| 1. |
- Marincevic-Zuniga, Yanara, et al.
(författare)
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Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
- 2017
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Ingår i: Journal of Hematology & Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.
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| 2. |
- Abrahamsson, Malin, et al.
(författare)
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Degeneration pattern in somatic embryos of Pinus sylvestris L.
- 2017
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Ingår i: In Vitro Cellular and Developmental Biology - Plant. - : Springer Science and Business Media LLC. - 1054-5476 .- 1475-2689. ; 53, s. 86-96
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Tidskriftsartikel (refereegranskat)abstract
- Somatic embryos can be used for propagating forest trees vegetatively, which is of great importance for capturing the genetic gain in breeding programs. However, many economically important Pinus species are difficult or impossible to propagate via somatic embryogenesis. In order to get a better understanding of the difficulties to propagate Pinus species via somatic embryogenesis, we are studying the developmental pathway of somatic embryos in different cell lines. In a previous study, we showed that the morphology of early somatic embryos in Scots pine (Pinus sylvestris) differs between cell lines giving rise to normal or abnormal cotyledonary embryos. In this study, we have compared the proliferation and degeneration pattern of early and late embryos in a normal and abnormal cell line. In both cell lines, a high frequency of the embryos degenerated. Among the degenerating embryos, two main degeneration patterns could be distinguished. In the normal cell line, the embryos degenerated similar to how the subordinate embryos are degraded in the seed. In the abnormal cell line, the degeneration of the embryos resulted in a continuous loop of embryo degeneration and differentiation of new embryos. We observed a similar degeneration pattern when embryogenic tissue was initiated from megagametophytes containing zygotic embryos at the stage of cleavage polyembryony. Based on our results, we suggest that the degeneration pattern in abnormal cell lines starts during initiation of embryogenic cultures.
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| 3. |
- Abrahamsson, Malin, et al.
(författare)
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Patterning during somatic embryogenesis in Scots pine in relation to polar auxin transport and programmed cell death
- 2012
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Ingår i: Plant Cell, Tissue and Organ Culture. - : Springer Science and Business Media LLC. - 0167-6857 .- 1573-5044. ; 109, s. 391-400
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Tidskriftsartikel (refereegranskat)abstract
- Somatic embryogenesis is a useful tool to propagate conifers vegetatively. However, a major limitation in many pine species is the low quality of cotyledonary somatic embryos. The aim of this study has been to elucidate the developmental pathway of somatic embryos in Scots pine (Pinus sylvestris), to identify deviations from the normal pathway and to identify processes that might disturb normal development. Initially we compared the developmental pathway of somatic embryogenesis in representative cell lines yielding cotyledonary embryos with normal and abnormal morphology. Early embryos carrying suspensor cells in excess of the normal number (supernumerary) were more frequent in cell lines giving rise to abnormal cotyledonary embryos. In this study we show that the frequency of early somatic embryos with supernumerary suspensor cells increased after treatment with the auxin transport inhibitor 1-N-naphtylphthalamic acid (NPA). Furthermore, the yield of developing embryos increased significantly after treatment with the antiauxin 2-(4-chlorophenoxy)-2-methylpropionic acid (PCIB), but the morphology of the embryos was not affected. The number of cells undergoing PCD was analyzed using a TUNEL-assay. The frequency of TUNEL-positive cells was high both in proliferating cultures and during differentiation of early somatic embryos. However, the pattern of TUNEL-positive cells was similar in normal somatic embryos and in embryos with supernumerary suspensor cells. Together our results suggest that the presence of supernumerary suspensor cells in early somatic embryos of Scots pine is caused by disturbed polar auxin transport and results in aberrant embryo development.
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| 4. |
- Abrahamsson, Malin, et al.
(författare)
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Somatic Embryogenesis in Scots Pine (Pinus sylvestris L.)
- 2018
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Ingår i: STEP WISE PROTOCOLS FOR SOMATIC EMBRYOGENESIS OF IMPORTANT WOODY PLANTS, VOL I, 2ND EDITION. - Cham : Springer International Publishing. - 9783319894829 ; 84:84, s. 123-133
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Bokkapitel (refereegranskat)abstract
- Scots pine (Pinus sylvestris L.) can be propagated via somatic embryogenesis. However, the protocols available today are not sufficient for large-scale propagation. The method needs to be optimized in order to increase the initiation frequency of embryogenic cell lines giving rise to high quality cotyledonary embryos, and to improve somatic embryo germination. Protocols presented in this chapter have been used to carry out fundamental research, where the resulting knowledge will be valuable for improving culture conditions for large scale propagation of Pinus species via somatic embryogenesis.
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| 5. |
- Abrahamsson, Sara
(författare)
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Genetic dissection of quantitative traits in Scots pine
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The phenotypic expressions of Scots pine, have been extensively studied over the years, but the gene regulation behind the traits has only just begun to be elucidated. The overall aim of this thesis was to start dissecting the genetics behind a number of adaptive traits in Scots pine and examine how they are influenced by relatedness using different molecular tools. In a full-sib family of Scots pine the genetic variation in autumn frost hardiness and height growth was revelead by measuring open-pollinated offspring. A significant genetic variation for both traits was found, a prerequisite to identify quantitative trait loci (QTL). A conceptual statistical model in the Bayesian framework for identifying QTLs in dynamic traits i.e. traits that vary over time, was developed and applied in a QTL study based on a full-sib family of 250 trees. A set of 160 AFLPs were utilized. QTLs for three latent traits were identified: one for the slope (growth) and two for the quadratic term (growth cessation). As a tool to identify candidate genes for the study of quantitative adaptive traits, gene regulation under continuous red (cR) and far-red (cFR) light was studied in hypocotyls from open-pollinated seeds from a natural population in northern Sweden using microarray technology. The gene expression patterns for the light response pathway in Scots pine under cFR show clear differences from those of angiosperms, wherein we observed up-regulation of cryptochrome1. This gene has, therefore, become a strong candidate gene that deserves further studies to elucidate the genetics behind Scots pine adaptation. Not knowing the genetic relationship and inbreeding of trees, and how it influences the phenotypic expression, can lead to over- or underestimation of additive genetic values resulting in biased heritability estimates. A natural population of Scots pine, earlier identified as being highly inbreed, was used to investigate the influence of inbreeding by the correlation between heterozygosity and propotion of sound seed (PSS), average seed weight and proportion of rare alleles (PRA). Heterozygosity fitness correlation (HFC) was found positive for PSS and negative for PRA most likely due to recessive deleterious alleles purged in homozygotes. The study provided evidence that, as predicted by theory, inbreeding enhances HFC in a species with high outbreeding rate and high number of lethal equivalents as Scots pine.
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| 6. |
- Abrahamsson, Sara, et al.
(författare)
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Inheritance of height growth and autumn cold hardiness based on two generations of full-sib and half-sib families of Pinus sylvestris
- 2012
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Ingår i: Scandinavian Journal of Forest Research. - : Informa UK Limited. - 0282-7581 .- 1651-1891. ; 27, s. 405-413
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variability in height growth and autumn cold hardiness were evaluated in a full-sib family of Scots pine (Pinus sylvestris (L.)) in a field trial in northern Sweden and 358 open pollinated families generated from the progeny of the full-sib cross. Height and autumn cold hardiness were assessed in the progeny of the full-sib cross at 9-19 years of age and on 3995 open pollinated progenies at three years of age. The autumn cold hardiness [critical temperature (CT)] of trees and progenies was tested by artificial freeze testing of detached needles at various temperatures. Significant genetic variation was found among progenies in both height growth and cold hardiness with a narrow sense heritability of 0.16 and 0.37, respectively. There was also a significant positive genetic correlation (r(a) = 0.39) between height growth and CT with taller trees showing later autumn cold acclimation. It was concluded that there is significant additive genetic variance for height and CT which warrants a potential for mapping quantitative trait loci. Furthermore, the low heritability for height growth shows the importance of removing the environmental influence by using additive genetic predictions instead of phenotypic measurements thereby improving the accuracy of genetic associations.
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| 7. |
- Abrahamsson, Sara, et al.
(författare)
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Maternal heterozygosity and progeny fitness association in an inbred Scots pine population
- 2013
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Ingår i: Genetica. - : Springer Netherlands. - 0016-6707 .- 1573-6857. ; 141:1-3, s. 41-50
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Tidskriftsartikel (refereegranskat)abstract
- Associations between heterozygosity and fitness traits have typically been investigated in populations characterized by low levels of inbreeding. We investigated the associations between standardized multilocus heterozygosity (stMLH) in mother trees (obtained from12 nuclear microsatellite markers) and five fitness traits measured in progenies from an inbred Scots pine population. The traits studied were proportion of sound seed, mean seed weight, germination rate, mean family height of one-year old seedlings under greenhouse conditions (GH) and mean family height of three-year old seedlings under field conditions (FH). The relatively high average inbreeding coefficient (F) in the population under study corresponds to a mixture of trees with different levels of co-ancestry, potentially resulting from a recent bottleneck. We used both frequentist and Bayesian methods of polynomial regression to investigate the presence of linear and non-linear relations between stMLH and each of the fitness traits. No significant associations were found for any of the traits except for GH, which displayed negative linear effect with stMLH. Negative HFC for GH could potentially be explained by the effect of heterosis caused by mating of two inbred mother trees (Lippman and Zamir 2006), or outbreeding depression at the most heterozygote trees and its negative impact on the fitness of the progeny, while their simultaneous action is also possible (Lynch. 1991). However,since this effect wasn’t detected for FH, we cannot either rule out that the greenhouse conditions introduce artificial effects that disappear under more realistic field conditions.
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| 8. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 9. |
- Calleja-Rodriguez, Ainhoa, et al.
(författare)
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Analysis of phenotypic- and Estimated Breeding Values (EBV) to dissect the genetic architecture of complex traits in a Scots pine three-generation pedigree design
- 2019
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Ingår i: Journal of Theoretical Biology. - : Elsevier BV. - 0022-5193 .- 1095-8541. ; 462, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- In forest tree breeding, family-based Quantitative Trait Loci (QTL) studies are valuable as methods to dissect the complexity of a trait and as a source of candidate genes. In the field of conifer research, our study contributes to the evaluation of phenotypic and predicted breeding values for the identification of QTL linked to complex traits in a three-generation pedigree population in Scots pine (Pinus sylvestris L.). A total of 11 470 open pollinated F-2-progeny trees established at three different locations, were measured for growth and adaptive traits. Breeding values were predicted for their 360 mothers, originating from a single cross of two grand-parents. A multilevel LASSO association analysis was conducted to detect QTL using genotypes of the mothers with the corresponding phenotypes and Estimated Breeding Values (EBV). Different levels of genotype-by-environment (G x E) effects among sites at different years, were detected for survival and height. Moderate-to-low narrow sense heritabilities and EBV accuracies were found for all traits and all sites. We identified 18 AFLPs and 12 SNPs to be associated with QTL for one or more traits. 62 QTL were significant with percentages of variance explained ranging from 1.7 to 18.9%. In those cases where the same marker was associated to a phenotypic or an ebvQTL, the ebvQTL always explained higher proportion of the variance, maybe due to the more accurate nature of Estimated Breeding Values (EBV). Two SNP-QTL showed pleiotropic effects for traits related with hardiness, seed, cone and flower production. Furthermore, we detected several QTL with significant effects across multiple ages, which could be considered as strong candidate loci for early selection. The lack of reproducibility of some QTL detected across sites may be due to environmental heterogeneity reflected by the genotype- and QTL-by-environment effects. (C) 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.
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| 10. |
- Calleja-Rodriguez, Ainhoa, et al.
(författare)
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Evaluation of the efficiency of genomic versus pedigree predictions for growth and wood quality traits in Scots pine
- 2020
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background Genomic selection (GS) or genomic prediction is a promising approach for tree breeding to obtain higher genetic gains by shortening time of progeny testing in breeding programs. As proof-of-concept for Scots pine (Pinus sylvestris L.), a genomic prediction study was conducted with 694 individuals representing 183 full-sib families that were genotyped with genotyping-by-sequencing (GBS) and phenotyped for growth and wood quality traits. 8719 SNPs were used to compare different genomic with pedigree prediction models. Additionally, four prediction efficiency methods were used to evaluate the impact of genomic breeding value estimations by assigning diverse ratios of training and validation sets, as well as several subsets of SNP markers. Results Genomic Best Linear Unbiased Prediction (GBLUP) and Bayesian Ridge Regression (BRR) combined with expectation maximization (EM) imputation algorithm showed slightly higher prediction efficiencies than Pedigree Best Linear Unbiased Prediction (PBLUP) and Bayesian LASSO, with some exceptions. A subset of approximately 6000 SNP markers, was enough to provide similar prediction efficiencies as the full set of 8719 markers. Additionally, prediction efficiencies of genomic models were enough to achieve a higher selection response, that varied between 50-143% higher than the traditional pedigree-based selection. Conclusions Although prediction efficiencies were similar for genomic and pedigree models, the relative selection response was doubled for genomic models by assuming that earlier selections can be done at the seedling stage, reducing the progeny testing time, thus shortening the breeding cycle length roughly by 50%.
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