Browsing by Subject "ARCHITECTURE"

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  • Myllymaki, Satu-Marja; Kämäräinen, Ulla-Reetta; Liu, Xiaonan; Cruz, Sara Pereira; Miettinen, Sini; Vuorela, Mikko; Varjosalo, Markku; Manninen, Aki (2019)
    Integrin-mediated laminin adhesions mediate epithelial cell anchorage to basement membranes and are critical regulators of epithelial cell polarity. Integrins assemble large multiprotein complexes that link to the cytoskeleton and convey signals into the cells. Comprehensive proteomic analyses of actin network-linked focal adhesions (FA) have been performed, but the molecular composition of intermediate filament-linked hemidesmosomes (HD) remains incompletely characterized. Here we have used proximity-dependent biotin identification (BioID) technology to label and characterize the interactome of epithelia-specific beta 4-integrin that, as alpha 6 beta 4-heterodimer, forms the core of HDs. The analysis identified similar to 150 proteins that were specifically labeled by BirA-tagged integrin-beta 4. In addition to known HDs proteins, the interactome revealed proteins that may indirectly link integrin-beta 4 to actin-connected protein complexes, such as FAs and dystrophin/dystroglycan complexes. The specificity of the screening approach was validated by confirming the HD localization of two candidate beta 4-interacting proteins, utrophin (UTRN) and ELKS/Rab6-interacting/CAST family member 1 (ERC1). Interestingly, although establishment of functional HDs depends on the formation of alpha 6 beta 4-heterodimers, the assembly of beta 4-interactome was not strictly dependent on alpha 6-integrin expression. Our survey to the HD interactome sets a precedent for future studies and provides novel insight into the mechanisms of HD assembly and function of the beta 4-integrin.
  • Salo, Raimo A.; Belevich, Ilya; Jokitalo, Eija; Gröhn, Olli; Sierra, Alejandra (2021)
    Validation and interpretation of diffusion magnetic resonance imaging (dMRI) requires detailed understanding of the actual microstructure restricting the diffusion of water molecules. In this study, we used serial block-face scanning electron microscopy (SBEM), a three-dimensional electron microscopy (3D-EM) technique, to image seven white and grey matter volumes in the rat brain. SBEM shows excellent contrast of cellular membranes, which are the major components restricting the diffusion of water in tissue. Additionally, we performed 3D structure tensor (3D-ST) analysis on the SBEM volumes and parameterised the resulting orientation distributions using Watson and angular central Gaussian (ACG) probability distributions as well as spherical harmonic (SH) decomposition. We analysed how these parameterisations described the underlying orientation distributions and compared their orientation and dispersion with corresponding parameters from two dMRI methods, neurite orientation dispersion and density imaging (NODDI) and constrained spherical deconvolution (CSD). Watson and ACG parameterisations and SH decomposition captured well the 3D-ST orientation distributions, but ACG and SH better represented the distributions due to its ability to model asymmetric dispersion. The dMRI parameters corresponded well with the 3D-ST parameters in the white matter volumes, but the correspondence was less evident in the more complex grey matter. SBEM imaging and 3D-ST analysis also revealed that the orientation distributions were often not axially symmetric, a property neatly captured by the ACG distribution. Overall, the ability of SBEM to image diffusion barriers in intricate detail, combined with 3D-ST analysis and parameterisation, provides a step forward toward interpreting and validating the dMRI signals in complex brain tissue microstructure.
  • Fedirko, Veronika; Jenab, Mazda; Meplan, Catherine; Jones, Jeb S.; Zhu, Wanzhe; Schomburg, Lutz; Siddiq, Afshan; Hybsier, Sandra; Overvad, Kim; Tjonneland, Anne; Omichessan, Hanane; Perduca, Vittorio; Boutron-Ruault, Marie-Christine; Kuehn, Tilman; Katzke, Verena; Aleksandrova, Krasimira; Trichopoulou, Antonia; Karakatsani, Anna; Kotanidou, Anastasia; Tumino, Rosario; Panico, Salvatore; Masala, Giovanna; Agnoli, Claudia; Naccarati, Alessio; Bueno-de-Mesquita, Bas; Vermeulen, Roel C. H.; Weiderpass, Elisabete; Skeie, Guri; Nost, Therese Haugdahl; Lujan-Barroso, Leila; Ramon Quiros, J.; Maria Huerta, Jose; Rodriguez-Barranco, Miguel; Barricarte, Aurelio; Gylling, Bjoern; Harlid, Sophia; Bradbury, Kathryn E.; Wareham, Nick; Khaw, Kay-Tee; Gunter, Marc; Murphy, Neil; Freisling, Heinz; Tsilidis, Kostas; Aune, Dagfinn; Riboli, Elio; Hesketh, John E.; Hughes, David J. (2019)
    Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (P-ACT = 0.10; P-ACT significance threshold was P <0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.
  • Kivikoski, Mikko; Rastas, Pasi; Löytynoja, Ari; Merila, Juha (2021)
    We describe an integrative approach to improve contiguity and haploidy of a reference genome assembly and demonstrate its impact with practical examples. With two novel features of Lep-Anchor software and a combination of dense linkage maps, overlap detection and bridging long reads, we generated an improved assembly of the nine-spined stickleback (Pungitius pungitius) reference genome. We were able to remove a significant number of haplotypic contigs, detect more genetic variation and improve the contiguity of the genome, especially that of X chromosome. However, improved scaffolding cannot correct for mosaicism of erroneously assembled contigs, demonstrated by a de novo assembly of a 1.6-Mbp inversion. Qualitatively similar gains were obtained with the genome of three-spined stickleback (Gasterosteus aculeatus). Since the utility of genome-wide sequencing data in biological research depends heavily on the quality of the reference genome, the improved and fully automated approach described here should be helpful in refining reference genome assemblies.
  • Pers, Tune H.; Karjalainen, Juha M.; Chan, Yingleong; Westra, Harm-Jan; Wood, Andrew R.; Yang, Jian; Lui, Julian C.; Vedantam, Sailaja; Gustafsson, Stefan; Esko, Tonu; Frayling, Tim; Speliotes, Elizabeth K.; Boehnke, Michael; Raychaudhuri, Soumya; Fehrmann, Rudolf S. N.; Hirschhorn, Joel N.; Franke, Lude; Genetic Invest ANthropometric Trai; Kaprio, Jaakko (2015)
    The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.
  • Patwardhan, Ardan; Brandt, Robert; Butcher, Sarah J.; Collinson, Lucy; Gault, David; Grunewald, Kay; Hecksel, Corey; Huiskonen, Juha T.; Iudin, Andrii; Jones, Martin L.; Korir, Paul K.; Koster, Abraham J.; Lagerstedt, Ingvar; Lawson, Catherine L.; Mastronarde, David; McCormick, Matthew; Parkinson, Helen; Rosenthal, Peter B.; Saalfeld, Stephan; Saibil, Helen R.; Sarntivijai, Sirarat; Valero, Irene Solanes; Subramaniam, Sriram; Swedlow, Jason R.; Tudose, Ilinca; Winn, Martyn; Kleywegt, Gerard J. (2017)
    The integration of cellular and molecular structural data is key to understanding the function of macromolecular assemblies and complexes in their in vivo context. Here we report on the outcomes of a workshop that discussed how to integrate structural data from a range of public archives. The workshop identified two main priorities: the development of tools and file formats to support segmentation (that is, the decomposition of a three-dimensional volume into regions that can be associated with defined objects), and the development of tools to support the annotation of biological structures.
  • Lwakatare, Lucy Ellen; Kilamo, Terhi; Karvonen, Teemu; Sauvola, Tanja; Heikkilä, Ville; Itkonen, Juha; Kuvaja, Pasi; Mikkonen, Tommi; Oivo, Markku; Lassenius, Casper (2019)
    Context: DevOps is considered important in the ability to frequently and reliably update a system in operational state. DevOps presumes cross-functional collaboration and automation between software development and operations. DevOps adoption and implementation in companies is non-trivial due to required changes in technical, organisational and cultural aspects. Objectives: This exploratory study presents detailed descriptions of how DevOps is implemented in practice. The context of our empirical investigation is web application and service development in small and medium sized companies. Method: A multiple-case study was conducted in five different development contexts with successful DevOps implementations since its benefits, such as quick releases and minimum deployment errors, were achieved. Data was mainly collected through interviews with 26 practitioners and observations made at the companies. Data was analysed by first coding each case individually using a set of predefined themes and thereafter perform a cross-case synthesis. Results: Our analysis yielded some of the following results: (I) software development team attaining ownership and responsibility to deploy software changes in production is crucial in DevOps. (ii) toolchain usage and support in deployment pipeline activities accelerates the delivery of software changes, bug fixes and handling of production incidents. (ii) the delivery speed to production is affected by context factors, such as manual approvals by the product owner (iii) steep learning curve for new skills is experienced by both software developers and operations staff, who also have to cope with working under pressure. Conclusion: Our findings contributes to the overall understanding of DevOps concept, practices and its perceived impacts, particularly in small and medium sized companies. We discuss two practical implications of the results.
  • Li, Yuhong; Su, Xiang; Ding, Aaron Yi; Lindgren, Anders; Liu, Xiaoli; Prehofer, Christian; Riekki, Jukka; Rahmani, Rahim; Tarkoma, Sasu; Hui, Pan (2020)
    The Internet of Things (IoT) connects smart devices to enable various intelligent services. The deployment of IoT encounters several challenges, such as difficulties in controlling and managing IoT applications and networks, problems in programming existing IoT devices, long service provisioning time, underused resources, as well as complexity, isolation and scalability, among others. One fundamental concern is that current IoT networks lack flexibility and intelligence. A network-wide flexible control and management are missing in IoT networks. In addition, huge numbers of devices and large amounts of data are involved in IoT, but none of them have been tuned for supporting network management and control. In this paper, we argue that Software-defined Networking (SDN) together with the data generated by IoT applications can enhance the control and management of IoT in terms of flexibility and intelligence. We present a review for the evolution of SDN and IoT and analyze the benefits and challenges brought by the integration of SDN and IoT with the help of IoT data. We discuss the perspectives of knowledge-driven SDN for IoT through a new IoT architecture and illustrate how to realize Industry IoT by using the architecture. We also highlight the challenges and future research works toward realizing IoT with the knowledge-driven SDN.
  • Broad Genomics Platform; DiscovEHR Collaboration; CHARGE; LuCamp; ProDiGY; GoT2D; ESP; SIGMA-T2D; T2D-GENES; AMP-T2D-GENES; Flannick, Jason; Mercader, Josep M.; Koistinen, Heikki A.; Kuusisto, Johanna; Groop, Leif; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Boehnke, Michael (2019)
    Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 10(-3)). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
  • Weissbrod, Omer; Hormozdiari, Farhad; Benner, Christian; Cui, Ran; Ulirsch, Jacob; Gazal, Steven; Schoech, Armin P.; van de Geijn, Bryce; Reshef, Yakir; Marquez-Luna, Carla; O'Connor, Luke; Pirinen, Matti; Finucane, Hilary K.; Price, Alkes L. (2020)
    Fine-mapping aims to identify causal variants impacting complex traits. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy by leveraging functional annotations across the entire genome-not just genome-wide-significant loci-to specify prior probabilities for fine-mapping methods such as SuSiE or FINEMAP. In simulations, PolyFun + SuSiE and PolyFun + FINEMAP were well calibrated and identified >20% more variants with a posterior causal probability >0.95 than identified in their nonfunctionally informed counterparts. In analyses of 49 UK Biobank traits (average n = 318,000), PolyFun + SuSiE identified 3,025 fine-mapped variant-trait pairs with posterior causal probability >0.95, a >32% improvement versus SuSiE. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 28 (hair color) to 3,400 (height) to 2 million (number of children). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures. PolyFun is a computationally scalable framework for functionally informed fine-mapping that makes full use of genome-wide data. It prioritizes more variants than previous methods when applied to 49 complex traits from UK Biobank.
  • McLaughlin, Russell L.; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R.; O'Brien, Margaret; Kahn, Rene S.; Ophoff, Roel A.; Goris, An; Bradley, Daniel G.; Al-Chalabi, Ammar; van den Berg, Leonard H.; Luykx, Jurjen J.; Hardiman, Orla; Veldink, Jan H.; Project MinE GWAS Consortium; Schizophrenia Working Grp Psychiat; Palotie, Aarno (2017)
    We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
  • Vinuela, Ana; Varshney, Arushi; van de Bunt, Martijn; Prasad, Rashmi B.; Asplund, Olof; Bennett, Amanda; Boehnke, Michael; Brown, Andrew A.; Erdos, Michael R.; Fadista, Joao; Hansson, Ola; Hatem, Gad; Howald, Cedric; Iyengar, Apoorva K.; Johnson, Paul; Krus, Ulrika; MacDonald, Patrick E.; Mahajan, Anubha; Manning Fox, Jocelyn E.; Narisu, Narisu; Nylander, Vibe; Orchard, Peter; Oskolkov, Nikolay; Panousis, Nikolaos I.; Payne, Anthony; Stitzel, Michael L.; Vadlamudi, Swarooparani; Welch, Ryan; Collins, Francis S.; Mohlke, Karen L.; Gloyn, Anna L.; Scott, Laura J.; Dermitzakis, Emmanouil T.; Groop, Leif; Parker, Stephen C. J.; McCarthy, Mark I. (2020)
    Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.
  • Momozawa, Yukihide; Merveille, Anne-Christine; Battaille, Geraldine; Wiberg, Maria; Koch, Jørgen; Willesen, Jakob Lundgren; Proschowsky, Helle Friis; Gouni, Vassiliki; Chetboul, Valerie; Tiret, Laurent; Fredholm, Merete; Seppälä, Eija H.; Lohi, Hannes; Georges, Michel; Lequarre, Anne-Sophie (2020)
    The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1-47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8-78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.
  • Pervjakova, N.; Kukushkina, V.; Haller, T.; Kasela, S.; Joensuu, A.; Kristiansson, K.; Annilo, T.; Perola, M.; Salomaa, V.; Jousilahti, P.; Metspalu, A.; Magi, R. (2018)
    The aim of the study was to explore the parent-of-origin effects (POEs) on a range of human nuclear magnetic resonance metabolites. Materials & methods: We search for POEs in 14,815 unrelated individuals from Estonian and Finnish cohorts using POE method for the genotype data imputed with 1000 G reference panel and 82 nuclear magnetic resonance metabolites. Results: Meta-analysis revealed the evidence of POE for the variant rs1412727 in PTPRD gene for the metabolite: triglycerides in medium very low-density lipoprotein. No POEs were detected for genetic variants that were previously known to have main effect on circulating metabolites. Conclusion: We demonstrated possibility to detect POEs for human metabolites, but the POEs are weak, and therefore it is hard to detect those using currently available sample sizes.
  • Ahluwalia, Tarunveer S; Prins, Bram P; Abdollahi, Mohammadreza; Armstrong, Nicola J; Aslibekyan, Stella; Bain, Lisa; Jefferis, Barbara; Baumert, Jens; Beekman, Marian; Ben-Shlomo, Yoav; Bis, Joshua C; Mitchell, Braxton D; de Geus, Eco; Delgado, Graciela E; Marek, Diana; Eriksson, Joel; Kajantie, Eero; Kanoni, Stavroula; Kemp, John P; Lu, Chen; Marioni, Riccardo E; McLachlan, Stela; Milaneschi, Yuri; Nolte, Ilja M; Petrelis, Alexandros M; Porcu, Eleonora; Sabater-Lleal, Maria; Naderi, Elnaz; Seppälä, Ilkka; Shah, Tina; Singhal, Gaurav; Standl, Marie; Teumer, Alexander; Thalamuthu, Anbupalam; Thiering, Elisabeth; Trompet, Stella; Ballantyne, Christie M; Benjamin, Emelia J; Casas, Juan P; Toben, Catherine; Dedoussis, George; Deelen, Joris; Durda, Peter; Engmann, Jorgen; Feitosa, Mary F; Grallert, Harald; Hammarstedt, Ann; Harris, Sarah E; Homuth, Georg; Hottenga, Jouke-Jan; Jalkanen, Sirpa; Jamshidi, Yalda; Jawahar, Magdalene C; Jess, Tine; Kivimaki, Mika; Kleber, Marcus E; Lahti, Jari; Liu, Yongmei; Marques-Vidal, Pedro; Mellström, Dan; Mooijaart, Simon P; Müller-Nurasyid, Martina; Penninx, Brenda; Revez, Joana A; Rossing, Peter; Räikkönen, Katri; Sattar, Naveed; Scharnagl, Hubert; Sennblad, Bengt; Silveira, Angela; Pourcain, Beate St; Timpson, Nicholas J; Trollor, Julian; Group, CHARGE Inflammation Working; van Dongen, Jenny; Van Heemst, Diana; Visvikis-Siest, Sophie; Vollenweider, Peter; Völker, Uwe; Waldenberger, Melanie; Willemsen, Gonneke; Zabaneh, Delilah; Morris, Richard W; Arnett, Donna K; Baune, Bernhard T; Boomsma, Dorret I; Chang, Yen-Pei C; Deary, Ian J; Deloukas, Panos; Eriksson, Johan G; Evans, David M; Ferreira, Manuel A; Gaunt, Tom; Gudnason, Vilmundur; Hamsten, Anders; Heinrich, Joachim; Hingorani, Aroon; Humphries, Steve E; Jukema, J Wouter; Koenig, Wolfgang; Kumari, Meena; Kutalik, Zoltan; Lawlor, Deborah A; Lehtimäki, Terho; März, Winfried; Mather, Karen A; Naitza, Silvia; Nauck, Matthias; Ohlsson, Claes; Price, Jackie F; Raitakari, Olli; Rice, Ken; Sachdev, Perminder S; Slagboom, Eline; Sørensen, Thorkild I A; Spector, Tim; Stacey, David; Stathopoulou, Maria G; Tanaka, Toshiko; Wannamethee, S Goya; Whincup, Peter; Rotter, Jerome I; Dehghan, Abbas; Boerwinkle, Eric; Psaty, Bruce M; Snieder, Harold; Alizadeh, Behrooz Z (2021)
    Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
  • Int Parkinson's Dis Genomics Cons; Guerreiro, Rita; Escott-Price, Valentina; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna (2019)
    Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
  • Nava, Michele M.; Miroshnikova, Yekaterina A.; Biggs, Leah C.; Whitefield, Daniel B.; Metge, Franziska; Boucas, Jorge; Vihinen, Helena; Jokitalo, Eija; Li, Xinping; García Arcos, Juan Manuel; Hoffmann, Bernd; Merkel, Rudolf; Niessen, Carien M.; Dahl, Kris Noel; Wickström, Sara A. (2020)
    Summary Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.
  • Nagaeva, Elina; Zubarev, Ivan; Gonzales, Carolina Bengtsson; Forss, Mikko; Nikouei, Kasra; de Miguel, Elena; Elsilä, Lauri; Linden, Anni-Maija; Hjerling-Leffler, Jens; Augustine, George J.; Korpi, Esa R. (2020)
    The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.
  • Elbers, Jean P.; Rogers, Mark F.; Perelman, Polina L.; Proskuryakova, Anastasia A.; Serdyukova, Natalia A.; Johnson, Warren E.; Horin, Petr; Corander, Jukka; Murphy, David; Burger, Pamela A. (2019)
    Researchers have assembled thousands of eukaryotic genomes using Illumina reads, but traditional mate-pair libraries cannot span all repetitive elements, resulting in highly fragmented assemblies. However, both chromosome conformation capture techniques, such as Hi-C and Dovetail Genomics Chicago libraries and long-read sequencing, such as Pacific Biosciences and Oxford Nanopore, help span and resolve repetitive regions and therefore improve genome assemblies. One important livestock species of arid regions that does not have a high-quality contiguous reference genome is the dromedary (Camelus dromedarius). Draft genomes exist but are highly fragmented, and a high-quality reference genome is needed to understand adaptation to desert environments and artificial selection during domestication. Dromedaries are among the last livestock species to have been domesticated, and together with wild and domestic Bactrian camels, they are the only representatives of the Camelini tribe, which highlights their evolutionary significance. Here we describe our efforts to improve the North African dromedary genome. We used Chicago and Hi-C sequencing libraries from Dovetail Genomics to resolve the order of previously assembled contigs, producing almost chromosome-level scaffolds. Remaining gaps were filled with Pacific Biosciences long reads, and then scaffolds were comparatively mapped to chromosomes. Long reads added 99.32 Mbp to the total length of the new assembly. Dovetail Chicago and Hi-C libraries increased the longest scaffold over 12-fold, from 9.71 Mbp to 124.99 Mbp and the scaffold N50 over 50-fold, from 1.48 Mbp to 75.02 Mbp. We demonstrate that Illumina de novo assemblies can be substantially upgraded by combining chromosome conformation capture and long-read sequencing.
  • Int IBD Genetics Consortium; NIDDK IBD Genetics Consortium; T2D-Genes Consortium; Rivas, Manuel A.; Koskela, Jukka; Pirinen, Matti; Kurki, Mitja; Saavalainen, Paivi; Farkkila, Martti; Kontula, Kimmo; Palotie, Aarno; Daly, Mark J. (2018)
    As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at, also available in gnomAD at We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at, including those that account for 10 +/- 100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p. Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to fourfold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p <0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p