Browsing by Subject "ELEMENTS"

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  • Laht, Mailis; Karkman, Antti; Voolaid, Veiko; Ritz, Christian; Tenson, Tanel; Virta, Marko; Kisand, Veljo (2014)
  • Everson, Richard; Pettitt, Louise; Forman, Oliver P.; Dower-Tylee, Olivia; McLaughlin, Bryan; Ahonen, Saija; Kaukonen, Maria; Komaromy, Andras M.; Lohi, Hannes; Mellersh, Cathryn S.; Sansom, Jane; Ricketts, Sally L. (2017)
    The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10(-11)) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10(-19)). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a similar to 20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10(-27)). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.
  • Salminen-Paatero, Susanna; Hou, Xiaolin; Olszewski, Grzegorz; Ekerljung, Lina; Tovedal, Annika; Vesterlund, Anna; Andersson, Angelica; Kangas, Satu; Ramebäck, Henrik (2021)
    Radioanalytical methods for the determination of isotopes of Pu, Am and Cm in water samples from nuclear power plants were compared and further developed in a Nordic project (Optimethod) through two intercomparison exercises among Nordic laboratories. With this intercomparison, the analytical performance of some laboratories was improved by modification of the analytical method and adopting new techniques. The obtained results from the two intercomparisons for alpha emitting transuranium isotopes are presented, and the lessons learnt from these intercomparison exercises are discussed.
  • Baryshnikov, Glib; Valiev, Rashid R.; Nasibullin, Rinat T.; Sundholm, Dage; Kurten, Theo; Ågren, Hans (2020)
    The recently synthesized cyclo[18]carbon molecule has been characterized in a number of studies by calculating electronic, spectroscopic, and mechanical properties. However, cyclo[18] carbon is only one member of the class of cyclo[n]carbons-standalone carbon allotrope representatives. Many of the larger members of this class of molecules have not been thoroughly investigated. In this work, we calculate the magnetically induced current density of cyclo[n]carbons in order to elucidate how electron delocalization and aromatic properties change with the size of the molecular ring (n), where n is an even number between 6 and 100. We find that the Hiickel rules for aromaticity (4k + 2) and antiaromaticity (4k) become degenerate for large C-n rings (n > 50), which can be understood as a transition from a delocalized electronic structure to a nonaromatic structure with localized current density fluxes in the triple bonds. Actually, the calculations suggest that cyclo[n]carbons with n > 50 are nonaromatic cyclic polyalkynes. The influence of the amount of nonlocal exchange and the asymptotic behavior of the exchange-correlation potential of the employed density functionals on the strength of the magnetically induced ring current and the aromatic character of the large cyclo[n]carbons is also discussed.
  • Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; Ruiz de Garibay, Gorka; Librado, Pablo; Sanchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Nuria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Catala, Isabel; Brunet, Joan; Feliubadalo, Lidia; Tornero, Eva; Benitez, Javier; Osorio, Ana; Cajal, Teresa Ramon Y.; Nevanlinna, Heli; Aittomaki, Kristiina; Arun, Banu K.; Toland, Amanda E.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Greene, Mark H.; Mai, Phuong L.; Nussbaum, Robert L.; Andrulis, Irene L.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Diez, Orland; Hansen, Thomas V.; Jonson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldes, Trinidad; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R.; Teixeira,; Hogervorst, Frans B. L.; van der Hout, Annemarie H.; Seynaeve, Caroline; van der Luijt, Rob B.; Ligtenberg, Marjolijn J. L.; Devilee, Peter; Wijnen, Juul T.; Rookus, Matti A.; Meijers-Heijboer, Hanne E. J.; Blok, Marinus J.; van den Ouweland, Ans M. W.; Aalfs, Cora M.; Rodriguez, Gustavo C.; Phillips, Kelly-Anne A.; Piedmonte, Marion; Nerenstone, Stacy R.; Bae-Jump, Victoria L.; O'Malley, David M.; Ratner, Elena S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J.; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A.; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M.; Miron, Alex; Neuhausen, Susan L.; Terry, Mary Beth; Chung, Wendy K.; Daly, Mary B.; Goldgar, David E.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elisabeth J.; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K.; Olah, Edith; Narod, Steven A.; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N.; Hamann, Ute; Spurdle, Amanda B.; Healey, Sue; Weitzel, Jeffrey N.; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gomez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Leone, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, Francois; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.; Maxwell, Christopher A.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lazaro, Conxi; Easton, Douglas F.; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J.; Antoniou, Antonis C.; Angel Pujana, Miguel; BCFR; SWE-BRCA; KConFab Investigators; GEMO (2015)
    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
  • Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W.; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B.; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Taari, Kimmo; PRACTICAL Consortium (2016)
    Although genome-wide association studies have identified over 100 risk loci that explain similar to 33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
  • Isenberg, Stefan; Weller, Stefan; Kargin, Denis; Valic, Srecko; Schwederski, Brigitte; Kelemen, Zsolt; Bruhn, Clemens; Krekic, Kristijan; Maurer, Martin; Feil, Christoph M.; Nieger, Martin; Gudat, Dietrich; Nyulaszi, Laszlo; Pietschnig, Rudolf (2019)
    Invited for this month's cover picture are the groups of Professors Rudolf Pietschnig at the University of Kassel, Professor Dietrich Gudat at the University of Stuttgart and Professor Laszlo Nyulaszi at the Budapest University of Technology and Economics. The cover picture shows the thermally induced homolytic cleavage of the central P-P bond in a phosphorus-rich bis-ferrocenophane furnishing P-centered radicals (as evidenced by the computed spin-density highlighted in blue). The central P-6 unit in the title compound is a structural analog of the connecting unit in Hittorf's violet phosphorus, which links the orthogonally arranged tubular entities. A portrait of the German physicist Johann Wilhelm Hittorf is included. Read the full text of their Full Paper at 10.1002/open.201900182.
  • Carbone, S.; Onasch, T.; Saarikoski, S.; Timonen, H.; Saarnio, K.; Sueper, D.; Ronkko, T.; Pirjola, L.; Häyrinen, A.; Worsnop, D.; Hillamo, R. (2015)
    A method to detect and quantify mass concentrations of trace metals on soot particles by the Aerodyne soot-particle aerosol mass spectrometer (SP-AMS) was developed and evaluated in this study. The generation of monodisperse Regal black (RB) test particles with trace amounts of 13 different metals (Na, Al, Ca, V, Cr, Mn, Fe, Ni, Cu, Zn, Rb, Sr and Ba) allowed for the determination of the relative ionization efficiency of each metal relative to black carbon (RIEmeas). The observed RIEmeas/RIEtheory values were larger than unity for Na, Rb, Ca, Sr and Ba due to thermal surface ionization (TSI) on the surface of the laser-heated RB particles. Values closer to unity were obtained for the transition metals Zn, Cu, V and Cr. Mn, Fe, and Ni presented the lowest RIEmeas/RIEtheory ratios and highest deviation from unity. The latter discrepancy is unexplained; however it may be related to problems with our calibration method and/or the formation of metal complexes that were not successfully quantified. The response of the metals to the laser power was investigated and the results indicated that a minimum pump laser current of 0.6 A was needed in order to vaporize the metals and the refractory black carbon (rBC). Isotopic patterns of metals were resolved from high-resolution mass spectra, and the mass-weighted size distributions for each individual metal ion were obtained using the high-resolution particle time-of-flight (HR-PToF) method. The RIEmeas values obtained in this study were applied to the data of emission measurements in a heavy-fuel-oil-fired heating station. Emission measurements revealed a large number of trace metals, including evidence for metal oxides and metallic salts, such as vanadium sulfate, calcium sulfate, iron sulfate and barium sulfate, which were identified in the SP-AMS high-resolution mass spectra. SP-AMS measurements of Ba, Fe, and V agreed with ICP-MS analyzed filter samples within a factor of 2 when emitted rBC mass loadings were elevated.
  • Skarp, C. P. A.; Akinrinade, O.; Nilsson, A. J. E.; Ellstrom, P.; Myllykangas, S.; Rautelin, H. (2015)
    Campylobacter jejuni is a major pathogen in bacterial gastroenteritis worldwide and can cause bacteremia in severe cases. C. jejuni is highly structured into clonal lineages of which the ST677CC lineage has been overrepresented among C. jejuni isolates derived from blood. In this study, we characterized the genomes of 31 C. jejuni blood isolates and 24 faecal isolates belonging to ST677CC in order to study the genome biology related to C. jejuni invasiveness. We combined the genome analyses with phenotypical evidence on serum resistance which was associated with phase variation of wcbK; a GDP-mannose 4,6-dehydratase involved in capsular biosynthesis. We also describe the finding of a Type III restriction-modification system unique to the ST-794 sublineage. However, features previously considered to be related to pathogenesis of C. jejuni were either absent or disrupted among our strains. Our results refine the role of capsule features associated with invasive disease and accentuate the possibility of methylation and restriction enzymes in the potential of C. jejuni to establish invasive infections. Our findings underline the importance of studying clinically relevant well-characterized bacterial strains in order to understand pathogenesis mechanisms important in human infections.
  • Valanko, Sebastian; Heino, Jani; Westerbom, Mats; Viitasalo, Markku; Norkko, Alf (2015)
    The majority of studies in metacommunity ecology have focused on systems other than marine benthic ecosystems, thereby providing an impetus to broaden the focus of metacommunity research to comprise marine systems. These systems are more open than many other systems and may thus exhibit relatively less discrete patterns in community structure across space. Metacommunity structure of soft-sediment benthic invertebrates was examined using a fine-grained (285 sites) data set collected during one summer across a large spatial extent (1700km(2)). We applied the elements of metacommunity structure (EMS) approach, allowing multiple hypothesis of variation in community structure to be tested. We demonstrated several patterns associated with environmental variation and associated processes that could simultaneously assemble species to occur at the sites. A quasi-Clementsian pattern was observed frequently, suggesting interdependent ecological relationships among species or similar response to an underlying environmental gradient across sites. A quasi-nested clumped species loss pattern was also observed, which suggests nested habitat specialization. Species richness declined with depth (from 0.5 to 44.8m). We argue that sensitive species may survive in shallower water, which are more stable with regard to oxygen conditions and present greater habitat complexity, in contrast to deeper waters, which may experience periodic disturbance due to hypoxia. Future studies should better integrate disturbance in terms of temporal dynamics and dispersal rates in the EMS approach. We highlight that shallow water sites may act as sources of recruitment to deeper water sites that are relatively more prone to periodic disturbances due to hypoxia. However, these shallow sites are not currently monitored and should be better prioritized in future conservation strategies in marine systems.
  • Tobiasson, Magnus; Abdulkadir, Hani; Lennartsson, Andreas; Katayama, Shintaro; Marabita, Francesco; De Paepe, Ayla; Karimi, Mohsen; Krjutskov, Kaarel; Einarsdottir, Elisabet; Grovdal, Michael; Jansson, Monika; Ben Azenkoud, Asmaa; Corddedu, Lina; Lehmann, Soren; Ekwall, Karl; Kere, Juha; Hellstrom-Lindberg, Eva; Ungerstedt, Johanna (2017)
    Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
  • Kurki, Mitja I.; Saarentaus, Elmo Christian; Pietiläinen, Olli; Gormley, Padraigh; Lal, Dennis; Kerminen, Sini; Torniainen-Holm, Minna; Hämäläinen, Eija; Rahikkala, Elisa; Keski-Filppula, Riikka; Rauhala, Merja; Korpi-Heikkila, Satu; Komulainen-Ebrahim, Jonna; Helander, Heli; Vieira, Päivi; Männikkö, Minna; Peltonen, Markku; Havulinna, Aki; Salomaa, Veikko; Pirinen, Matti; Suvisaari, Jaana; Moilanen, Jukka S.; Körkkö, Jarmo; Kuismin, Outi; Daly, Mark; Palotie, Aarno (2019)
    The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.
  • Katainen, Riku; Donner, Iikki; Cajuso, Tatiana; Kaasinen, Eevi; Palin, Kimmo; Mäkinen, Veli; Aaltonen, Lauri A.; Pitkänen, Esa (2018)
    Next-generation sequencing (NGS) is routinely applied in life sciences and clinical practice, but interpretation of the massive quantities of genomic data produced has become a critical challenge. The genome-wide mutation analyses enabled by NGS have had a revolutionary impact in revealing the predisposing and driving DNA alterations behind a multitude of disorders. The workflow to identify causative mutations from NGS data, for example in cancer and rare diseases, commonly involves phases such as quality filtering, case-control comparison, genome annotation, and visual validation, which require multiple processing steps and usage of various tools and scripts. To this end, we have introduced an interactive and user-friendly multi-platform-compatible software, BasePlayer, which allows scientists, regardless of bioinformatics training, to carry out variant analysis in disease genetics settings. A genome-wide scan of regulatory regions for mutation clusters can be carried out with a desktop computer in -10 min with a dataset of 3 million somatic variants in 200 whole-genome-sequenced (WGS) cancers.
  • Turzhanova, Ainur; Khapilina, Oxana; Tumenbayeva, A; Shevtsov, Vladislav; Raiser, Olesya; Kalendar, Ruslan (2020)
    The genus Alternaria is a widely distributed major plant pathogen that can act as a saprophyte in plant debris. Fungi of this genus frequently infect cereal crops and cause such diseases as black point and wheat leaf blight, which decrease the yield and quality of cereal products. A total of 25 Alternaria sp. isolates were collected from germ grains of various wheat cultivars from different geographic regions in Kazakhstan. We investigated the genetic relationships of the main Alternaria species related to black point disease of wheat in Kazakhstan, using the inter-primer binding site (iPBS) DNA profiling technique. We used 25 retrotransposon-based iPBS primers to identify the differences among and within Alternaria species populations, and analyzed the variation using clustering (UPGMA) and statistical approaches (AMOVA). Isolates of Alternaria species clustered into two main genetic groups, with species of A.alternata and A.tennuissima forming one cluster, and isolates of A. infectoria forming another. The genetic diversity found using retrotransposon profiles was strongly correlated with geographic data. Overall, the iPBS fingerprinting technique is highly informative and useful for the evaluation of genetic diversity and relationships of Alternaria species.
  • 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.
  • Pan, David Z.; Miao, Zong; Comenho, Caroline; Rajkumar, Sandhya; Koka, Amogha; Lee, Seung Hyuk T.; Alvarez, Marcus; Kaminska, Dorota; Ko, Arthur; Sinsheimer, Janet S.; Mohlke, Karen L.; Mancuso, Nicholas; Munoz-Hernandez, Linda Liliana; Herrera-Hernandez, Miguel; Tusie-Luna, Maria Teresa; Aguilar-Salinas, Carlos; Pietiläinen, Kirsi H.; Pihlajamäki, Jussi; Laakso, Markku; Garske, Kristina M.; Pajukanta, Päivi (2021)
    Background: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. Methods: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n similar to 1400) and WHRadjBMI GWAS data (n similar to 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. Results: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. Conclusions: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.
  • Xu, Wen-hua; Pyykkö, Pekka (2016)
    It is explicitly verified that the atomic 7p(1) ground-state configuration of Lr originates from relativistic effects. Without relativity one has 6d(1). All three ionization potentials IP1-3 of Lr resemble those of Lu. Simple model studies on mono-and trihydrides, monocarbonyls or trichlorides suggest no major chemical differences between Lr and the lanthanides.
  • Genome Aggregation Database Prod T; Genome Aggregation Database Consor; Wang, Qingbo; Pierce-Hoffman, Emma; Cummings, Beryl B.; MacArthur, Daniel G.; Groop, Leif; Färkkilä, Martti; Palotie, Aarno; Remes, Anne M.; Ripatti, Samuli; Salomaa, Veikko; Soininen, Hilkka; Suvisaari, Jaana; Tuomi, Tiinamaija; Vartiainen, Erkki; Wessman, Maija (2020)
    Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs. Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.
  • Heidari, Parviz; Abdullah,; Faraji, Sahar; Poczai, Péter (2021)
    Magnesium (Mg) is an element involved in various key cellular processes in plants. Mg transporter (MGT) genes play an important role in magnesium distribution and ionic balance maintenance. Here, MGT family members were identified and characterized in three species of the plant family Malvaceae, Theobroma cacao, Corchorus capsularis, and Gossypium hirsutum, to improve our understanding of their structure, regulatory systems, functions, and possible interactions. We identified 18, 41, and 16 putative non-redundant MGT genes from the genome of T. cacao, G. hirsutum, and C. capsularis, respectively, which clustered into three groups the maximum likelihood tree. Several segmental/tandem duplication events were determined between MGT genes. MGTs appear to have evolved slowly under a purifying selection. Analysis of gene promoter regions showed that MGTs have a high potential to respond to biotic/abiotic stresses and hormones. The expression patterns of MGT genes revealed a possible role in response to P. megakarya fungi in T. cacao, whereas MGT genes showed differential expression in various tissues and response to several abiotic stresses, including cold, salt, drought, and heat stress in G. hirsutum. The co-expression network of MGTs indicated that genes involved in auxin-responsive lipid metabolism, cell wall organization, and photoprotection can interact with MGTs.
  • NHGRI Ctr Common; Abel, Haley J.; Larson, David E.; Regier, Allison A.; Hall, Ira M.; Daly, Mark J.; Palotie, Aarno; Ripatti, Samuli; Salomaa, Veikko; Taskinen, Marja-Riitta (2020)
    Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles. A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline(1)to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.