vitro. CsA selectively impaired chemokine-induced T-cell chemotaxis while integrin-mediated migration was unaffected. The inhibition of T-cell chemotaxis correlated with reduced AKT/PKB but not ERK activation following exposure to the chemokine CXCL-12/SDF-1. In addition, CsA, but not SDZ-RAD, prevents some T-cell receptor-mediated effects on T-cell motility. Finally, we show that CsA, but not SDZ-RAD inhibits tissue infiltration by T cells in vivo. Our data suggest a prominent antiinflammatory role for CsA in T-cell-mediated tissue damage, by inhibiting T-cell trafficking into tissues in addition to containing clonal expansion.

Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture.

PubMed

Jothi, Raja; Balaji, S; Wuster, Arthur; Grochow, Joshua A; Gsponer, Jörg; Przytycka, Teresa M; Aravind, L; Babu, M Madan

2009-01-01

Although several studies have provided important insights into the general principles of biological networks, the link between network organization and the genome-scale dynamics of the underlying entities (genes, mRNAs, and proteins) and its role in systems behavior remain unclear. Here we show that transcription factor (TF) dynamics and regulatory network organization are tightly linked. By classifying TFs in the yeast regulatory network into three hierarchical layers (top, core, and bottom) and integrating diverse genome-scale datasets, we find that the TFs have static and dynamic properties that are similar within a layer and different across layers. At the protein level, the top-layer TFs are relatively abundant, long-lived, and noisy compared with the core- and bottom-layer TFs. Although variability in expression of top-layer TFs might confer a selective advantage, as this permits at least some members in a clonal cell population to initiate a response to changing conditions, tight regulation of the core- and bottom-layer TFs may minimize noise propagation and ensure fidelity in regulation. We propose that the interplay between network organization and TF dynamics could permit differential utilization of the same underlying network by distinct members of a clonal cell population.

Gene-Specific Demethylation as Targeted Therapy in MDS

DTIC Science & Technology

2017-07-01

SUPPLEMENTARY NOTES 14. ABSTRACT Myelodysplastic Syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and...clonal hematopoietic disorders characterized by bone marrow failure and risk of progression to Acute Myeloid Leukemia (AML) in approximately 30 percent

Different osteochondral potential of clonal cell lines derived from adult human trabecular bone.

PubMed

Osyczka, Anna M; Nöth, Ulrich; Danielson, Keith G; Tuan, Rocky S

2002-06-01

Cells derived from human trabecular bones have been shown to have multipotential differentiation ability along osteogenic, chondrogenic, and adipogenic lineages. In this study, we have derived two clonal sublines of human trabecular bone cells by means of stable transduction with human papilloma virus E6/E7 genes. Our results showed that these clonal sublines differ in their osteochondral potential, but are equally adipogenic, indicative of the heterogeneous nature of the parental cell population. The availability of these cell lines should be useful for the analysis of the mechanisms regulating the differentiation of adult mesenchymal progenitor cells.

Incidence, size and spatial structure of clones in second-growth stands of coast redwood, Sequoia sempervirens (Cupressaceae).

PubMed

Douhovnikoff, Vladimir; Cheng, Adelaide M; Dodd, Richard S

2004-07-01

The ecology and evolutionary potential of coast redwood (Sequoia sempervirens) is significantly influenced by the important role clonal spread plays in its reproduction and site persistence. In nine second-growth stands, amplified fragment length polymorphisms (AFLPs) were used to identify redwood clonal architecture. Clones (multistem genets) dominated sites by representing an average of 70% of stems measured, ranging in size from two to 20 stems. As a result, a relatively small number of genets can monopolize a disproportionate amount of site resources, are more likely to persist over time, and have greater on-site genetic representation. Clones were not limited to fairy-ring structures, but consisted of a wide range of shapes including concentric rings, ring chains, disjunct, and linear structures. Between-ramet distances of up to 40 m were measured, indicating that clonal reproduction is not limited to basal stump resprouting. Clonal structure in second-growth stands was similar to earlier reports from old growth, emphasizing the importance of site persistence and long-term, gradual site development. Smaller ramet numbers per genet in old growth is probably due to local within-genet self thinning. Management and conservation of redwoods will benefit from a better understanding of the dynamics and structure of clonal spread in these forests.

Critical analysis of the stringent complete response in multiple myeloma: contribution of sFLC and bone marrow clonality

PubMed Central

Paiva, Bruno; López-Anglada, Lucía; Mateos, María-Victoria; Cedena, Teresa; Vidríales, María-Belén; Sáez-Gómez, María Auxiliadora; Contreras, Teresa; Oriol, Albert; Rapado, Inmaculada; Teruel, Ana-Isabel; Cordón, Lourdes; Blanchard, María Jesús; Bengoechea, Enrique; Palomera, Luis; de Arriba, Felipe; Cueto-Felgueroso, Cecilia; Orfao, Alberto; Bladé, Joan; San Miguel, Jesús F.; Lahuerta, Juan José

2015-01-01

Stringent complete response (sCR) criteria are used in multiple myeloma as a deeper response category compared with CR, but prospective validation is lacking, it is not always clear how evaluation of clonality is performed, and is it not known what the relative clinical influence is of the serum free light chain ratio (sFLCr) and bone marrow (BM) clonality to define more sCR. To clarify this controversy, we focused on 94 patients that reached CR, of which 69 (73%) also fulfilled the sCR criteria. Patients with sCR displayed slightly longer time to progression (median, 62 vs 53 months, respectively; P = .31). On analyzing this contribution to the prognosis of sFLCr or clonality, it was found that the sFLCr does not identify patients in CR at distinct risk; by contrast, low-sensitive multiparametric flow cytometry (MFC) immunophenotyping (2 colors), which is equivalent to immunohistochemistry, identifies a small number of patients (5 cases) with high residual tumor burden and dismal outcome; nevertheless, using traditional 4-color MFC, persistent clonal BM disease was detectable in 36% of patients, who, compared with minimal residual disease-negative cases, had a significantly inferior outcome. These results show that the current definition of sCR should be revised. PMID:26089396

Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis.

PubMed

Chaudry, Sabah F; Chevassut, Timothy J T

2017-01-01

Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation. Dysfunction of epigenetic modifiers contributes significantly to the pathogenesis of AML. One frequently mutated gene involved in epigenetic modification is DNMT3A (DNA methyltransferase-3-alpha), a DNA methyltransferase that alters gene expression by de novo methylation of cytosine bases at CpG dinucleotides. Approximately 22% of AML and 36% of cytogenetically normal AML cases carry DNMT3A mutations and around 60% of these mutations affect the R882 codon. These mutations have been associated with poor prognosis and adverse survival outcomes for AML patients. Advances in whole-exome sequencing techniques have recently identified a large number of DNMT3A mutations present in clonal cells in normal elderly individuals with no features of haematological malignancy. Categorically distinct from other preleukaemic conditions, this disorder has been termed clonal haematopoiesis of indeterminate potential (CHIP). Further insight into the mutational landscape of CHIP may illustrate the consequence of particular mutations found in DNMT3A and identify specific "founder" mutations responsible for clonal expansion that may contribute to leukaemogenesis. This review will focus on current research and understanding of DNMT3A mutations in both AML and CHIP.

Analysis of the clonal repertoire of gene-corrected cells in gene therapy.

PubMed

Paruzynski, Anna; Glimm, Hanno; Schmidt, Manfred; Kalle, Christof von

2012-01-01

Gene therapy-based clinical phase I/II studies using integrating retroviral vectors could successfully treat different monogenetic inherited diseases. However, with increased efficiency of this therapy, severe side effects occurred in various gene therapy trials. In all cases, integration of the vector close to or within a proto-oncogene contributed substantially to the development of the malignancies. Thus, the in-depth analysis of integration site patterns is of high importance to uncover potential clonal outgrowth and to assess the safety of gene transfer vectors and gene therapy protocols. The standard and nonrestrictive linear amplification-mediated PCR (nrLAM-PCR) in combination with high-throughput sequencing exhibits technologies that allow to comprehensively analyze the clonal repertoire of gene-corrected cells and to assess the safety of the used vector system at an early stage on the molecular level. It enables clarifying the biological consequences of the vector system on the fate of the transduced cell. Furthermore, the downstream performance of real-time PCR allows a quantitative estimation of the clonality of individual cells and their clonal progeny. Here, we present a guideline that should allow researchers to perform comprehensive integration site analysis in preclinical and clinical studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Genomic Analysis of the Emergence and Rapid Global Dissemination of the Clonal Group 258 Klebsiella pneumoniae Pandemic

PubMed Central

Driebe, Elizabeth M.; MacCannell, Duncan R.; Roe, Chandler; Lemmer, Darrin; de Man, Tom; Rasheed, J. Kamile; Engelthaler, David M.; Keim, Paul; Limbago, Brandi M.

2015-01-01

Multidrug-resistant Klebsiella pneumoniae producing the KPC carbapenemase have rapidly spread throughout the world, causing severe healthcare-associated infections with limited antimicrobial treatment options. Dissemination of KPC-producing K. pneumoniae is largely attributed to expansion of a single dominant strain, ST258. In this study, we explore phylogenetic relationships and evolution within ST258 and its clonal group, CG258, using whole genome sequence analysis of 167 isolates from 20 countries collected over 17 years. Our results show a common ST258 ancestor emerged from its diverse parental clonal group around 1995 and likely acquired bla KPC prior to dissemination. Over the past two decades, ST258 has remained highly clonal despite diversity in accessory elements and divergence in the capsule polysaccharide synthesis locus. Apart from the large recombination event that gave rise to ST258, few mutations set it apart from its clonal group. However, one mutation occurs in a global transcription regulator. Characterization of outer membrane protein sequences revealed a profile in ST258 that includes a truncated OmpK35 and modified OmpK37. Our work illuminates potential genomic contributors to the pathogenic success of ST258, helps us better understand the global dissemination of this strain, and identifies genetic markers unique to ST258. PMID:26196384

A hybrid intelligent algorithm for portfolio selection problem with fuzzy returns

NASA Astrophysics Data System (ADS)

Li, Xiang; Zhang, Yang; Wong, Hau-San; Qin, Zhongfeng

2009-11-01

Portfolio selection theory with fuzzy returns has been well developed and widely applied. Within the framework of credibility theory, several fuzzy portfolio selection models have been proposed such as mean-variance model, entropy optimization model, chance constrained programming model and so on. In order to solve these nonlinear optimization models, a hybrid intelligent algorithm is designed by integrating simulated annealing algorithm, neural network and fuzzy simulation techniques, where the neural network is used to approximate the expected value and variance for fuzzy returns and the fuzzy simulation is used to generate the training data for neural network. Since these models are used to be solved by genetic algorithm, some comparisons between the hybrid intelligent algorithm and genetic algorithm are given in terms of numerical examples, which imply that the hybrid intelligent algorithm is robust and more effective. In particular, it reduces the running time significantly for large size problems.

A family of variable step-size affine projection adaptive filter algorithms using statistics of channel impulse response

NASA Astrophysics Data System (ADS)

Shams Esfand Abadi, Mohammad; AbbasZadeh Arani, Seyed Ali Asghar

2011-12-01

This paper extends the recently introduced variable step-size (VSS) approach to the family of adaptive filter algorithms. This method uses prior knowledge of the channel impulse response statistic. Accordingly, optimal step-size vector is obtained by minimizing the mean-square deviation (MSD). The presented algorithms are the VSS affine projection algorithm (VSS-APA), the VSS selective partial update NLMS (VSS-SPU-NLMS), the VSS-SPU-APA, and the VSS selective regressor APA (VSS-SR-APA). In VSS-SPU adaptive algorithms the filter coefficients are partially updated which reduce the computational complexity. In VSS-SR-APA, the optimal selection of input regressors is performed during the adaptation. The presented algorithms have good convergence speed, low steady state mean square error (MSE), and low computational complexity features. We demonstrate the good performance of the proposed algorithms through several simulations in system identification scenario.

[Combining speech sample and feature bilateral selection algorithm for classification of Parkinson's disease].

PubMed

Zhang, Xiaoheng; Wang, Lirui; Cao, Yao; Wang, Pin; Zhang, Cheng; Yang, Liuyang; Li, Yongming; Zhang, Yanling; Cheng, Oumei

2018-02-01

Diagnosis of Parkinson's disease (PD) based on speech data has been proved to be an effective way in recent years. However, current researches just care about the feature extraction and classifier design, and do not consider the instance selection. Former research by authors showed that the instance selection can lead to improvement on classification accuracy. However, no attention is paid on the relationship between speech sample and feature until now. Therefore, a new diagnosis algorithm of PD is proposed in this paper by simultaneously selecting speech sample and feature based on relevant feature weighting algorithm and multiple kernel method, so as to find their synergy effects, thereby improving classification accuracy. Experimental results showed that this proposed algorithm obtained apparent improvement on classification accuracy. It can obtain mean classification accuracy of 82.5%, which was 30.5% higher than the relevant algorithm. Besides, the proposed algorithm detected the synergy effects of speech sample and feature, which is valuable for speech marker extraction.

Clonal predominance of CD8+ T cells in patients with unexplained neutropenia

PubMed Central

Wlodarski, Marcin Wojciech; Nearman, Zachary; Jiang, Ying; Lichtin, Alan; Maciejewski, Jaroslaw Pawel

2008-01-01

Objective T-cell-mediated autoimmunity may be involved in some cases of idiopathic neutropenia. We hypothesized that a precise T-cell receptor repertoire analysis may uncover cytotoxic T-cell (CTL) expansions that are less pronounced than those seen in T large granular lymphocyte leukemia (T-LGL), but are pathophysiologically analogous and thus can serve as markers of a T-cell-mediated process. Materials and Methods Using rational algorithms for T-cell receptor analysis and in vivo tracking of CTL responses previously established in our laboratory, we studied patients with unexplained chronic neutropenia (n = 20), T-LGL (n = 15), and healthy controls (n = 12). We further investigated the involvement of soluble inhibitory factors by coculture assays. To determine the level of immune activation, we studied interferon-g expression in CD8+cells using Taqman polymerase chain reaction. Results Fifteen expanded (immunodominant) CTL clones were detected in 12 of 20 patients. In comparison to LGL leukemia, these clones were less immunodominant, but clearly discernible from subclinical lymphoproliferations in controls. As a surrogate of cytotoxic activity, we found markedly increased production of interferon-γ in most of the neutropenia patients, irrespective of the presence of immunodominant CTL clones. Conclusions These results suggest that, while immunodominant CTL clones are detectable in a proportion of patients only, CTL-mediated pathophysiology may be a general mechanism operating in idiopathic neutropenia. Oligogoclonal CTL expansions in chronic neutropenia may indicate an ongoing autoimmune process, while highly polarized monoclonalities in a subset of neutropenic LGL patients may represent the “extreme” end of the clonal continuum. PMID:18279717

Development of a two-stage gene selection method that incorporates a novel hybrid approach using the cuckoo optimization algorithm and harmony search for cancer classification.

PubMed

Elyasigomari, V; Lee, D A; Screen, H R C; Shaheed, M H

2017-03-01

For each cancer type, only a few genes are informative. Due to the so-called 'curse of dimensionality' problem, the gene selection task remains a challenge. To overcome this problem, we propose a two-stage gene selection method called MRMR-COA-HS. In the first stage, the minimum redundancy and maximum relevance (MRMR) feature selection is used to select a subset of relevant genes. The selected genes are then fed into a wrapper setup that combines a new algorithm, COA-HS, using the support vector machine as a classifier. The method was applied to four microarray datasets, and the performance was assessed by the leave one out cross-validation method. Comparative performance assessment of the proposed method with other evolutionary algorithms suggested that the proposed algorithm significantly outperforms other methods in selecting a fewer number of genes while maintaining the highest classification accuracy. The functions of the selected genes were further investigated, and it was confirmed that the selected genes are biologically relevant to each cancer type. Copyright © 2017. Published by Elsevier Inc.