Browsing by Subject "REARRANGEMENTS"

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  • Pratas, Diogo; Hosseini, Morteza; Silva, Jorge M.; Pinho, Armando J. (2019)
    The development of efficient data compressors for DNA sequences is crucial not only for reducing the storage and the bandwidth for transmission, but also for analysis purposes. In particular, the development of improved compression models directly influences the outcome of anthropological and biomedical compression-based methods. In this paper, we describe a new lossless compressor with improved compression capabilities for DNA sequences representing different domains and kingdoms. The reference-free method uses a competitive prediction model to estimate, for each symbol, the best class of models to be used before applying arithmetic encoding. There are two classes of models: weighted context models (including substitutional tolerant context models) and weighted stochastic repeat models. Both classes of models use specific sub-programs to handle inverted repeats efficiently. The results show that the proposed method attains a higher compression ratio than state-of-the-art approaches, on a balanced and diverse benchmark, using a competitive level of computational resources. An efficient implementation of the method is publicly available, under the GPLv3 license.
  • Genome Aggregation Database Prod T; Genome Aggregation Database Consor; Collins, Ryan L.; Brand, Harrison; Karczewski, Konrad J.; Talkowski, Michael E.; Färkkilä, Martti; Groop, Leif; Holi, Matti M.; Kaprio, Jaakko; Palotie, Aarno; Ripatti, Samuli; Tuomi, Tiinamaija; Wessman, Maija; Kallela, Mikko (2020)
    Structural variants (SVs) rearrange large segments of DNA(1) and can have profound consequences in evolution and human disease(2,3). As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)(4) have become integral in the interpretation of single-nucleotide variants (SNVs)(5). However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage(6). We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings(7). This SV resource is freely distributed via the gnomAD browser(8) and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
  • Jaatinen, Jenni; Veija, Tuukka; Salmikangas, Marko; Böhling, Tom; Sihto, Harri; Koljonen, Virve (2021)
    Merkel cell carcinoma (MCC) is a rare skin cancer with only limited therapeutic options for advanced disease. We previously showed that oncogene ALK is frequently expressed at the RNA level in MCC and further that ALK positivity by immunohistochemistry is frequent and correlates strongly with Merkel cell polyomavirus (MCPyV) positivity. In this study, we investigated whether ALK receptor is active in MCC tumor samples and MCC cell lines, and whether ALK would be a prospective treatment target in MCC. We utilized tissue microarrays constructed from 136 primary MCC tumor samples as well as nine previously established MCC cell lines to determine the presence of ALK and phosphorylated ALK (p-ALK) via immunohistochemistry. Almost half of the analyzed MCC tumors displayed ALK phosphorylation (47.8%). Analysis of MCC tumor samples revealed that the presence of p-ALK correlated to MCPyV positivity, younger age, nonexistence of metastases at diagnosis and ultimately to better MCC-specific survival. In contrast to MCC tumor samples only two out of nine MCC cell lines showed only low ALK phosphorylation by immunohistochemistry. Our study reveals clear disparity in ALK activity between patient derived tumors and cell line samples and therefore, more advanced disease models such as xenografts are necessary to resolve whether ALK is a useful treatment target in MCC.
  • Otto, Christian F.; Herzberger, Colin; Liu, Ming; Namyslo, Jan C.; Nieger, Martin; Freese, Tyll; Lederle, Felix; Hübner, Eike G.; Schmidt, Andreas (2020)
    The natural product punicine (Punica granatum) exists in two tautomeric forms, the cross-conjugated mesomeric betaine 1-(pyridinium-1-yl)-2-hydroxy-phenyl-5-olate and the conjugated mesomeric betaine 1-(pyridinium-1-yl)-5-hydroxy-phenyl-2-olate. Punicine as well as its picoline derivatives reacted with tris(pentafluorophenyl)borane exclusively at the 2'-olate group to form zwitterionic borates. Correspondingly, the 5'-dehydroxy derivate of punicine, the conjugated heterocyclic mesomeric betaine 1-(pyridinium-1-yl)-phenyl-2-olate and its picoline derivatives also gave borates, whereas analogous reactions of the cross-conjugated isomer 2'-dehydroxypunicine [1-(pyridinium-1-yl)-phenyl-3-olatel did not result in the formation of stable adducts. (C) 2020 Elsevier Ltd. All rights reserved.
  • Saura, Anssi; Von Schoultz, Barbara; Saura, Anja O.; Brown, JR., Keith S. (2013)
  • Multamäki, Elina; Nanekar, Rahul; Morozov, Dmitry; Lievonen, Topias; Golonka, David; Wahlgren, Weixiao Yuan; Stucki-Buchli, Brigitte; Rossi, Jari; Hytönen, Vesa P.; Westenhoff, Sebastian; Ihalainen, Janne A.; Möglich, Andreas; Takala, Heikki (2021)
    Bacterial phytochrome photoreceptors usually belong to two-component signaling systems which transmit environmental stimuli to a response regulator through a histidine kinase domain. Phytochromes switch between red light-absorbing and far-red light-absorbing states. Despite exhibiting extensive structural responses during this transition, the model bacteriophytochrome from Deinococcus radiodurans (DrBphP) lacks detectable kinase activity. Here, we resolve this long-standing conundrum by comparatively analyzing the interactions and output activities of DrBphP and a bacteriophytochrome from Agrobacterium fabrum (Agp1). Whereas Agp1 acts as a conventional histidine kinase, we identify DrBphP as a light-sensitive phosphatase. While Agp1 binds its cognate response regulator only transiently, DrBphP does so strongly, which is rationalized at the structural level. Our data pinpoint two key residues affecting the balance between kinase and phosphatase activities, which immediately bears on photoreception and two-component signaling. The opposing output activities in two highly similar bacteriophytochromes suggest the use of light-controllable histidine kinases and phosphatases for optogenetics. The bacteriophytochrome DrBphP from Deinococcus radiodurans shows high sequence homology to the histidine kinase Agp1 from Agrobacterium fabrum but lacks kinase activity. Here, the authors structurally and biochemically analyse DrBphP and Agp1, showing that DrBphP is a light-activatable phosphatase.
  • Pettersson, Maria; Viljakainen, Heli; Loid, Petra; Mustila, Taina; Pekkinen, Minna; Armenio, Miriam; Andersson-Assarsson, Johanna C.; Makitie, Outi; Lindstrand, Anna (2017)
    Context: Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity. Objective: To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue. Design and Setting: A case-control study in a tertiary academic center. Participants: CNV analysis was performed on 90 subjects with early-onset obesity and 67 normalweight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses. Main Outcome Measures: We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue. Results: We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5). Conclusions: Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
  • OPAL Study Grp; AOCS Grp; DeVries, Amber A.; Dennis, Joe; Tyrer, Jonathan P. (2022)
    Background Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Methods Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. Results We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (P-EOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR](HGSOC) = 5.74 del), and BRCA2 (P-HGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. Conclusions CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
  • Tšuiko, Olga; Dmitrijeva, Tuuli; Kask, Katrin; Tammur, Pille; Tõnisson, Neeme; Salumets, Andres; Jatsenko, Tatjana (2019)
    Balanced translocation carriers are burdened with fertility issues due to improper chromosome segregation in gametes, resulting in either implantation failure, miscarriage or birth of a child with chromosomal disorders. At the same time, these individuals are typically healthy with no signs of developmental problems, hence they often are unaware of their condition. Yet, because of difficulties in conceiving, balanced translocation carriers often turn to assisted reproduction, some of whom may also undergo preimplantation genetic testing for aneuploidy (PGT-A) to improve the likelihood of achieving a successful pregnancy.
  • Silva, Milton; Pratas, Diogo; Pinho, Armando J. (2020)
    Background: The increasing production of genomic data has led to an intensified need for models that can cope efficiently with the lossless compression of DNA sequences. Important applications include long-term storage and compression-based data analysis. In the literature, only a few recent articles propose the use of neural networks for DNA sequence compression. However, they fall short when compared with specific DNA compression tools, such as GeCo2. This limitation is due to the absence of models specifically designed for DNA sequences. In this work, we combine the power of neural networks with specific DNA models. For this purpose, we created GeCo3, a new genomic sequence compressor that uses neural networks for mixing multiple context and substitution-tolerant context models. Findings: We benchmark GeCo3 as a reference-free DNA compressor in 5 datasets, including a balanced and comprehensive dataset of DNA sequences, the Y-chromosome and human mitogenome, 2 compilations of archaeal and virus genomes, 4 whole genomes, and 2 collections of FASTQ data of a human virome and ancient DNA. GeCo3 achieves a solid improvement in compression over the previous version (GeCo2) of 2.4%, 7.1%, 6.1%, 5.8%, and 6.0%, respectively. To test its performance as a reference-based DNA compressor, we benchmark GeCo3 in 4 datasets constituted by the pairwise compression of the chromosomes of the genomes of several primates. GeCo3 improves the compression in 12.4%, 11.7%, 10.8%, and 10.1% over the state of the art. The cost of this compression improvement is some additional computational time (1.7-3 times slower than GeCo2). The RAM use is constant, and the tool scales efficiently, independently of the sequence size. Overall, these values outperform the state of the art. Conclusions: GeCo3 is a genomic sequence compressor with a neural network mixing approach that provides additional gains over top specific genomic compressors. The proposed mixing method is portable, requiring only the probabilities of the models as inputs, providing easy adaptation to other data compressors or compression-based data analysis tools. GeCo3 is released under GPLv3 and is available for free download at https://github.com/cobilab/geco3.
  • David, Dezso; Anand, Deepti; Araujo, Carlos; Gloss, Brian; Fino, Joana; Dinger, Marcel; Lindahl, Päivi; Pöyhönen, Minna; Laivuori, Hannele; Lavinha, Joao (2018)
    Keratolenticular dysgenesis (KLD) and ectopia lends are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely nonfunctional chimeric transcripts comprising up to OAF exon 3, derived from the der(11) allele, have also been identified. This locus has been implicated by publicly available genome-wide association data in corneal disease and corneal topography. The expression of the poliovirus receptor-related 1(PVRL1) or nectin cell adhesion molecule 1 (NECTIN1), a paralogue of nectin cell adhesion molecule 3 (PVRL3) associated with congenital ocular defects, situated 500 kb upstream from 11q23.3 breakpoint, is increased. The 18q11.2 breakpoint is localized between cutaneous T-cell lymphoma-associated antigen 1(CTAGE1) and retinoblastoma binding protein 8 (RBBP8) genes. Genomic imbalance that could contribute to the observed phenotype was excluded. Analysis of gene expression datasets throughout normal murine ocular lens embryogenesis suggests that OAF expression is significantly enriched in the lens from early stages of development through adulthood, whereas PVRL1 is lens-enriched until E12.5 and then down-regulated. This contrasts with the observation that the proposita's lymphoblastoid cell lines exhibit low OAF and high PVRL1 expression as compared to control, which offers further support that the alterations described above are most likely responsible for the clinical phenotype. Finally, gene interaction topology data for PVRL1 also agree with our proposal that disruption of OAF by the translocation breakpoint and misregulation of PVRL1 due to a position effect contribute to the observed ocular and neurological phenotype.
  • Takala, Heikki; Lehtivuori, Heli K.; Berntsson, Oskar; Hughes, Ashley; Nanekar, Rahul; Niebling, Stephan; Panman, Matthijs; Henry, Leocadie; Menzel, Andreas; Westenhoff, Sebastian; Ihalainen, Janne A. (2018)
    Phytochromes are photoreceptors in plants, fungi, and various microorganisms and cycle between metastable red light-absorbing (Pr) and far-red light-absorbing (Pfr) states. Their light responses are thought to follow a conserved structural mechanism that is triggered by isomerization of the chromophore. Downstream structural changes involve refolding of the so-called tongue extension of the phytochrome-specific GAF-related (PHY) domain of the photoreceptor. The tongue is connected to the chromophore by conserved DIP and PRXSF motifs and a conserved tyrosine, but the role of these residues in signal transduction is not clear. Here, we examine the tongue interactions and their interplay with the chromophore by substituting the conserved tyrosine (Tyr(263)) in the phytochrome from the extremophile bacterium Deinococcus radiodurans with phenylalanine. Using optical and FTIR spectroscopy, X-ray solution scattering, and crystallography of chromophore-binding domain (CBD) and CBD-PHY fragments, we show that the absence of the Tyr(263) hydroxyl destabilizes the -sheet conformation of the tongue. This allowed the phytochrome to adopt an -helical tongue conformation regardless of the chromophore state, hence distorting the activity state of the protein. Our crystal structures further revealed that water interactions are missing in the Y263F mutant, correlating with a decrease of the photoconversion yield and underpinning the functional role of Tyr(263) in phytochrome conformational changes. We propose a model in which isomerization of the chromophore, refolding of the tongue, and globular conformational changes are represented as weakly coupled equilibria. The results also suggest that the phytochromes have several redundant signaling routes.
  • Multamäki, Elina; de Fuentes, Andres Garcia; Sieryi, Oleksii; Bykov, Alexander; Gerken, Uwe; Ranzani, Americo Tavares; Koehler, Juergen; Meglinski, Igor; Moeglich, Andreas; Takala, Heikki (2022)
    In optogenetics, as in nature, sensory photoreceptors serve to control cellular processes by light. Bacteriophytochrome (BphP) photoreceptors sense red and farred light via a biliverdin chromophore and, in response, cycle between the spectroscopically, structurally, and functionally distinct Pr and Pfr states. BphPs commonly belong to two-component systems that control the phosphorylation of cognate response regulators and downstream gene expression through histidine kinase modules. We recently demonstrated that the paradigm BphP from Deinococcus radiodurans exclusively acts as a phosphatase but that its photosensory module can control the histidine kinase activity of homologous receptors. Here, we apply this insight to reprogram two widely used setups for bacterial gene expression from blue-light to red-light control. The resultant pREDusk and pREDawn systems allow gene expression to be regulated down and up, respectively, uniformly under red light by 100-fold or more. Both setups are realized as portable, single plasmids that encode all necessary components including the biliverdin-producing machinery. The triggering by red light affords high spatial resolution down to the single-cell level. As pREDusk and pREDawn respond sensitively to red light, they support multiplexing with optogenetic systems sensitive to other light colors. Owing to the superior tissue penetration of red light, the pREDawn system can be triggered at therapeutically safe light intensities through material layers, replicating the optical properties of the skin and skull. Given these advantages, pREDusk and pREDawn enable red-light-regulated expression for diverse use cases in bacteria.
  • Campbell, Peter J.; Getz, Gad; Korbel, Jan O.; Stuart, Joshua M.; Jennings, Jennifer L.; Stein, Lincoln D.; Perry, Marc D.; Nahal-Bose, Hardeep K.; Ouellette, B. F. Francis; Li, Constance H.; Rheinbay, Esther; Nielsen, G. Petur; Sgroi, Dennis C.; Wu, Chin-Lee; Faquin, William C.; Deshpande, Vikram; Boutros, Paul C.; Lazar, Alexander J.; Hoadley, Katherine A.; Louis, David N.; Dursi, L. Jonathan; Yung, Christina; Bailey, Matthew H.; Saksena, Gordon; Raine, Keiran M.; Buchhalter, Ivo; Kleinheinz, Kortine; Schlesner, Matthias; Zhang, Junjun; Wang, Wenyi; Wheeler, David A.; Ding, Li; Simpson, Jared T.; O'Connor, Brian D.; Yakneen, Sergei; Ellrott, Kyle; Miyoshi, Naoki; Butler, Adam P.; Royo, Romina; Shorser, Solomon; Vazquez, Miguel; Rausch, Tobias; Tiao, Grace; Waszak, Sebastian M.; Rodriguez-Martin, Bernardo; Shringarpure, Suyash; Wu, Dai-Ying; Demidov, German M.; Delaneau, Olivier; Hayashi, Shuto; Imoto, Seiya; Habermann, Nina; Segre, Ayellet; Garrison, Erik; Cafferkey, Andy; Alvarez, Eva G.; Maria Heredia-Genestar, Jose; Muyas, Francesc; Drechsel, Oliver; Bruzos, Alicia L.; Temes, Javier; Zamora, Jorge; Baez-Ortega, Adrian; Kim, Hyung-Lae; Mashl, R. Jay; Ye, Kai; DiBiase, Anthony; Huang, Kuan-lin; Letunic, Ivica; McLellan, Michael D.; Newhouse, Steven J.; Shmaya, Tal; Kumar, Sushant; Wedge, David C.; Wright, Mark H.; Yellapantula, Venkata D.; Gerstein, Mark; Khurana, Ekta; Marques-Bonet, Tomas; Navarro, Arcadi; Bustamante, Carlos D.; Siebert, Reiner; Nakagawa, Hidewaki; Easton, Douglas F.; Ossowski, Stephan; Tubio, Jose M. C.; De La Vega, Francisco M.; Estivill, Xavier; Yuen, Denis; Mihaiescu, George L.; Omberg, Larsson; Ferretti, Vincent; Sabarinathan, Radhakrishnan; Pich, Oriol; Gonzalez-Perez, Abel; Weiner, Amaro Taylor; Fittall, Matthew W.; Demeulemeester, Jonas; Tarabichi, Maxime; Roberts, Nicola D.; Van Loo, Peter; Cortes-Ciriano, Isidro; Urban, Lara; Park, Peter; Bin Zhu, Lingli; Pitkaenen, Esa; Li, Yilong; Saini, Natalie; Klimczak, Leszek J.; Weischenfeldt, Joachim; Sidiropoulos, Nikos; Alexandrov, Ludmil B.; Rabionet, Raquel; Escaramis, Georgia; Bosio, Mattia; Holik, Aliaksei Z.; Susak, Hana; Prasad, Aparna; Erkek, Serap; Calabrese, Claudia; Raeder, Benjamin; Harrington, Eoghan; Mayes, Simon; Turner, Daniel; Juul, Sissel; Roberts, Steven A.; Song, Lei; Koster, Roelof; Mirabello, Lisa; Hua, Xing; Tanskanen, Tomas J.; Tojo, Marta; Chen, Jieming; Aaltonen, Lauri A.; Ratsch, Gunnar; Schwarz, Roland F.; Butte, Atul J.; Brazma, Alvis; Chanock, Stephen J.; Chatterjee, Nilanjan; Stegle, Oliver; Harismendy, Olivier; Bova, G. Steven; Gordenin, Dmitry A.; Haan, David; Sieverling, Lina; Feuerbach, Lars; Chalmers, Don; Joly, Yann; Knoppers, Bartha M.; Molnar-Gabor, Fruzsina; Phillips, Mark; Thorogood, Adrian; Townend, David; Goldman, Mary; Fonseca, Nuno A.; Xiang, Qian; Craft, Brian; Pineiro-Yanez, Elena; Munoz, Alfonso; Petryszak, Robert; Fullgrabe, Anja; Al-Shahrour, Fatima; Keays, Maria; Haussler, David; Weinstein, John; Huber, Wolfgang; Valencia, Alfonso; Papatheodorou, Irene; Zhu, Jingchun; Fan, Yu; Torrents, David; Bieg, Matthias; Chen, Ken; Chong, Zechen; Cibulskis, Kristian; Eils, Roland; Fulton, Robert S.; Gelpi, Josep L.; Gonzalez, Santiago; Gut, Ivo G.; Hach, Faraz; Heinold, Michael; Hu, Taobo; Huang, Vincent; Hutter, Barbara; Jaeger, Natalie; Jung, Jongsun; Kumar, Yogesh; Lalansingh, Christopher; Leshchiner, Ignaty; Livitz, Dimitri; Ma, Eric Z.; Maruvka, Yosef E.; Milovanovic, Ana; Nielsen, Morten Muhlig; Paramasivam, Nagarajan; Pedersen, Jakob Skou; Puiggros, Montserrat; Sahinalp, S. Cenk; Sarrafi, Iman; Stewart, Chip; Stobbe, Miranda D.; Wala, Jeremiah A.; Wang, Jiayin; Wendl, Michael C.; Werner, Johannes; Wu, Zhenggang; Xue, Hong; Yamaguchi, Takafumi N.; Yellapantula, Venkata; Davis-Dusenbery, Brandi N.; Grossman, Robert L.; Kim, Youngwook; Heinold, Michael C.; Hinton, Jonathan; Jones, David R.; Menzies, Andrew; Stebbings, Lucy; Hess, Julian M.; Rosenberg, Mara; Dunford, Andrew J.; Gupta, Manaswi; Imielinski, Marcin; Meyerson, Matthew; Beroukhim, Rameen; Reimand, Juri; Dhingra, Priyanka; Favero, Francesco; Dentro, Stefan C.; Wintersinger, Jeff; Rudneva, Vasilisa; Park, Ji Wan; Hong, Eun Pyo; Heo, Seong Gu; Kahles, Andre; Kjong-Van Lehmann; Soulette, Cameron M.; Shiraishi, Yuichi; Liu, Fenglin; He, Yao; Demircioglu, Deniz; Davidson, Natalie R.; Greger, Liliana; Li, Siliang; Liu, Dongbing; Stark, Stefan G.; Zhang, Fan; Amin, Samirkumar B.; Bailey, Peter J.; Chateigner, Aurelien; Frenkel-Morgenstern, Milana; Hou, Yong; Huska, Matthew R.; Kilpinen, Helena; Lamaze, Fabien C.; Li, Chang; Li, Xiaobo; Li, Xinyue; Liu, Xingmin; Marin, Maximillian G.; Markowski, Julia; Nandi, Tannistha; Ojesina, Akinyemi; Pan-Hammarstrom, Qiang; Park, Peter J.; Pedamallu, Chandra Sekhar; Su, Hong; Tan, Patrick; Teh, Bin Tean; Wang, Jian; Xiong, Heng; Ye, Chen; Yung, Christina; Zhang, Xiuqing; Zheng, Liangtao; Zhu, Shida; Awadalla, Philip; Creighton, Chad J.; Wu, Kui; Yang, Huanming; Goke, Jonathan; Zhang, Zemin; Brooks, Angela N.; Martincorena, Inigo; Rubio-Perez, Carlota; Juul, Malene; Schumacher, Steven; Shapira, Ofer; Tamborero, David; Mularoni, Loris; Hornshoj, Henrik; Deu-Pons, Jordi; Muinos, Ferran; Bertl, Johanna; Guo, Qianyun; Bazant, Wojciech; Barrera, Elisabet; Al-Sedairy, Sultan T.; Aretz, Axel; Bell, Cindy; Betancourt, Miguel; Buchholz, Christiane; Calvo, Fabien; Chomienne, Christine; Dunn, Michael; Edmonds, Stuart; Green, Eric; Gupta, Shailja; Hutter, Carolyn M.; Jegalian, Karine; Jones, Nic; Lu, Youyong; Nakagama, Hitoshi; Nettekoven, Gerd; Planko, Laura; Scott, David; Shibata, Tatsuhiro; Shimizu, Kiyo; Stratton, Michael R.; Yugawa, Takashi; Tortora, Giampaolo; VijayRaghavan, K.; Zenklusen, Jean C.; Knoppers, Bartha M.; Aminou, Brice; Bartolome, Javier; Boroevich, Keith A.; Boyce, Rich; Buchanan, Alex; Byrne, Niall J.; Chen, Zhaohong; Cho, Sunghoon; Choi, Wan; Clapham, Peter; Dow, Michelle T.; Dursi, Lewis Jonathan; Eils, Juergen; Farcas, Claudiu; Fayzullaev, Nodirjon; Flicek, Paul; Heath, Allison P.; Hofmann, Oliver; Hong, Jongwhi H.; Hudson, Thomas J.; Huebschmann, Daniel; Ivkovic, Sinisa; Jeon, Seung-Hyup; Jiao, Wei; Kabbe, Rolf; Kerssemakers, Jules N. A.; Kim, Hyunghwan; Kim, Jihoon; Koscher, Michael; Koures, Antonios; Kovacevic, Milena; Lawerenz, Chris; Liu, Jia; Mijalkovic, Sanja; Mijalkovic-Lazic, Ana Mijalkovic; Miyano, Satoru; Nastic, Mia; Nicholson, Jonathan; Ocana, David; Ohi, Kazuhiro; Ohno-Machado, Lucila; Pihl, Todd D.; Prinz, Manuel; Radovic, Petar; Short, Charles; Sofia, Heidi J.; Spring, Jonathan; Struck, Adam J.; Tijanic, Nebojsa; Vicente, David; Wang, Zhining; Williams, Ashley; Woo, Youngchoon; Wright, Adam J.; Yang, Liming; Hamilton, Mark P.; Johnson, Todd A.; Kahraman, Abdullah; Kellis, Manolis; Polak, Paz; Sallari, Richard; Sinnott-Armstrong, Nasa; von Mering, Christian; Beltran, Sergi; Gerhard, Daniela S.; Gut, Marta; Trotta, Jean-Remi; Whalley, Justin P.; Niu, Beifang; Espiritu, Shadrielle M. G.; Gao, Shengjie; Huang, Yi; Lalansingh, Christopher M.; Teague, Jon W.; Wendl, Michael C.; Abascal, Federico; Bader, Gary D.; Bandopadhayay, Pratiti; Barenboim, Jonathan; Brunak, Soren; Fita, Joana Carlevaro; Chakravarty, Dimple; Chan, Calvin Wing Yiu; Choi, Jung Kyoon; Diamanti, Klev; Fink, J. Lynn; Frigola, Joan; Gambacorti-Passerini, Carlo; Garsed, Dale W.; Haradhvala, Nicholas J.; Harmanci, Arif O.; Helmy, Mohamed; Herrmann, Carl; Hobolth, Asger; Hodzic, Ermin; Hong, Chen; Isaev, Keren; Izarzugaza, Jose M. G.; Johnson, Rory; Juul, Randi Istrup; Kim, Jaegil; Kim, Jong K.; Komorowski, Jan; Lanzos, Andres; Larsson, Erik; Lee, Donghoon; Li, Shantao; Li, Xiaotong; Lin, Ziao; Liu, Eric Minwei; Lochovsky, Lucas; Lou, Shaoke; Madsen, Tobias; Marchal, Kathleen; Fundichely, Alexander Martinez; McGillivray, Patrick D.; Meyerson, William; Paczkowska, Marta; Park, Keunchil; Park, Kiejung; Pons, Tirso; Pulido-Tamayo, Sergio; Reyes Salazar, Iker; Reyna, Matthew A.; Rubin, Mark A.; Salichos, Leonidas; Sander, Chris; Schumacher, Steven E.; Shackleton, Mark; Shen, Ciyue; Shrestha, Raunak; Shuai, Shimin; Tsunoda, Tatsuhiko; Umer, Husen M.; Uuskula-Reimand, Liis; Verbeke, Lieven P. C.; Wadelius, Claes; Wadi, Lina; Warrell, Jonathan; Wu, Guanming; Yu, Jun; Zhang, Jing; Zhang, Xuanping; Zhang, Yan; Zhao, Zhongming; Zou, Lihua; Lawrence, Michael S.; Raphael, Benjamin J.; Bailey, Peter J.; Craft, David; Goldman, Mary J.; Aburatani, Hiroyuki; Binder, Hans; Dinh, Huy Q.; Heath, Simon C.; Hoffmann, Steve; Imbusch, Charles David; Kretzmer, Helene; Laird, Peter W.; Martin-Subero, Jose; Nagae, Genta; Shen, Hui; Wang, Qi; Weichenhan, Dieter; Zhou, Wanding; Berman, Benjamin P.; Brors, Benedikt; Plass, Christoph; Akdemir, Kadir C.; Bowtell, David D. L.; Burns, Kathleen H.; Busanovich, John; Chan, Kin; Dueso-Barroso, Ana; Edwards, Paul A.; Etemadmoghadam, Dariush; Haber, James E.; Jones, David T. W.; Ju, Young Seok; Kazanov, Marat D.; Koh, Youngil; Kumar, Kiran; Lee, Eunjung Alice; Lee, Jake June-Koo; Lynch, Andy G.; Macintyre, Geoff; Markowetz, Florian; Navarro, Fabio C. P.; Pearson, John; Rippe, Karsten; Scully, Ralph; Villasante, Izar; Waddell, Nicola; Yang, Lixing; Yao, Xiaotong; Yoon, Sung-Soo; Zhang, Cheng-Zhong; Bergstrom, Erik N.; Boot, Arnoud; Covington, Kyle; Fujimoto, Akihiro; Huang, Mi Ni; Islam, S. M. Ashiqul; McPherson, John R.; Morganella, Sandro; Mustonen, Ville; Ng, Alvin Wei Tian; Prokopec, Stephenie D.; Vazquez-Garcia, Ignacio; Wu, Yang; Yousif, Fouad; Yu, Willie; Rozen, Steven G.; Rudneva, Vasilisa A.; Shringarpure, Suyash S.; Turner, Daniel J.; Xia, Tian; Atwal, Gurnit; Chang, David K.; Cooke, Susanna L.; Faltas, Bishoy M.; Haider, Syed; Kaiser, Vera B.; Karlic, Rosa; Kato, Mamoru; Kubler, Kirsten; Margolin, Adam; Martin, Sancha; Nik-Zainal, Serena; P'ng, Christine; Semple, Colin A.; Smith, Jaclyn; Sun, Ren X.; Thai, Kevin; Wright, Derek W.; Yuan, Ke; Biankin, Andrew; Garraway, Levi; Grimmond, Sean M.; Adams, David J.; Anur, Pavana; Cao, Shaolong; Christie, Elizabeth L.; Cmero, Marek; Cun, Yupeng; Dawson, Kevin J.; Dentro, Stefan C.; Deshwar, Amit G.; Donmez, Nilgun; Drews, Ruben M.; Gerstung, Moritz; Ha, Gavin; Haase, Kerstin; Jerman, Lara; Ji, Yuan; Jolly, Clemency; Lee, Juhee; Lee-Six, Henry; Malikic, Salem; Mitchell, Thomas J.; Morris, Quaid D.; Oesper, Layla; Peifer, Martin; Peto, Myron; Rosebrock, Daniel; Rubanova, Yulia; Salcedo, Adriana; Sengupta, Subhajit; Shi, Ruian; Shin, Seung Jun; Spiro, Oliver; Vembu, Shankar; Wintersinger, Jeffrey A.; Yang, Tsun-Po; Yu, Kaixian; Zhu, Hongtu; Spellman, Paul T.; Weinstein, John N.; Chen, Yiwen; Fujita, Masashi; Han, Leng; Hasegawa, Takanori; Komura, Mitsuhiro; Li, Jun; Mizuno, Shinichi; Shimizu, Eigo; Wang, Yumeng; Xu, Yanxun; Yamaguchi, Rui; Yang, Fan; Yang, Yang; Yoon, Christopher J.; Yuan, Yuan; Liang, Han; Alawi, Malik; Borozan, Ivan; Brewer, Daniel S.; Cooper, Colin S.; Desai, Nikita; Grundhoff, Adam; Iskar, Murat; Su, Xiaoping; Zapatka, Marc; Lichter, Peter; Alsop, Kathryn; Bruxner, Timothy J. C.; Christ, Angelika N.; Cordner, Stephen M.; Cowin, Prue A.; Drapkin, Ronny; Fereday, Sian; George, Joshy; Hamilton, Anne; Holmes, Oliver; Hung, Jillian A.; Kassahn, Karin S.; Kazakoff, Stephen H.; Kennedy, Catherine J.; Leonard, Conrad R.; Mileshkin, Linda; Miller, David K.; Arnau, Gisela Mir; Mitchell, Chris; Newell, Felicity; Nones, Katia; Patch, Ann-Marie; Quinn, Michael C.; Taylor, Darrin F.; Thorne, Heather; Traficante, Nadia; Vedururu, Ravikiran; Waddell, Nick M.; Waring, Paul M.; Wood, Scott; Xu, Qinying; DeFazio, Anna; Anderson, Matthew J.; Antonello, Davide; Barbour, Andrew P.; Bassi, Claudio; Bersani, Samantha; Cataldo, Ivana; Chantrill, Lorraine A.; Chiew, Yoke-Eng; Chou, Angela; Cingarlini, Sara; Cloonan, Nicole; Corbo, Vincenzo; Davi, Maria Vittoria; Duthie, Fraser R.; Gill, Anthony J.; Graham, Janet S.; Harliwong, Ivon; Jamieson, Nigel B.; Johns, Amber L.; Kench, James G.; Landoni, Luca; Lawlor, Rita T.; Mafficini, Andrea; Merrett, Neil D.; Miotto, Marco; Musgrove, Elizabeth A.; Nagrial, Adnan M.; Oien, Karin A.; Pajic, Marina; Pinese, Mark; Robertson, Alan J.; Rooman, Ilse; Rusev, Borislav C.; Samra, Jaswinder S.; Scardoni, Maria; Scarlett, Christopher J.; Scarpa, Aldo; Sereni, Elisabetta; Sikora, Katarzyna O.; Simbolo, Michele; Taschuk, Morgan L.; Toon, Christopher W.; Vicentini, Caterina; Wu, Jianmin; Zeps, Nikolajs; Behren, Andreas; Burke, Hazel; Cebon, Jonathan; Dagg, Rebecca A.; De Paoli-Iseppi, Ricardo; Dutton-Regester, Ken; Field, Matthew A.; Fitzgerald, Anna; Hersey, Peter; Jakrot, Valerie; Johansson, Peter A.; Kakavand, Hojabr; Kefford, Richard F.; Lau, Loretta M. S.; Long, Georgina; Pickett, Hilda A.; Pritchard, Antonia L.; Pupo, Gulietta M.; Saw, Robyn P. M.; Schramm, Sarah-Jane; Shang, Catherine A.; Shang, Ping; Spillane, Andrew J.; Stretch, Jonathan R.; Tembe, Varsha; Thompson, John F.; Vilain, Ricardo E.; Wilmott, James S.; Yang, Jean Y.; Hayward, Nicholas K.; Mann, Graham J.; Scolyer, Richard A.; Bartlett, John; Bavi, Prashant; Chadwick, Dianne E.; Chan-Seng-Yue, Michelle; Cleary, Sean; Connor, Ashton A.; Czajka, Karolina; Denroche, Robert E.; Dhani, Neesha C.; Eagles, Jenna; Gallinger, Steven; Grant, Robert C.; Hedley, David; Hollingsworth, Michael A.; Jang, Gun Ho; Johns, Jeremy; Kalimuthu, Sangeetha; Liang, Sheng-Ben; Lungu, Ilinca; Luo, Xuemei; Mbabaali, Faridah; McPherson, Treasa A.; Miller, Jessica K.; Moore, Malcolm J.; Notta, Faiyaz; Pasternack, Danielle; Petersen, Gloria M.; Roehrl, Michael H. A.; Sam, Michelle; Selander, Iris; Serra, Stefano; Shahabi, Sagedeh; Thayer, Sarah P.; Timms, Lee E.; Wilson, Gavin W.; Wilson, Julie M.; Wouters, Bradly G.; McPherson, John D.; Beck, Timothy A.; Bhandari, Vinayak; Collins, Colin C.; Fleshner, Neil E.; Fox, Natalie S.; Fraser, Michael; Heisler, Lawrence E.; Lalonde, Emilie; Livingstone, Julie; Meng, Alice; Sabelnykova, Veronica Y.; Shiah, Yu-Jia; Van Der Kwast, Theodorus; Bristow, Robert G.; Ding, Shuai; Fan, Daiming; Li, Lin; Nie, Yongzhan; Xiao, Xiao; Xing, Rui; Yang, Shanlin; Yu, Yingyan; Zhou, Yong; Banks, Rosamonde E.; Bourque, Guillaume; Brennan, Paul; Letourneau, Louis; Riazalhosseini, Yasser; Scelo, Ghislaine; Vasudev, Naveen; Viksna, Juris; Lathrop, Mark; Tost, Jorg; Ahn, Sung-Min; Aparicio, Samuel; Arnould, Laurent; Aure, M. R.; Bhosle, Shriram G.; Birney, Ewan; Borg, Ake; Boyault, Sandrine; Brinkman, Arie B.; Brock, Jane E.; Broeks, Annegien; Borresen-Dale, Anne-Lise; Caldas, Carlos; Chin, Suet-Feung; Davies, Helen; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Ehinger, Anna; Eyfjord, Jorunn E.; Fatima, Aquila; Foekens, John A.; Futreal, P. A.; Garred, Oystein; Giri, Dilip D.; Glodzik, Dominik; Grabau, Dorthe; Hilmarsdottir, Holmfridur; Hooijer, Gerrit K.; Jacquemier, Jocelyne; Jang, Se Jin; Jonasson, Jon G.; Jonkers, Jos; Kim, Hyung-Yong; King, Tari A.; Knappskog, Stian; Kong, Gu; Krishnamurthy, Savitri; Lakhani, Sunil R.; Langerod, Anita; Larsimont, Denis; Lee, Hee Jin; Lee, Jeong-Yeon; Lee, Ming Ta Michael; Lingjaerde, Ole Christian; MacGrogan, Gaetan; Martens, John W. M.; O'Meara, Sarah; Pauporte, Iris; Pinder, Sarah; Pivot, Xavier; Provenzano, Elena; Purdie, Colin A.; Ramakrishna, Manasa; Ramakrishnan, Kamna; Reis-Filho, Jorge; Richardson, Andrea L.; Ringner, Markus; Rodriguez, Javier Bartolome; Rodriguez-Gonzalez, F. German; Romieu, Gilles; Salgado, Roberto; Sauer, Torill; Shepherd, Rebecca; Sieuwerts, Anieta M.; Simpson, Peter T.; Smid, Marcel; Sotiriou, Christos; Span, Paul N.; Stefansson, Olafur Andri; Stenhouse, Alasdair; Stunnenberg, Henk G.; Sweep, Fred; Tan, Benita Kiat Tee; Thomas, Gilles; Thompson, Alastair M.; Tommasi, Stefania; Treilleux, Isabelle; Tutt, Andrew; Ueno, Naoto T.; Van Laere, Steven; Van den Eynden, Gert G.; Vermeulen, Peter; Viari, Alain; Vincent-Salomon, Anne; Wong, Bernice H.; Yates, Lucy; Zou, Xueqing; van Deurzen, Carolien H. M.; van de Vijver, Marc J.; van't Veer, Laura; Ammerpohl, Ole; Aukema, Sietse; Bergmann, Anke K.; Bernhart, Stephan H.; Borkhardt, Arndt; Borst, Christoph; Burkhardt, Birgit; Claviez, Alexander; Goebler, Maria Elisabeth; Haake, Andrea; Haas, Siegfried; Hansmann, Martin; Hoell, Jessica; Hummel, Michael; Karsch, Dennis; Klapper, Wolfram; Kneba, Michael; Kreuz, Markus; Kube, Dieter; Kueppers, Ralf; Lenze, Dido; Loeffler, Markus; Lopez, Cristina; Mantovani-Loeffler, Luisa; Moeller, Peter; Ott, German; Radlwimmer, Bernhard; Richter, Julia; Rohde, Marius; Rosenstiel, Philip C.; Rosenwald, Andreas; Schilhabel, Markus B.; Schreiber, Stefan; Stadler, Peter F.; Staib, Peter; Stilgenbauer, Stephan; Sungalee, Stephanie; Szczepanowski, Monika; Toprak, Umut H.; Truemper, Lorenz H. P.; Wagener, Rabea; Zenz, Thorsten; Hovestadt, Volker; von Kalle, Christof; Kool, Marcel; Korshunov, Andrey; Landgraf, Pablo; Lehrach, Hans; Northcott, Paul A.; Pfister, Stefan M.; Reifenberger, Guido; Warnatz, Hans-Joerg; Wolf, Stephan; Yaspo, Marie-Laure; Assenov, Yassen; Gerhauser, Clarissa; Minner, Sarah; Schlomm, Thorsten; Simon, Ronald; Sauter, Guido; Sueltmann, Holger; Biswas, Nidhan K.; Maitra, Arindam; Majumder, Partha P.; Sarin, Rajiv; Barbi, Stefano; Bonizzato, Giada; Cantu, Cinzia; Dei Tos, Angelo P.; Fassan, Matteo; Grimaldi, Sonia; Luchini, Claudio; Malleo, Giuseppe; Marchegiani, Giovanni; Milella, Michele; Paiella, Salvatore; Pea, Antonio; Pederzoli, Paolo; Ruzzenente, Andrea; Salvia, Roberto; Sperandio, Nicola; Arai, Yasuhito; Hama, Natsuko; Hiraoka, Nobuyoshi; Hosoda, Fumie; Nakamura, Hiromi; Ojima, Hidenori; Okusaka, Takuji; Totoki, Yasushi; Urushidate, Tomoko; Fukayama, Masashi; Ishikawa, Shumpei; Katai, Hitoshi; Katoh, Hiroto; Komura, Daisuke; Rokutan, Hirofumi; Saito-Adachi, Mihoko; Suzuki, Akihiro; Taniguchi, Hirokazu; Tatsuno, Kenji; Ushiku, Tetsuo; Yachida, Shinichi; Yamamoto, Shogo; Aikata, Hiroshi; Arihiro, Koji; Ariizumi, Shun-ichi; Chayama, Kazuaki; Furuta, Mayuko; Gotoh, Kunihito; Hayami, Shinya; Hirano, Satoshi; Kawakami, Yoshiiku; Maejima, Kazuhiro; Nakamura, Toru; Nakano, Kaoru; Ohdan, Hideki; Sasaki-Oku, Aya; Tanaka, Hiroko; Ueno, Masaki; Yamamoto, Masakazu; Yamaue, Hiroki; Choo, Su Pin; Cutcutache, Ioana; Khuntikeo, Narong; Ong, Choon Kiat; Pairojkul, Chawalit; Popescu, Irinel; Ahn, Keun Soo; Aymerich, Marta; Lopez-Guillermo, Armando; Lopez-Otin, Carlos; Puente, Xose S.; Campo, Elias; Amary, Fernanda; Baumhoer, Daniel; Behjati, Sam; Bjerkehagen, Bodil; Futreal, P. A.; Myklebost, Ola; Pillay, Nischalan; Tarpey, Patrick; Tirabosco, Roberto; Zaikova, Olga; Flanagan, Adrienne M.; Boultwood, Jacqueline; Bowen, David T.; Cazzola, Mario; Green, Anthony R.; Hellstrom-Lindberg, Eva; Malcovati, Luca; Nangalia, Jyoti; Papaemmanuil, Elli; Vyas, Paresh; Ang, Yeng; Barr, Hugh; Beardsmore, Duncan; Eldridge, Matthew; Gossage, James; Grehan, Nicola; Hanna, George B.; Hayes, Stephen J.; Hupp, Ted R.; Khoo, David; Lagergren, Jesper; Lovat, Laurence B.; MacRae, Shona; O'Donovan, Maria; O'Neill, J. Robert; Parsons, Simon L.; Preston, Shaun R.; Puig, Sonia; Roques, Tom; Sanders, Grant; Sothi, Sharmila; Tavare, Simon; Tucker, Olga; Turkington, Richard; Underwood, Timothy J.; Welch, Ian; Fitzgerald, Rebecca C.; Berney, Daniel M.; De Bono, Johann S.; Cahill, Declan; Camacho, Niedzica; Dennis, Nening M.; Dudderidge, Tim; Edwards, Sandra E.; Fisher, Cyril; Foster, Christopher S.; Ghori, Mohammed; Gill, Pelvender; Gnanapragasam, Vincent J.; Gundem, Gunes; Hamdy, Freddie C.; Hawkins, Steve; Hazell, Steven; Howat, William; Isaacs, William B.; Karaszi, Katalin; Kay, Jonathan D.; Khoo, Vincent; Kote-Jarai, Zsofia; Kremeyer, Barbara; Kumar, Pardeep; Lambert, Adam; Leongamornlert, Daniel A.; Livni, Naomi; Lu, Yong-Jie; Luxton, Hayley J.; Marsden, Luke; Massie, Charlie E.; Matthews, Lucy; Mayer, Erik; McDermott, Ultan; Merson, Sue; Neal, David E.; Ng, Anthony; Nicol, David; Ogden, Christopher; Rowe, Edward W.; Shah, Nimish C.; Thomas, Sarah; Thompson, Alan; Verrill, Clare; Visakorpi, Tapio; Warren, Anne Y.; Whitaker, Hayley C.; Zhang, Hongwei; van As, Nicholas; Eeles, Rosalind A.; Abeshouse, Adam; Agrawal, Nishant; Akbani, Rehan; Al Ahmadie, Hikmat; Albert, Monique; Aldape, Kenneth; Ally, Adrian; Appelbaum, Elizabeth L.; Armenia, Joshua; Asa, Sylvia; Auman, J. Todd; Balasundaram, Miruna; Balu, Saianand; Barnholtz-Sloan, Jill; Bathe, Oliver F.; Baylin, Stephen B.; Benz, Christopher; Berchuck, Andrew; Berrios, Mario; Bigner, Darell; Birrer, Michael; Bodenheimer, Tom; Boice, Lori; Bootwalla, Moiz S.; Bosenberg, Marcus; Bowlby, Reanne; Boyd, Jeffrey; Broaddus, Russell R.; Brock, Malcolm; Brooks, Denise; Bullman, Susan; Caesar-Johnson, Samantha J.; Carey, Thomas E.; Carlsen, Rebecca; Cerfolio, Robert; Chandan, Vishal S.; Chen, Hsiao-Wei; Cherniack, Andrew D.; Chien, Jeremy; Cho, Juok; Chuah, Eric; Cibulskis, Carrie; Cope, Leslie; Cordes, Matthew G.; Curley, Erin; Czerniak, Bogdan; Danilova, Ludmila; Davis, Ian J.; Defreitas, Timothy; Demchok, John A.; Dhalla, Noreen; Dhir, Rajiv; Doddapaneni, HarshaVardhan; El-Naggar, Adel; Felau, Ina; Ferguson, Martin L.; Finocchiaro, Gaetano; Fong, Kwun M.; Frazer, Scott; Friedman, William; Fronick, Catrina C.; Fulton, Lucinda A.; Gabriel, Stacey B.; Gao, Jianjiong; Gehlenborg, Nils; Gershenwald, Jeffrey E.; Ghossein, Ronald; Giama, Nasra H.; Gibbs, Richard A.; Gomez, Carmen; Govindan, Ramaswamy; Hayes, D. Neil; Hegde, Apurva M.; Heiman, David; Heins, Zachary; Hepperla, Austin J.; Holbrook, Andrea; Holt, Robert A.; Hoyle, Alan P.; Hruban, Ralph H.; Hu, Jianhong; Huang, Mei; Huntsman, David; Huse, Jason; Donahue, Christine A. Iacobuzio; Ittmann, Michael; Jayaseelan, Joy C.; Jefferys, Stuart R.; Jones, Corbin D.; Jones, Steven J. M.; Juhl, Hartmut; Kang, Koo Jeong; Karlan, Beth; Kasaian, Katayoon; Kebebew, Electron; Kim, Hark Kyun; Korchina, Viktoriya; Kundra, Ritika; Lai, Phillip H.; Lander, Eric; Le, Xuan; Lee, Darlene; Levine, Douglas A.; Lewis, Lora; Ley, Tim; Li, Haiyan Irene; Lin, Pei; Linehan, W. M.; Liu, Fei Fei; Lu, Yiling; Lype, Lisa; Ma, Yussanne; Maglinte, Dennis T.; Mardis, Elaine R.; Marks, Jeffrey; Marra, Marco A.; Matthew, Thomas J.; Mayo, Michael; McCune, Karen; Meier, Samuel R.; Meng, Shaowu; Mieczkowski, Piotr A.; Mikkelsen, Tom; Miller, Christopher A.; Mills, Gordon B.; Moore, Richard A.; Morrison, Carl; Mose, Lisle E.; Moser, Catherine D.; Mungall, Andrew J.; Mungall, Karen; Mutch, David; Muzny, Donna M.; Myers, Jerome; Newton, Yulia; Noble, Michael S.; O'Donnell, Peter; O'Neill, Brian Patrick; Ochoa, Angelica; Park, Joong-Won; Parker, Joel S.; Pass, Harvey; Pastore, Alessandro; Pennell, Nathan A.; Perou, Charles M.; Petrelli, Nicholas; Potapova, Olga; Rader, Janet S.; Ramalingam, Suresh; Rathmell, W. Kimryn; Reuter, Victor; Reynolds, Sheila M.; Ringel, Matthew; Roach, Jeffrey; Roberts, Lewis R.; Robertson, A. Gordon; Sadeghi, Sara; Saller, Charles; Sanchez-Vega, Francisco; Schadendorf, Dirk; Schein, Jacqueline E.; Schmidt, Heather K.; Schultz, Nikolaus; Seethala, Raja; Senbabaoglu, Yasin; Shelton, Troy; Shi, Yan; Shih, Juliann; Shmulevich, Ilya; Shriver, Craig; Signoretti, Sabina; Simons, Janae; Singer, Samuel; Sipahimalani, Payal; Skelly, Tara J.; McCune, Karen Smith; Socci, Nicholas D.; Soloway, Matthew G.; Sood, Anil K.; Tam, Angela; Tan, Donghui; Tarnuzzer, Roy; Thiessen, Nina; Thompson, R. Houston; Thorne, Leigh B.; Tsao, Ming; Umbricht, Christopher; Van Den Berg, David J.; Van Meir, Erwin G.; Veluvolu, Umadevi; Voet, Douglas; Wang, Linghua; Weinberger, Paul; Weisenberger, Daniel J.; Wigle, Dennis; Wilkerson, Matthew D.; Wilson, Richard K.; Winterhoff, Boris; Wiznerowicz, Maciej; Wong, Tina; Wong, Winghing; Xi, Liu; Yau, Christina; Zhang, Hailei; Zhang, Hongxin; Zhang, Jiashan (2020)
    Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).
  • Torregrosa-Munumer, Ruben; Hangas, Anu; Goffart, Steffi; Blei, Daniel; Zsurka, Gabor; Griffith, Jack; Kunz, Wolfram S.; Pohjoismäki, Jaakko L. O. (2019)
    Replication stalling has been associated with the formation of pathological mitochondrial DNA (mtDNA) rearrangements. Yet, almost nothing is known about the fate of stalled replication intermediates in mitochondria. We show here that replication stalling in mitochondria leads to replication fork regression and mtDNA double-strand breaks. The resulting mtDNA fragments are normally degraded by a mechanism involving the mitochondrial exonuclease MGME1, and the loss of this enzyme results in accumulation of linear and recombining mtDNA species. Additionally, replication stress promotes the initiation of alternative replication origins as an apparent means of rescue by fork convergence. Besides demonstrating an interplay between two major mechanisms rescuing stalled replication forks - mtDNA degradation and homology-dependent repair - our data provide evidence that mitochondria employ similar mechanisms to cope with replication stress as known from other genetic systems.
  • Nazaryan-Petersen, Lusine; Eisfeldt, Jesper; Pettersson, Maria; Lundin, Johanna; Nilsson, Daniel; Wincent, Josephine; Lieden, Agne; Lovmar, Lovisa; Ottosson, Jesper; Gacic, Jelena; Mäkitie, Outi; Nordgren, Ann; Vezzi, Francesco; Wirta, Valtteri; Käller, Max; Hjortshoj, Tina Duelund; Jespersgaard, Cathrine; Houssari, Rayan; Pignata, Laura; Bak, Mads; Tommerup, Niels; Lundberg, Elisabeth Syk; Tümer, Zeynep; Lindstrand, Anna (2018)
    Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.
  • Wiechmann, Sascha; Freese, Tyll; Drafz, Martin H. H.; Hübner, Eike G.; Namyslo, Jan C.; Nieger, Martin; Schmidt, Andreas (2014)
  • Sävilammi, Tiina; Primmer, Craig R.; Varadharajan, Srinidhi; Guyomard, Rene; Guiguen, Yann; Sandve, Simen R.; Vollestad, L. Asbjorn; Papakostas, Spiros; Lien, Sigbjorn (2019)
    Salmonids represent an intriguing taxonomical group for investigating genome evolution in vertebrates due to their relatively recent last common whole genome duplication event, which occurred between 80 and 100 million years ago. Here, we report on the chromosome-level genome assembly of European grayling (Thymallus thymallus), which represents one of the earliest diverged salmonid subfamilies. To achieve this, we first generated relatively long genomic scaffolds by using a previously published draft genome assembly along with long-read sequencing data and a linkage map. We then merged those scaffolds by applying synteny evidence from the Atlantic salmon (Salmo salar) genome. Comparisons of the European grayling genome assembly to the genomes of Atlantic salmon and Northern pike (Esox lucius), the latter used as a nonduplicated outgroup, detailed aspects of the characteristic chromosome evolution process that has taken place in European grayling. While Atlantic salmon and other salmonid genomes are portrayed by the typical occurrence of numerous chromosomal fusions, European grayling chromosomes were confirmed to be fusion-free and were characterized by a relatively large proportion of paracentric and pericentric inversions. We further reported on transposable elements specific to either the European grayling or Atlantic salmon genome, on the male-specific sdY gene in the European grayling chromosome 11A, and on regions under residual tetrasomy in the homeologous European grayling chromosome pairs 9A-9B and 25A-25B. The same chromosome pairs have been observed under residual tetrasomy in Atlantic salmon and in other salmonids, suggesting that this feature has been conserved since the subfamily split.
  • Silva, Jorge Miguel; Pratas, Diogo; Caetano, Tania; Matos, Sergio (2022)
    Background Viruses are among the shortest yet highly abundant species that harbor minimal instructions to infect cells, adapt, multiply, and exist. However, with the current substantial availability of viral genome sequences, the scientific repertory lacks a complexity landscape that automatically enlights viral genomes' organization, relation, and fundamental characteristics. Results This work provides a comprehensive landscape of the viral genome's complexity (or quantity of information), identifying the most redundant and complex groups regarding their genome sequence while providing their distribution and characteristics at a large and local scale. Moreover, we identify and quantify inverted repeats abundance in viral genomes. For this purpose, we measure the sequence complexity of each available viral genome using data compression, demonstrating that adequate data compressors can efficiently quantify the complexity of viral genome sequences, including subsequences better represented by algorithmic sources (e.g., inverted repeats). Using a state-of-the-art genomic compressor on an extensive viral genomes database, we show that double-stranded DNA viruses are, on average, the most redundant viruses while single-stranded DNA viruses are the least. Contrarily, double-stranded RNA viruses show a lower redundancy relative to single-stranded RNA. Furthermore, we extend the ability of data compressors to quantify local complexity (or information content) in viral genomes using complexity profiles, unprecedently providing a direct complexity analysis of human herpesviruses. We also conceive a features-based classification methodology that can accurately distinguish viral genomes at different taxonomic levels without direct comparisons between sequences. This methodology combines data compression with simple measures such as GC-content percentage and sequence length, followed by machine learning classifiers. Conclusions This article presents methodologies and findings that are highly relevant for understanding the patterns of similarity and singularity between viral groups, opening new frontiers for studying viral genomes' organization while depicting the complexity trends and classification components of these genomes at different taxonomic levels. The whole study is supported by an extensive website (https://asilab.github.io/canvas/) for comprehending the viral genome characterization using dynamic and interactive approaches.
  • Edlund, Petra; Takala, Heikki; Claesson, Elin; Henry, Leocadie; Dods, Robert; Lehtivuori, Heli; Panman, Matthijs; Pande, Kanupriya; White, Thomas; Nakane, Takanori; Berntsson, Oskar; Gustavsson, Emil; Bath, Petra; Modi, Vaibhav; Roy-Chowdhury, Shatabdi; Zook, James; Berntsen, Peter; Pandey, Suraj; Poudyal, Ishwor; Tenboer, Jason; Kupitz, Christopher; Barty, Anton; Fromme, Petra; Koralek, Jake D.; Tanaka, Tomoyuki; Spence, John; Liang, Mengning; Hunter, Mark S.; Boutet, Sebastien; Nango, Eriko; Moffat, Keith; Groenhof, Gerrit; Ihalainen, Janne; Stojkovic, Emina A.; Schmidt, Marius; Westenhoff, Sebastian (2016)
    Phytochromes are a family of photoreceptors that control light responses of plants, fungi and bacteria. A sequence of structural changes, which is not yet fully understood, leads to activation of an output domain. Time-resolved serial femtosecond crystallography (SFX) can potentially shine light on these conformational changes. Here we report the room temperature crystal structure of the chromophore-binding domains of the Deinococcus radiodurans phytochrome at 2.1 angstrom resolution. The structure was obtained by serial femtosecond X-ray crystallography from microcrystals at an X-ray free electron laser. We find overall good agreement compared to a crystal structure at 1.35 angstrom resolution derived from conventional crystallography at cryogenic temperatures, which we also report here. The thioether linkage between chromophore and protein is subject to positional ambiguity at the synchrotron, but is fully resolved with SFX. The study paves the way for time-resolved structural investigations of the phytochrome photocycle with time-resolved SFX.