Browsing by Subject "Gene expression"

Sort by: Order: Results:

Now showing items 1-20 of 43
  • Kvist, Jouni; Athanasio, Camila Goncalves; Pfrender, Michael E.; Brown, James B.; Colbourne, John K.; Mirbahai, Leda (2020)
    Background Daphnia species reproduce by cyclic parthenogenesis involving both sexual and asexual reproduction. The sex of the offspring is environmentally determined and mediated via endocrine signalling by the mother. Interestingly, male and female Daphnia can be genetically identical, yet display large differences in behaviour, morphology, lifespan and metabolic activity. Our goal was to integrate multiple omics datasets, including gene expression, splicing, histone modification and DNA methylation data generated from genetically identical female and male Daphnia pulex under controlled laboratory settings with the aim of achieving a better understanding of the underlying epigenetic factors that may contribute to the phenotypic differences observed between the two genders. Results In this study we demonstrate that gene expression level is positively correlated with increased DNA methylation, and histone H3 trimethylation at lysine 4 (H3K4me3) at predicted promoter regions. Conversely, elevated histone H3 trimethylation at lysine 27 (H3K27me3), distributed across the entire transcript length, is negatively correlated with gene expression level. Interestingly, male Daphnia are dominated with epigenetic modifications that globally promote elevated gene expression, while female Daphnia are dominated with epigenetic modifications that reduce gene expression globally. For examples, CpG methylation (positively correlated with gene expression level) is significantly higher in almost all differentially methylated sites in male compared to female Daphnia. Furthermore, H3K4me3 modifications are higher in male compared to female Daphnia in more than 3/4 of the differentially regulated promoters. On the other hand, H3K27me3 is higher in female compared to male Daphnia in more than 5/6 of differentially modified sites. However, both sexes demonstrate roughly equal number of genes that are up-regulated in one gender compared to the other sex. Since, gene expression analyses typically assume that most genes are expressed at equal level among samples and different conditions, and thus cannot detect global changes affecting most genes. Conclusions The epigenetic differences between male and female in Daphnia pulex are vast and dominated by changes that promote elevated gene expression in male Daphnia. Furthermore, the differences observed in both gene expression changes and epigenetic modifications between the genders relate to pathways that are physiologically relevant to the observed phenotypic differences.
  • Kvist, Jouni; Athanàsio, Camila G; Pfrender, Michael E; Brown, James B; Colbourne, John K; Mirbahai, Leda (BioMed Central, 2020)
    Abstract Background Daphnia species reproduce by cyclic parthenogenesis involving both sexual and asexual reproduction. The sex of the offspring is environmentally determined and mediated via endocrine signalling by the mother. Interestingly, male and female Daphnia can be genetically identical, yet display large differences in behaviour, morphology, lifespan and metabolic activity. Our goal was to integrate multiple omics datasets, including gene expression, splicing, histone modification and DNA methylation data generated from genetically identical female and male Daphnia pulex under controlled laboratory settings with the aim of achieving a better understanding of the underlying epigenetic factors that may contribute to the phenotypic differences observed between the two genders. Results In this study we demonstrate that gene expression level is positively correlated with increased DNA methylation, and histone H3 trimethylation at lysine 4 (H3K4me3) at predicted promoter regions. Conversely, elevated histone H3 trimethylation at lysine 27 (H3K27me3), distributed across the entire transcript length, is negatively correlated with gene expression level. Interestingly, male Daphnia are dominated with epigenetic modifications that globally promote elevated gene expression, while female Daphnia are dominated with epigenetic modifications that reduce gene expression globally. For examples, CpG methylation (positively correlated with gene expression level) is significantly higher in almost all differentially methylated sites in male compared to female Daphnia. Furthermore, H3K4me3 modifications are higher in male compared to female Daphnia in more than 3/4 of the differentially regulated promoters. On the other hand, H3K27me3 is higher in female compared to male Daphnia in more than 5/6 of differentially modified sites. However, both sexes demonstrate roughly equal number of genes that are up-regulated in one gender compared to the other sex. Since, gene expression analyses typically assume that most genes are expressed at equal level among samples and different conditions, and thus cannot detect global changes affecting most genes. Conclusions The epigenetic differences between male and female in Daphnia pulex are vast and dominated by changes that promote elevated gene expression in male Daphnia. Furthermore, the differences observed in both gene expression changes and epigenetic modifications between the genders relate to pathways that are physiologically relevant to the observed phenotypic differences.
  • Miettinen, Juho; Kumari, Romika; Traustadottir, Gunnhildur Asta; Huppunen, Maiju-Emilia Anniina; Sergeev, Philipp; Majumder, Muntasir M.; Schepsky, Alexander; Gudjonsson, Thorarinn; Lievonen, Juha; Bazou, Despina; Dowling, Paul; O'Gorman, Peter; Slipicevic, Ana; Anttila, Pekka; Silvennoinen, Raija; Nupponen, Nina N.; Lehmann, Fredrik; Heckman, Caroline (2021)
    Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM.
  • Pashay Ahi, Ehsan; Duenser, Anna; Singh, Pooja; Gessl, Wolfgang; Sturmbauer, Christian (2020)
    Feeding is a complex behaviour comprised of satiety control, foraging, ingestion and subsequent digestion. Cichlids from the East African Great Lakes are renowned for their diverse trophic specializations, largely predicated on highly variable jaw morphologies. Thus, most research has focused on dissecting the genetic, morphological and regulatory basis of jaw and teeth development in these species. Here for the first time we explore another aspect of feeding, the regulation of appetite related genes that are expressed in the brain and control satiety in cichlid fishes. Using qPCR analysis, we first validate stably expressed reference genes in the brain of six haplochromine cichlid species at the end of larval development prior to foraging. We next evaluate the expression of 16 appetite related genes in herbivorous and carnivorous species from the parallel radiations of Lake Tanganyika, Malawi and Victoria. Interestingly, we find increased expression of two appetite-regulating genes (anorodgenic genes), cart and npy2r, in the brain of carnivorous species in all the three lakes. This supports the notion that appetite gene regulation might play a part in determining trophic niche specialization in divergent cichlid species, already prior to exposure to different diets. Our study contributes to the limited body of knowledge on the neurological circuitry that controls feeding transitions and adaptations in cichlids and other teleosts.
  • Czamara, Darina; Dieckmann, Linda; Roeh, Simone; Kraemer, Sarah; Rancourt, Rebecca C.; Sammallahti, Sara; Kajantie, Eero; Laivuori, Hannele; Eriksson, Johan G.; Räikkönen, Katri; Henrich, Wolfgang; Plagemann, Andreas; Binder, Elisabeth B.; Braun, Thorsten; Entringer, Sonja (2021)
    Background Glucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans. Results We tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response. Conclusions Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.
  • Jalanka, Jonna; Lam, Ching; Bennett, Andrew; Hartikainen, Anna; Crispie, Fiona; Finnegan, Laura A.; Cotter, Paul D.; Spiller, Robin (2021)
    Background/Aims Diarrhea-predominant irritable bowel syndrome (IBS-D) has been previously associated with evidence of immune activation and altered microbiota. Our aim is to assess the effect of the anti-inflammatory agent, mesalazine, on inflammatory gene expression and microbiota composition in IBS-D. Methods We studied a subset of patients (n = 43) from a previously published 12-week radomized placebo-controlled trial of mesalazine. Mucosal biopsies were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction for a range of markers of inflammation, altered permeability, and sensory receptors including Toll-like receptors (TLRs) at randomization after treatment. All biopsy data were compared to 21 healthy controls. Patient's stool microbiota composition was analysed through 16S ribosomal RNA sequencing. Results We found no evidence of increased immune activation compared to healthy controls. However, we did find increased expression of receptors in both sensory pathways and innate immune response including TLR4. Higher TLR4 expression was associated with greater urgency. TLR4 expression correlated strongly with the expression of the receptors bradykinin receptor B2, chemerin chemokine-like receptor 1, and transient receptor potential cation channel, subfamily A, member 1 as well as TLR4's downstream adaptor myeloid differentiation factor 88. Mesalazine had minimal effect on either gene expression or microbiota composition. Conclusions Biopsies from a well-characterized IBS-D cohort showed no substantial inflammation. Mesalazine has little effect on gene expression and its previous reported effect on fecal microbiota associated with much greater inflammation found in inflammatory bowel diseases is likely secondary to reduced inflammation. Increased expression of TLR4 and correlated receptors in IBS may mediate a general increase in sensitivity to external stimuli, particularly those that signal via the TLR system.
  • Pashay Ahi, Ehsan; A. Lecaudey, Laurène; Ziegelbecker, Angelika; Steiner, Oliver; A. Glabonjat, Ronald; Goessler, Walter; Lass, Achim; Sefc, Kristina M. (2020)
    Background Carotenoids contribute significantly to animal body coloration, including the spectacular color pattern diversity among fishes. Fish, as other animals, derive carotenoids from their diet. Following uptake, transport and metabolic conversion, carotenoids allocated to body coloration are deposited in the chromatophore cells of the integument. The genes involved in these processes are largely unknown. Using RNA-Sequencing, we tested for differential gene expression between carotenoid-colored and white skin regions of a cichlid fish, Tropheus duboisi "Maswa", to identify genes associated with carotenoid-based integumentary coloration. To control for positional gene expression differences that were independent of the presence/absence of carotenoid coloration, we conducted the same analyses in a closely related population, in which both body regions are white. Results A larger number of genes (n = 50) showed higher expression in the yellow compared to the white skin tissue than vice versa (n = 9). Of particular interest was the elevated expression level of bco2a in the white skin samples, as the enzyme encoded by this gene catalyzes the cleavage of carotenoids into colorless derivatives. The set of genes with higher expression levels in the yellow region included genes involved in xanthophore formation (e.g., pax7 and sox10), intracellular pigment mobilization (e.g., tubb, vim, kif5b), as well as uptake (e.g., scarb1) and storage (e.g., plin6) of carotenoids, and metabolic conversion of lipids and retinoids (e.g., dgat2, pnpla2, akr1b1, dhrs). Triglyceride concentrations were similar in the yellow and white skin regions. Extracts of integumentary carotenoids contained zeaxanthin, lutein and beta-cryptoxanthin as well as unidentified carotenoid structures. Conclusion Our results suggest a role of carotenoid cleavage by Bco2 in fish integumentary coloration, analogous to previous findings in birds. The elevated expression of genes in carotenoid-rich skin regions with functions in retinol and lipid metabolism supports hypotheses concerning analogies and shared mechanisms between these metabolic pathways. Overlaps in the sets of differentially expressed genes (including dgat2, bscl2, faxdc2 and retsatl) between the present study and previous, comparable studies in other fish species provide useful hints to potential carotenoid color candidate genes.
  • Morandin, Claire; Tin, Mandy M. Y.; Abril, Silvia; Gomez, Crisanto; Pontieri, Luigi; Schiott, Morten; Sundström, Liselotte; Tsuji, Kazuki; Pedersen, Jes Soe; Helanterä, Heikki; Mikheyev, Alexander S. (2016)
    Background: Reproductive division of labor in eusocial insects is a striking example of a shared genetic background giving rise to alternative phenotypes, namely queen and worker castes. Queen and worker phenotypes play major roles in the evolution of eusocial insects. Their behavior, morphology and physiology underpin many ecologically relevant colony-level traits, which evolved in parallel in multiple species. Results: Using queen and worker transcriptomic data from 16 ant species we tested the hypothesis that conserved sets of genes are involved in ant reproductive division of labor. We further hypothesized that such sets of genes should also be involved in the parallel evolution of other key traits. We applied weighted gene co-expression network analysis, which clusters co-expressed genes into modules, whose expression levels can be summarized by their 'eigengenes'. Eigengenes of most modules were correlated with phenotypic differentiation between queens and workers. Furthermore, eigengenes of some modules were correlated with repeated evolution of key phenotypes such as complete worker sterility, the number of queens per colony, and even invasiveness. Finally, connectivity and expression levels of genes within the co-expressed network were strongly associated with the strength of selection. Although caste-associated sets of genes evolve faster than non-caste-associated, we found no evidence for queen-or worker-associated co-expressed genes evolving faster than one another. Conclusions: These results identify conserved functionally important genomic units that likely serve as building blocks of phenotypic innovation, and allow the remarkable breadth of parallel evolution seen in ants, and possibly other eusocial insects as well.
  • Mgbeahuruike, Anthony C.; Kovalchuk, Andriy; Ubhayasekera, Wimal; Nelson, David R.; Yadav, Jagjit S. (2017)
    The molecular mechanisms underlying the interaction of the pathogen, Heterobasidion annosum s.l., the conifer tree and the biocontrol fungus, Phlebiopsis gigantea have not been fully elucidated. Members of the cytochrome P450 (CYP) protein family may contribute to the detoxification of components of chemical defence of conifer trees by H. annosum during infection. Additionally, they may also be involved in the interaction between H. annosum and P. gigantea. A genome-wide analysis of CYPs in Heterobasidion irregulare was carried out alongside gene expression studies. According to the Standardized CYP Nomenclature criteria, the H. irregulare genome has 121 CYP genes and 17 CYP pseudogenes classified into 11 clans, 35 families, and 64 subfamilies. Tandem CYP arrays originating from gene duplications and belonging to the same family and subfamily were found. Phylogenetic analysis showed that all the families of H. irregulare CYPs were monophyletic groups except for the family CYP5144. Microarray analysis revealed the transcriptional pattern for 130 transcripts of CYP-encoding genes during growth on culture filtrate produced by P. gigantea. The high level of P450 gene diversity identified in this study could result from extensive gene duplications presumably caused by the high metabolic demands of H. irregulare in its ecological niches. (C) 2016 British Mycological Society. Published by Elsevier Ltd. All rights reserved.
  • Cheng, Jing; Kalliomaki, Marko; Heilig, Hans G. H. J.; Palva, Airi; Lahteenoja, Hannu; de Vos, Willem M.; Salojarvi, Jarkko; Satokari, Reetta (2013)
  • Alakärppä, Emmi; Taulavuori, Erja; Valledor, Luis; Marttila, Toni; Jokipii-Lukkari, Soile; Karppinen, Katja; Nguyen, Nga; Taulavuori, Kari; Häggman, Hely (2019)
    Plants have evolved a suite of photoreceptors to perceive information from the surrounding light conditions. The aim of this study was to examine photomorphogenic effects of light quality on the growth of Scots pine (Pinus sylvestris L.) seedlings representing southern (60 °N) and northern (68 °N) origins in Finland. We measured the growth characteristics and the expression of light-responsive genes from seedlings grown under two LED light spectra: (1) Retarder (blue and red wavelengths in ratio 0.7) inducing compact growth, and (2) Booster (moderate in blue, green and far-red wavelengths, and high intensity of red light) promoting shoot elongation. The results show that root elongation, biomass, and branching were reduced under Retarder spectrum in the seedlings representing both origins, while inhibition in seed germination and shoot elongation was mainly detected in the seedlings of northern origin. The expression of ZTL and HY5 was related to Scots pine growth under both light spectra. Moreover, the expression of PHYN correlated with growth when exposed to Retarder, whereas CRY2 expression was associated with growth under Booster. Our data indicates that blue light and the deficiency of far-red light limit the growth of Scots pine seedlings and that northern populations are more sensitive to blue light than southern populations. Furthermore, the data analyses suggest that ZTL and HY5 broadly participate in the light-mediated growth regulation of Scots pine, whereas PHYN responses to direct sunlight and the role of CRY2 is in shade avoidance. Altogether, our study extends the knowledge of light quality and differential gene expression affecting the early growth of Scots pines representing different latitudinal origins.
  • Marwah, Veer Singh; Scala, Giovanni; Kinaret, Pia Anneli Sofia; Serra, Angela; Alenius, Harri; Fortino, Vittorio; Greco, Dario (2019)
    BackgroundApplication of microarrays in omics technologies enables quantification of many biomolecules simultaneously. It is widely applied to observe the positive or negative effect on biomolecule activity in perturbed versus the steady state by quantitative comparison. Community resources, such as Bioconductor and CRAN, host tools based on R language that have become standard for high-throughput analytics. However, application of these tools is technically challenging for generic users and require specific computational skills. There is a need for intuitive and easy-to-use platform to process omics data, visualize, and interpret results.ResultsWe propose an integrated software solution, eUTOPIA, that implements a set of essential processing steps as a guided workflow presented to the user as an R Shiny application.ConclusionseUTOPIA allows researchers to perform preprocessing and analysis of microarray data via a simple and intuitive graphical interface while using state of the art methods.
  • Marwah, Veer S; Scala, Giovanni; Kinaret, Pia A S; Serra, Angela; Alenius, Harri; Fortino, Vittorio; Greco, Dario (BioMed Central, 2019)
    Abstract Background Application of microarrays in omics technologies enables quantification of many biomolecules simultaneously. It is widely applied to observe the positive or negative effect on biomolecule activity in perturbed versus the steady state by quantitative comparison. Community resources, such as Bioconductor and CRAN, host tools based on R language that have become standard for high-throughput analytics. However, application of these tools is technically challenging for generic users and require specific computational skills. There is a need for intuitive and easy-to-use platform to process omics data, visualize, and interpret results. Results We propose an integrated software solution, eUTOPIA, that implements a set of essential processing steps as a guided workflow presented to the user as an R Shiny application. Conclusions eUTOPIA allows researchers to perform preprocessing and analysis of microarray data via a simple and intuitive graphical interface while using state of the art methods.
  • Mukrimin, Mukrimin; Kovalchuk, Andriy; Ghimire, Rajendra P.; Kivimaenpaa, Minna; Sun, Hui; Holopainen, Jarmo K.; Asiegbu, Fred O. (2019)
    Main conclusion Two terpene compounds and four genes were identified as potential biomarkers for further evaluation for Scots pine susceptibility or tolerance against Heterobasidion annosum. Scots pine (Pinus sylvestris) is one of the main sources of timber in the boreal zone of Eurasia. Commercial pine plantations are vulnerable to root and butt rot disease caused by the fungus Heterobasidion annosum. The pathogen affects host growth rate, causes higher mortality and decreases in timber quality, resulting in considerable economic losses to forest owners. Genetic and biochemical factors contributing to Scots pine tolerance against H. annosum infection are not well understood. We assessed the predictive values of a set of potential genetic and chemical markers in a field experiment. We determined the expression levels of 25 genes and the concentrations of 36 terpenoid compounds in needles of 16 Scots pine trees randomly selected from a natural population prior to artificial infection. Stems of the same trees were artificially inoculated with H. annosum, and the length of necrotic lesions was documented 5 months post inoculation. Higher expression level of four genes included in our analysis and encoding predicted alpha-pinene synthase (two genes), geranyl diphosphate synthase (GPPS), and metacaspase 5 (MC5), could be associated with trees exhibiting increased levels of necrotic lesion formation in response to fungal inoculation. In contrast, concentrations of two terpenoid compounds, beta-caryophyllene and alpha-humulene, showed significant negative correlations with the lesion size. Further studies with larger sample size will help to elucidate new biomarkers or clarify the potential of the evaluated markers for use in Scots pine disease resistance breeding programs.
  • Verhagen, Irene; Laine, Veronika N.; Mateman, A. Christa; Pijl, Agata; de Wit, Ruben; van Lith, Bart; Kamphuis, Willem; Viitaniemi, Heidi M.; Williams, Tony D.; Caro, Samuel P.; Meddle, Simone L.; Gienapp, Phillip; van Oers, Kees; Visser, Marcel E. (2019)
    The timing of breeding is under selection in wild populations as a result of climate change, and understanding the underlying physiological processes mediating this timing provides insight into the potential rate of adaptation. Current knowledge on this variation in physiology is, however, mostly limited to males. We assessed whether individual differences in the timing of breeding in females are reflected in differences in candidate gene expression and, if so, whether these differences occur in the upstream (hypothalamus) or downstream (ovary and liver) parts of the neuroendocrine system. We used 72 female great tits from two generations of lines artificially selected for early and late egg laying, which were housed in climate-controlled aviaries and went through two breeding cycles within 1 year. In the first breeding season we obtained individual egg-laying dates, while in the second breeding season, using the same individuals, we sampled several tissues at three time points based on the timing of the first breeding attempt. For each tissue, mRNA expression levels were measured using qPCR for a set of candidate genes associated with the timing of reproduction and subsequently analysed for differences between generations, time points and individual timing of breeding. We found differences in gene expression between generations in all tissues, with the most pronounced differences in the hypothalamus. Differences between time points, and early- and late-laying females, were found exclusively in the ovary and liver. Altogether, we show that fine-tuning of the seasonal timing of breeding, and thereby the opportunity for adaptation in the neuroendocrine system, is regulated mostly downstream in the neuro-endocrine system.
  • Jonsson, Martina; Jestoi, Marika; Anthoni, Minna; Welling, Annikki; Loivamaa, Iida; Hallikainen, Ville; Kankainen, Matti; Lysoe, Erik; Koivisto, Pertti; Peltonen, Kimmo (2016)
    The mycotoxin enniatin B, a cyclic hexadepsipeptide produced by the plant pathogen Fusarium, is prevalent in grains and grain-based products in different geographical areas. Although enniatins have not been associated with toxic outbreaks, they have caused toxicity in vitro in several cell lines. In this study, the cytotoxic effects of enniatin B were assessed in relation to cellular energy metabolism, cell proliferation, and the induction of apoptosis in Balb 3T3 and HepG2 cells. The mechanism of toxicity was examined by means of whole genome expression profiling of exposed rat primary hepatocytes. Enniatin B altered cellular energy metabolism and reduced cell proliferation in Balb 3T3 and HepG2 cell lines. Furthermore, the proportion of apoptotic cell populations of Balb 3T3 cells slightly increased. On the other hand, enniatin B caused necrotic cell death in primary hepatocytes. Gene expression studies revealed the alteration of energy metabolism due to effects on mitochondrial organization and function and the assembly of complex I of the electron transport chain. (C) 2016 Elsevier Ltd. All rights reserved.
  • Ukkola-Vuoti, L.; Torniainen-Holm, M.; Ortega-Alonso, A.; Sinha, V.; Tuulio-Henriksson, A.; Paunio, T.; Lönnqvist, J.; Suvisaari, J.; Hennah, W. (2019)
    Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.
  • Purrington, Kristen S.; Visscher, Daniel W.; Wang, Chen; Yannoukakos, Drakoulis; Hamann, Ute; Nevanlinna, Heli; Cox, Angela; Giles, Graham G.; Eckel-Passow, Jeanette E.; Lakis, Sotiris; Kotoula, Vassiliki; Fountzilas, George; Kabisch, Maria; Ruediger, Thomas; Heikkila, Paivi; Blomqvist, Carl; Cross, Simon S.; Southey, Melissa C.; Olson, Janet E.; Gilbert, Judy; Deming-Halverson, Sandra; Kosma, Veli-Matti; Clarke, Christine; Scott, Rodney; Jones, J. Louise; Zheng, Wei; Mannermaa, Arto; Eccles, Diana M.; Vachon, Celine M.; Couch, Fergus J.; Jane Carpenter ABCTC Investigators (2016)
    Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic features of TN tumors, which reflect aspects of both tumor behavior and tumor microenvironment, and molecular TN subtypes. The histopathologic features of TN tumors were assessed by central review and 593 TN tumors were subjected to whole genome expression profiling using the Illumina Whole Genome DASL array. TN molecular subtypes were defined based on gene expression data associated with histopathologic features of TN tumors. Gene expression analysis yielded signatures for four TN subtypes (basal-like, androgen receptor positive, immune, and stromal) consistent with previous studies. Expression analysis also identified genes significantly associated with the 12 histological features of TN tumors. Development of signatures using these markers of histopathological features resulted in six distinct TN subtype signatures, including an additional basal-like and stromal signature. The additional basal-like subtype was distinguished by elevated expression of cell motility and glucose metabolism genes and reduced expression of immune signaling genes, whereas the additional stromal subtype was distinguished by elevated expression of immunomodulatory pathway genes. Histopathologic features that reflect heterogeneity in tumor architecture, cell structure, and tumor microenvironment are related to TN subtype. Accounting for histopathologic features in the development of gene expression signatures, six major subtypes of TN breast cancer were identified.
  • Katayama, Shintaro; Skoog, Tiina; Söderhäll, Cilla; Einarsdottir, Elisabet; Krjutskov, Kaarel; Kere, Juha (2019)
    Background Standard RNAseq methods using bulk RNA and recent single-cell RNAseq methods use DNA barcodes to identify samples and cells, and the barcoded cDNAs are pooled into a library pool before high throughput sequencing. In cases of single-cell and low-input RNAseq methods, the library is further amplified by PCR after the pooling. Preparation of hundreds or more samples for a large study often requires multiple library pools. However, sometimes correlation between expression profiles among the libraries is low and batch effect biases make integration of data between library pools difficult. Results We investigated 166 technical replicates in 14 RNAseq libraries made using the STRT method. The patterns of the library biases differed by genes, and uneven library yields were associated with library biases. The former bias was corrected using the NBGLM-LBC algorithm, which we present in the current study. The latter bias could not be corrected directly, but could be solved by omitting libraries with particularly low yields. A simulation experiment suggested that the library bias correction using NBGLM-LBC requires a consistent sample layout. The NBGLM-LBC correction method was applied to an expression profile for a cohort study of childhood acute respiratory illness, and the library biases were resolved. Conclusions The R source code for the library bias correction named NBGLM-LBC is available at and . This method is applicable to correct the library biases in various studies that use highly multiplexed sequencing-based profiling methods with a consistent sample layout with samples to be compared (e.g., "cases" and "controls") equally distributed in each library.
  • Katayama, Shintaro; Skoog, Tiina; Söderhäll, Cilla; Einarsdottir, Elisabet; Krjutškov, Kaarel; Kere, Juha (BioMed Central, 2019)
    Abstract Background Standard RNAseq methods using bulk RNA and recent single-cell RNAseq methods use DNA barcodes to identify samples and cells, and the barcoded cDNAs are pooled into a library pool before high throughput sequencing. In cases of single-cell and low-input RNAseq methods, the library is further amplified by PCR after the pooling. Preparation of hundreds or more samples for a large study often requires multiple library pools. However, sometimes correlation between expression profiles among the libraries is low and batch effect biases make integration of data between library pools difficult. Results We investigated 166 technical replicates in 14 RNAseq libraries made using the STRT method. The patterns of the library biases differed by genes, and uneven library yields were associated with library biases. The former bias was corrected using the NBGLM-LBC algorithm, which we present in the current study. The latter bias could not be corrected directly, but could be solved by omitting libraries with particularly low yields. A simulation experiment suggested that the library bias correction using NBGLM-LBC requires a consistent sample layout. The NBGLM-LBC correction method was applied to an expression profile for a cohort study of childhood acute respiratory illness, and the library biases were resolved. Conclusions The R source code for the library bias correction named NBGLM-LBC is available at https://shka.github.io/NBGLM-LBC and https://shka.bitbucket.io/NBGLM-LBC . This method is applicable to correct the library biases in various studies that use highly multiplexed sequencing-based profiling methods with a consistent sample layout with samples to be compared (e.g., “cases” and “controls”) equally distributed in each library.