Browsing by Subject "SEQUENCING DATA"

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  • Ahonen, Saija J.; Arumilli, Meharji; Lohi, Hannes (2013)
  • Kucuk, Can; Jiang, Bei; Hu, Xiaozhou; Zhang, Wenyan; Chan, John K. C.; Xiao, Wenming; Lack, Nathan; Alkan, Can; Williams, John C.; Avery, Kendra N.; Kavak, Pinar; Scuto, Anna; Sen, Emel; Gaulard, Philippe; Staudt, Lou; Iqbal, Javeed; Zhang, Weiwei; Cornish, Adam; Gong, Qiang; Yang, Qunpei; Sun, Hong; d'Amore, Francesco; Leppa, Sirpa; Liu, Weiping; Fu, Kai; de Leval, Laurence; McKeithan, Timothy; Chan, Wing C. (2015)
  • Alanko, Jarno; Alipanahi, Bahar; Settle, Jonathen; Boucher, Christina; Gagie, Travis (2021)
    Motivation: The de Bruijn graph has become a ubiquitous graph model for biological data ever since its initial introduction in the late 1990s. It has been used for a variety of purposes including genome assembly (Zerbino and Birney, 2008; Bankevich et al., 2012; Peng et al., 2012), variant detection (Alipanahi et al., 2020b; Iqbal et al., 2012), and storage of assembled genomes (Chikhi et al., 2016). For this reason, there have been over a dozen methods for building and representing the de Bruijn graph and its variants in a space and time efficient manner. Results: With the exception of a few data structures (Muggli et al., 2019; Holley and Melsted, 2020; Crawford et al.,2018), compressed and compact de Bruijn graphs do not allow for the graph to be efficiently updated, meaning that data can be added or deleted. The most recent compressed dynamic de Bruijn graph (Alipanahi et al., 2020a), relies on dynamic bit vectors which are slow in theory and practice. To address this shortcoming, we present a compressed dynamic de Bruijn graph that removes the necessity of dynamic bit vectors by buffering data that should be added or removed from the graph. We implement our method, which we refer to as BufBOSS, and compare its performance to Bifrost, DynamicBOSS, and FDBG. Our experiments demonstrate that BufBOSS achieves attractive trade-offs compared to other tools in terms of time, memory and disk, and has the best deletion performance by an order of magnitude. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
  • Hänninen, Ulrika A.; Katainen, Riku; Tanskanen, Tomas; Plaketti, Roosa-Maria; Laine, Riku; Hamberg, Jiri; Ristimäki, Ari; Pukkala, Eero; Taipale, Minna; Mecklin, Jukka-Pekka; Forsström, Linda M.; Pitkänen, Esa; Palin, Kimmo; Välimäki, Niko; Mäkinen, Netta; Aaltonen, Lauri A. (2018)
    Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.
  • Turunen, Joni A.; Wedenoja, Juho; Repo, Pauliina; Järvinen, Reetta-Stiina; Jäntti, Johannes E.; Mörtenhumer, Sanna; Riikonen, Antti S.; Lehesjoki, Anna-Elina; Majander, Anna; Kivelä, Tero T. (2018)
    PURPOSE: To describe the phenotype and the genetic defect in keratoendotheliitis fugax hereditaria, an autosomal dominant keratitis that periodically affects the corneal endothelium and stroma, leading in some patients to opacities and decreased visual acuity. DESIGN: Cross-sectional, hospital-based study. METHODS: PATIENT POPULATION: Thirty affected and 7 unaffected subjects from 7 families, and 4 sporadic patients from Finland. OBSERVATION PROCEDURES: Ophthalmic examination and photography, corneal topography, specular microscopy, and optical coherence tomography in 34 patients, whole exome sequencing in 10 patients, and Sanger sequencing in 34 patients. MAIN OUTCOME MEASURES: Clinical phenotype, disease causing genetic variants. RESULTS: Unilateral attacks of keratoendotheliitis typically occurred 1-6 times a year (median, 2.5), starting at a median age of 11 years (range, 5-28 years), and lasted for 1-2 days. The attacks were characterized by cornea pseudoguttata and haze in the posterior corneal stroma, sometimes with a mild anterior chamber reaction, and got milder and less frequent in middle age. Seventeen (50%) patients had bilateral stroma! opacities. The disease was inherited as an autosomal dominant trait. A likely pathogenic variant c.61G > C in the NLRP3 gene, encoding cryopyrin, was detected in all 34 tested patients and segregated with the disease. This variant is present in both Finnish and non-Finnish European populations at a frequency of about 0.02% and 0.01%, respectively. CONCLUSION: Keratoendotheliitis fugax hereditaria is an autoinflammatory cryopyrin-associated periodic syndrome caused by a missense mutation c.61G > C in exon 1 of NLRP3 in Finnish patients. It is additionally expected to occur in other populations of European descent. ((c) 2018 The Author(s). Published by Elsevier Inc.
  • Bauer, Anina; Jagannathan, Vidhya; Hoegler, Sandra; Richter, Barbara; McEwan, Neil A.; Thomas, Anne; Cadieu, Edouard; Andre, Catherine; Hytonen, Marjo K.; Lohi, Hannes; Welle, Monika M.; Roosje, Petra; Mellersh, Cathryn; Casal, Margret L.; Leeb, Tosso (2018)
    Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of similar to 1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN/:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.
  • Palmio, Johanna; Jonson, Per Harald; Evilä, Anni; Auranen, Mari; Straub, Volker; Bushby, Kate; Sarkozy, Anna; Kiuru-Enari, Sari; Sandell, Satu; Pihko, Helena; Hackman, Peter; Udd, Bjarne (2015)
    DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation. (C) 2015 Elsevier B.V. All rights reserved.
  • Teng, S.; Thomson, P. A.; McCarthy, S.; Kramer, M.; Muller, S.; Lihm, J.; Morris, S.; Soares, D. C.; Hennah, W.; Harris, S.; Camargo, L. M.; Malkov, V.; McIntosh, A. M.; Millar, J. K.; Blackwood, D. H.; Evans, K. L.; Deary, I. J.; Porteous, D. J.; McCombie, W. R. (2018)
    Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.
  • Hendricks, Audrey E.; Bochukova, Elena G.; Marenne, Gaelle; Keogh, Julia M.; Atanassova, Neli; Bounds, Rebecca; Wheeler, Eleanor; Mistry, Vanisha; Henning, Elana; Koerner, Antje; Muddyman, Dawn; McCarthy, Shane; Hinney, Anke; Hebebrand, Johannes; Scott, Robert A.; Langenberg, Claudia; Wareham, Nick J.; Surendran, Praveen; Howson, Joanna M.; Butterworth, Adam S.; Danesh, John; Nordestgaard, Borge G.; Nielsen, Sune F.; Afzal, Shoaib; Papadia, Sofia; Ashford, Sofie; Garg, Sumedha; Millhauser, Glenn L.; Palomino, Rafael I.; Kwasniewska, Alexandra; Tachmazidou, Ioanna; O'Rahilly, Stephen; Zeggini, Eleftheria; Barroso, Ines; Farooqi, I. Sadaf; Understanding Soc Sci Grp; EPIC-CVD Consortium; UK10K Consortium; Palotie, Aarno (2017)
    Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF similar to 0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 x 10(-3)), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.
  • Fitak, Robert R.; Mohandesan, Elmira; Corander, Jukka; Burger, Pamela A. (2016)
    The single-humped dromedary (Camelus dromedarius) is the most numerous and widespread of domestic camel species and is a significant source of meat, milk, wool, transportation and sport for millions of people. Dromedaries are particularly well adapted to hot, desert conditions and harbour a variety of biological and physiological characteristics with evolutionary, economic and medical importance. To understand the genetic basis of these traits, an extensive resource of genomic variation is required. In this study, we assembled at 653 coverage, a 2.06 Gb draft genome of a female dromedary whose ancestry can be traced to an isolated population from the Canary Islands. We annotated 21 167 protein-coding genes and estimated similar to 33.7% of the genome to be repetitive. A comparison with the recently published draft genome of an Arabian dromedary resulted in 1.91 Gb of aligned sequence with a divergence of 0.095%. An evaluation of our genome with the reference revealed that our assembly contains more error-free bases (91.2%) and fewer scaffolding errors. We identified similar to 1.4 million single-nucleotide polymorphisms with a mean density of 0.71 x 10(-3) per base. An analysis of demographic history indicated that changes in effective population size corresponded with recent glacial epochs. Our de novo assembly provides a useful resource of genomic variation for future studies of the camel's adaptations to arid environments and economically important traits. Furthermore, these results suggest that draft genome assemblies constructed with only two differently sized sequencing libraries can be comparable to those sequenced using additional library sizes, highlighting that additional resources might be better placed in technologies alternative to short-read sequencing to physically anchor scaffolds to genome maps.