Browsing by Subject "HUMAN-DISEASE"

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  • Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V.; Samocha, Kaitlin E.; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H.; Ware, James S.; Hill, Andrew J.; Cummings, Beryl B.; Tukiainen, Taru; Birnbaum, Daniel P.; Kosmicki, Jack A.; Duncan, Laramie E.; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hollman, Emma; Berghout, Joanne; Cooper, David N.; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I.; Moonshine, Ami Levy; Natarajan, Pradeep; Orozeo, Lorena; Peloso, Gina M.; Poplin, Ryan; Rivas, Manuel A.; Ruano-Rubio, Valentin; Rose, Samuel A.; Ruderfer, Douglas M.; Shakir, Khalid; Stenson, Peter D.; Stevens, Christine; Thomas, Brett P.; Tiao, Grace; Tusie-Luna, Maria T.; Weisburd, Ben; Palotie, Aarno; Tuomilehto, Jaakko; Daly, Mark J.; Exome Aggregation Consortium (2016)
    Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
  • EuroEPINOMICS-RES Consortium; Heyne, Henrike O.; Linnankivi, Tarja; Palotie, Aarno; Daly, Mark J.; Lehesjoki, Anna-Elina (2018)
    Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.
  • Hilander, Taru; Zhou, Xiao-Long; Konovalova, Svetlana; Zhang, Fu-Ping; Euro, Liliya; Shilov, Dmitri; Poutanen, Matti; Chihade, Joseph; Wang, En-Duo; Tyynismaa, Henna (2018)
    Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms.
  • Valimaki, Niko; Kuisma, Heli; Pasanen, Annukka; Heikinheimo, Oskari; Sjoberg, Jari; Butzow, Ralf; Sarvilinna, Nanna; Heinonen, Hanna-Riikka; Tolvanen, Jaana; Bramante, Simona; Tanskanen, Tomas; Auvinen, Juha; Uimari, Outi; Alkodsi, Amjad; Lehtonen, Rainer; Kaasinen, Eevi; Palin, Kimmo; Aaltonen, Lauri A. (2018)
    Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.
  • Antel, Jack; Ban, Maria; Baranzini, Sergio; Barcellos, Lisa; Barizzone, Nadia; Beecham, Ashley; Berge, Tone; Bernardinelli, Luisa; Booth, David; Bos, Steffan; Buck, Dorothea; Butkiewicz, Mariusz; Celius, Elisabeth G.; Comabella, Manuel; Compston, Alastair; Dedham, Katrina; Cotsapas, Chris; Alfonso, Sandra D'; De Jager, Phil; Dubois, Benedicte; Duquette, Pierre; Fontaine, Bertrand; Gasperi, Christiane; Gil, Elia; Goris, An; Gourraud, Pierre Antoine; Graetz, Christiane; Gyllenberg, Alexandra; Hadjigeorgiou, Georgios; Hafler, David; Hribko, Deanna; Haines, Jonathan; Harbo, Hanne; Hauser, Stephen; Warto, Shannon; Hawkins, Clive; Hemmer, Bernhard; Henry, Roland; Hintzen, Rogier; Horakova, Dana; Ivinson, Adrian; Howard, Melissa; Jelcic, Ilijas; Kaskow, Belinda; Kira, Jun-Ichi; Kleinova, Pavlina; Kockum, Ingrid; Kucerova, Karolina; Palotie, Aarno; Saarela, Janna; Int Multiple Sclerosis Genetics Co (2016)
    A recent study by Wang et al. (2016a) claims that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause multiple sclerosis in certain individuals and determines a patient's likelihood of primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium(IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al. (2016a), but we find no evidence that this variant is associated with either MS or disease subtype. Wang et al. (2016a) also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS-of which no examples exist-can therefore not be substantiated by data. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by Minikel and MacArthur (2016) and the response by Wang et al. (2016b), published in this issue.
  • Okser, Sebastian; Pahikkala, Tapio; Airola, Antti; Salakoski, Tapio; Ripatti, Samuli; Aittokallio, Tero (2014)
  • Fontana, Flavia; Figueiredo, Patricia; Martins, João Pedro; Santos, Hélder A. (2021)
    In vivo models remain a principle screening tool in the drug discovery pipeline. Here, the challenges associated with the need for animal experiments, as well as their impact on research, individual/societal, and economic contexts are discussed. A number of alternatives that, with further development, optimization, and investment, may replace animal experiments are also revised.
  • Ferreira, Pedro G.; Oti, Martin; Barann, Matthias; Wieland, Thomas; Ezquina, Suzana; Friedlander, Marc R.; Rivas, Manuel A.; Esteve-Codina, Anna; Rosenstiel, Philip; Strom, Tim M.; Lappalainen, Tuuli; Guigo, Roderic; Sammeth, Michael; GEUVADIS Consortium; Palotie, A. (2016)
    Recent advances in the cost-efficiency of sequencing technologies enabled the combined DNA-and RNA-sequencing of human individuals at the population-scale, making genome-wide investigations of the inter-individual genetic impact on gene expression viable. Employing mRNA-sequencing data from the Geuvadis Project and genome sequencing data from the 1000 Genomes Project we show that the computational analysis of DNA sequences around splice sites and poly-A signals is able to explain several observations in the phenotype data. In contrast to widespread assessments of statistically significant associations between DNA polymorphisms and quantitative traits, we developed a computational tool to pinpoint the molecular mechanisms by which genetic markers drive variation in RNA-processing, cataloguing and classifying alleles that change the affinity of core RNA elements to their recognizing factors. The in silico models we employ further suggest RNA editing can moonlight as a splicing-modulator, albeit less frequently than genomic sequence diversity. Beyond existing annotations, we demonstrate that the ultra-high resolution of RNA-Seq combined from 462 individuals also provides evidence for thousands of bona fide novel elements of RNA processing-alternative splice sites, introns, and cleavage sites-which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts.
  • Pimenoff, Ville N.; Houldcroft, Charlotte J.; Rifkin, Riaan F.; Underdown, Simon (2018)
    Analysis of pathogen genome data sequenced from clinical and historical samples has made it possible to perform phylogenetic analyses of sexually transmitted infections on a global scale, and to estimate the diversity, distribution, and coevolutionary host relationships of these pathogens, providing insights into pathogen emergence and disease prevention. Deep-sequenced pathogen genomes from clinical studies and ancient samples yield estimates of within-host and between-host evolutionary rates and provide data on changes in pathogen genomic stability and evolutionary responses. Here we examine three groups of pathogens transmitted mainly through sexual contact between modern humans to provide insight into ancient human behavior and history with their pathogens. Exploring ancient pathogen genomic divergence and the ancient viral-host parallel evolutionary histories will help us to reconstruct the origin of present-day geographical distribution and diversity of clinical pathogen infections, and will hopefully allow us to foresee possible environmentally induced pathogen evolutionary responses. Lastly, we emphasize that ancient pathogen DNA research should be combined with modern clinical pathogen data, and be equitable and provide advantages for all researchers worldwide, e.g., through shared data.
  • He, Huiling; Li, Wei; Wu, Dayong; Nagy, Rebecca; Liyanarachchi, Sandya; Akagi, Keiko; Jendrzejewski, Jaroslaw; Jiao, Hong; Hoag, Kevin; Wen, Bernard; Srinivas, Mukund; Waidyaratne, Gavisha; Wang, Rui; Wojcicka, Anna; Lattimer, Ilene R.; Stachlewska, Elzbieta; Czetwertynska, Malgorzata; Dlugosinska, Joanna; Gierlikowski, Wojciech; Ploski, Rafal; Krawczyk, Marek; Jazdzewski, Krystian; Kere, Juha; Symer, David E.; Jin, Victor; Wang, Qianben; de la Chapelle, Albert (2013)