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Phenotypic, Genomic and Functional Characterization Reveals No Differences between CD138++ and CD138low Subpopulations in Multiple Myeloma Cell Lines  [PDF]
Teresa Paíno, María E. Sarasquete, Bruno Paiva, Patryk Krzeminski, Laura San-Segundo, Luis A. Corchete, Alba Redondo, Mercedes Garayoa, Ramón García-Sanz, Norma C. Gutiérrez, Enrique M. Ocio, Jesús F. San-Miguel
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092378
Abstract: Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95–99%) and CD138low (1–5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.
Behavioral individuality reveals genetic control of phenotypic variability  [PDF]
Julien F. Ayroles,Sean M. Buchanan,Chelsea Jenney,Kyobi Skutt-Kakaria,Jennifer Grenier,Andrew G. Clark,Daniel L. Hartl,Benjamin L. de Bivort
Quantitative Biology , 2014,
Abstract: Variability is ubiquitous in nature and a fundamental feature of complex systems. Few studies, however, have investigated variance itself as a trait under genetic control. By focusing primarily on trait means and ignoring the effect of alternative alleles on trait variability, we may be missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used a panel of Drosophila inbred lines and focused on locomotor handedness, in an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals while others had low levels. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicated a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We have validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. This study reveals the constellation of phenotypes that can arise from a single genotype and it shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variability. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.
Integrated method for adaptability and phenotypic stability analysis
Vasconcelos, Edmar Soares de;Reis, Múcio Silva;Cruz, Cosme Dami?o;Sediyama, Tuneo;Scapim, Carlos Alberto;
Acta Scientiarum. Agronomy , 2011, DOI: 10.4025/actasciagron.v33i2.8272
Abstract: the objectives of this study were a description of the centroid method, which is used to investigate the phenotypic adaptability of genotypes and the inclusion of new ideotypes therein, creating the integrated method for adaptability and phenotypic stability analysis, as well as a comparison of the two methods in a study example. as an applied example of the new proposal, grain yield data of 14 soybean genotypes from experiments at four locations in the state of minas gerais were used. in a comparison, the qualitative and quantitative gains of the centroid method with seven ideotypes were higher than of the centroid method with only four ideotypes for adaptability analysis. with the incorporation of the new ideotypes into the centroid method other concepts for the adaptability and phenotypic stability analysis are represented and the modified method was designated "integrated method of adaptability and stability analysis". cs 801 genotype was classified as the genotype with best adaptability to the environments vi?osa, florestal, s?o gotardo and rio paranaiba. the stability of the genotypes cac 1, cs 741, splendor, ufv 16, ufv 19, ufvp iv-6, ufvp iv-8, ufvp v-15, ufvp v-7, and ufv98700739 was classified as general.
Single-Cell Profiling Reveals the Origin of Phenotypic Variability in Adipogenesis  [PDF]
Thuc T. Le, Ji-Xin Cheng
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005189
Abstract: Phenotypic heterogeneity in a clonal cell population is a well-observed but poorly understood phenomenon. Here, a single-cell approach is employed to investigate non-mutative causes of phenotypic heterogeneity during the differentiation of 3T3-L1 cells into fat cells. Using coherent anti-Stokes Raman scattering microscopy and flow cytometry, adipogenic gene expression, insulin signaling, and glucose import are visualized simultaneously with lipid droplet accumulation in single cells. Expression of adipogenic genes PPARγ, C/EBPα, aP2, LP2 suggests a commitment to fat cell differentiation in all cells. However, the lack of lipid droplet in many differentiating cells suggests adipogenic gene expression is insufficient for lipid droplet formation. Instead, cell-to-cell variability in lipid droplet formation is dependent on the cascade responses of an insulin signaling pathway which includes insulin sensitivity, kinase activity, glucose import, expression of an insulin degradation enzyme, and insulin degradation rate. Increased and prolonged insulin stimulation promotes lipid droplet accumulation in all differentiating cells. Single-cell profiling reveals the kinetics of an insulin signaling cascade as the origin of phenotypic variability in drug-inducible adipogenesis.
Analysis of Epithelial and Mesenchymal Markers in Ovarian Cancer Reveals Phenotypic Heterogeneity and Plasticity  [PDF]
Robert Strauss,Zong-Yi Li,Ying Liu,Ines Beyer,Jonas Persson,Pavel Sova,Thomas M?ller,Sari Pesonen,Akseli Hemminki,Petra Hamerlik,Charles Drescher,Nicole Urban,Jiri Bartek,André Lieber
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016186
Abstract: In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherinlow/cytoplasmic E-cadherinhigh/CD133high, CD44high, Tie2low) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.
Phenotypic landscape inference reveals multiple evolutionary paths to C$_4$ photosynthesis  [PDF]
Ben P. Williams,Iain G. Johnston,Sarah Covshoff,Julian M. Hibberd
Quantitative Biology , 2014, DOI: 10.7554/eLife.00961
Abstract: C$_4$ photosynthesis has independently evolved from the ancestral C$_3$ pathway in at least 60 plant lineages, but, as with other complex traits, how it evolved is unclear. Here we show that the polyphyletic appearance of C$_4$ photosynthesis is associated with diverse and flexible evolutionary paths that group into four major trajectories. We conducted a meta-analysis of 18 lineages containing species that use C$_3$, C$_4$, or intermediate C$_3$-C$_4$ forms of photosynthesis to parameterise a 16-dimensional phenotypic landscape. We then developed and experimentally verified a novel Bayesian approach based on a hidden Markov model that predicts how the C$_4$ phenotype evolved. The alternative evolutionary histories underlying the appearance of C$_4$ photosynthesis were determined by ancestral lineage and initial phenotypic alterations unrelated to photosynthesis. We conclude that the order of C$_4$ trait acquisition is flexible and driven by non-photosynthetic drivers. This flexibility will have facilitated the convergent evolution of this complex trait.
Phenotypic and Gene Expression Differences between DA, BN and WOKW Rats  [PDF]
J?rn Lange, Thomas Barz, Axel Ekkernkamp, Barbara Wilke, Ingrid Kl?ting, Niels Follak
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038981
Abstract: Background Because inbred rat strains are widely used as laboratory models, knowledge of phenotypic and genetic variations between strains will be useful to obtain insight into the relationship between different strains. Methods and Results We studied phenotypic traits: of each strain – BN/K, DA/K and WOKW –10 male rats were studied for body weight and serum constituents at an age of 10 and 30 weeks. In addition, a total of 95 rats were studied for life expectancy. At an age of 30 weeks, these male rats were killed by an overdose of anesthetic (Sevofluran, Abbott), and the subcutaneous and visceral adipose tissue as well as bone tissue were removed to study the expression of 20 genes. There were significant differences in body weight, serum lipids and leptin at an age of 30 weeks between strains. Regarding life expectancy, BN rats lived longest (1072±228d). The highest gene expression was found in bone of BN rats. In adipose tissues, Nfkb1 is only expressed in subcutaneous adipocytes, and 5 genes, Col2a1, Mmp9, Tnfa, Ins1 and Cyp24a1, are not expressed in adipocytes. The ranking BN = DA>WOKW was observed in only one gene in subcutaneous (Fto) and visceral adipocytes (Col6a1). There were no significant differences in gene expression of one gene in subcutaneous adipocytes and of 3 genes in visceral adipocytes. Comparing the gene expression in visceral and subcutaneous adipocytes, only one gene showed a comparable behavior (Bmp1). Conclusion From these results, it can be concluded that obvious phenotypic differences are caused by genetic differences between three rat strains, BN, DA and WOKW, as supported by gene expression studies in bone and adipose tissues. Especially BN rats can be used to study the genetic basis of long life.
Phenotypic plasticity, QTL mapping and genomic characterization of bud set in black poplar
Francesco Fabbrini, Muriel Gaudet, Catherine Bastien, Giusi Zaina, Antoine Harfouche, Isacco Beritognolo, Nicolas Marron, Michele Morgante, Giuseppe Scarascia-Mugnozza, Maurizio Sabatti
BMC Plant Biology , 2012, DOI: 10.1186/1471-2229-12-47
Abstract: Six crucial phenological stages of bud set were scored. Night length appeared to be the most important signal triggering the onset of growth cessation. Nevertheless, the effect of other environmental factors, such as temperature, increased during the process. Moreover, a considerable role of genotype × environment (G × E) interaction was found in all phenological stages with the lowest temperature appearing to influence the sensitivity of the most plastic genotypes.Descriptors of growth cessation and bud onset explained the largest part of phenotypic variation of the entire process. Quantitative trait loci (QTL) for these traits were detected. For the four selected traits (the onset of growth cessation (date2.5), the transition from shoot to bud (date1.5), the duration of bud formation (subproc1) and bud maturation (subproc2)) eight and sixteen QTL were mapped on the maternal and paternal map, respectively. The identified QTL, each one characterized by small or modest effect, highlighted the complex nature of traits involved in bud set process. Comparison between map location of QTL and P. trichocarpa genome sequence allowed the identification of 13 gene models, 67 bud set-related expressional and six functional candidate genes (CGs). These CGs are functionally related to relevant biological processes, environmental sensing, signaling, and cell growth and development. Some strong QTL had no obvious CGs, and hold great promise to identify unknown genes that affect bud set.This study provides a better understanding of the physiological and genetic dissection of bud set in poplar. The putative QTL identified will be tested for associations in P. nigra natural populations. The identified QTL and CGs will also serve as useful targets for poplar breeding.Broad-leaved trees grown in temperate zones must avoid periods unfavorable for growth, such as harsh winter weather conditions, synchronizing their annual growth cycle with seasonality. Hence, they have evolved mechanisms
Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression
Olafur A Stefansson, Jon G Jonasson, Kristrun Olafsdottir, Hordur Bjarnason, Oskar Th Johannsson, Sigridur K Bodvarsdottir, Sigridur Valgeirsdottir, Jorunn E Eyfjord
Breast Cancer Research , 2011, DOI: 10.1186/bcr3020
Abstract: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy.Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis.The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.Germline mutations in one allele of the BRCA2 tumor-suppressor gene confer greatly increased risk of developing breast cancer [1]. The BRCA2 gene is known to be involved in error-free DNA repair of double-strand breaks (DSBs) through homologous recombination (HR) [2]. Defects in this mechanism lead to repair of DSBs by error-prone nonhomologous end joining (NH
Integrated method for adaptability and phenotypic stability analysis = Método integrado para análise de adaptabilidade e estabilidade fenotipica
Edmar Soares de Vasconcelos,Múcio Silva Reis,Cosme Dami?o Cruz,Tuneo Sediyama
Acta Scientiarum : Agronomy , 2011,
Abstract: The objectives of this study were a description of the Centroid Method, which is used to investigate the phenotypic adaptability of genotypes and the inclusion of new ideotypes therein, creating the Integrated Method for adaptability and phenotypic stability analysis, as well as a comparison of the two methods in a study example. As an applied example of the new proposal, grain yield data of 14 soybean genotypes from experiments at four locations in the state of Minas Gerais were used. In a comparison, the qualitative and quantitative gains of the Centroid Method with seven ideotypes were higher than of the Centroid Method with only four ideotypes for adaptability analysis. With the incorporation of the new ideotypes into theCentroid Method other concepts for the adaptability and phenotypic stability analysis are represented and the modified method was designated “Integrated Method of Adaptability and Stability Analysis”. CS 801 genotype was classified as the genotype with best adaptability to the environments Vi osa, Florestal, S o Gotardo and Rio Paranaiba. The stability of the genotypes CAC 1, CS 741, Splendor, UFV 16, UFV 19, UFVP IV-6, UFVP IV-8, UFVP V-15, UFVP V-7,and UFV98700739 was classified as general. Os objetivos deste trabalho foram apresentar uma modifica o ao método original do Centróide inserindo novos ideótipos, gerando uma proposta denominada Método Integrado para análise adaptabilidade e estabilidade fenotípica e comparar as duas metodologias. Como exemplo de aplica o da nova proposta foi utilizado dados de produtividade de gr os de quatorze genótipos de soja obtidos em experimentos conduzidos em quatro locais, no Estado de Minas Gerais. O novo método do Centróide com sete ideótipos propiciou ganhos qualitativos e quantitativos perante o método original do Centróide que possuía apenas quatro ideótipos para análise de adaptabilidade. Os novos ideótipos inseridos ao método do Centróide original permitem que esserepresente outros conceitos para a análise da adaptabilidade e estabilidade fenotípica, sendo designado por Método Integrado de análise de adaptabilidade e estabilidade. CS 801 foi classificado como o genótipo de melhor adaptabilidade aos ambientes Vi osa, Florestal, S o Gotardo e Rio Paranaíba. Os genótipos CAC 1, CS 741, Splendor, UFV 16, UFV 19, UFVP IV- 6, UFVP IV-8, UFVP V-15, UFVP V-7 e UFV98700739 foram classificados como de estabilidade geral.
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