Nature Genetics Contents: April 2014 pp 317 - 415

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Start a Free Trial! Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement They're recruiting scientists just like you! The Naturejobs Career Expo is coming to Boston, Massachusetts on May 20, 2014. Take advantage of this free opportunity to meet employers, attend workshops and further develop your career. Don't wait-register today!      Editorial Top Converging on neurodegenerative mechanisms   p317 doi:10.1038/ng.2954 Diverse neurodegenerative diseases share a common pathological feature, namely the accumulation of misfolded proteins. However, both drug development and research need more standardization of the biomarkers for the protein types involved. The bold strategy of integrating high-throughput genetic and chemical screens in yeast with experiments in neurons derived from genetically modified human induced pluripotent stem cells (iPSCs) is producing many significant new molecular insights into disease mechanisms. Correspondence Top Global optimization of somatic variant identification in cancer genomes with a global community challenge OPEN   pp318 - 319 Paul C Boutros, Adam D Ewing, Kyle Ellrott, Thea C Norman, Kristen K Dang, Yin Hu, Michael R Kellen, Christine Suver, J Christopher Bare, Lincoln D Stein, Paul T Spellman, Gustavo Stolovitzky, Stephen H Friend, Adam A Margolin & Joshua M Stuart doi:10.1038/ng.2932 News and Views Top RHOA mutations in peripheral T cell lymphoma   pp320 - 321 Jan Cools doi:10.1038/ng.2937 Peripheral T cell lymphomas are rare but aggressive non-Hodgkin lymphomas derived from mature T lymphocytes or natural killer (NK) cells. New studies identify recurrent dominant-negative mutation of the RHOA GTPase gene in these lymphomas. See also: Letter by Yoo et al. Ancient human oral plaque preserves a wealth of biological data   pp321 - 323 Jessica L Metcalf, Luke K Ursell and Rob Knight doi:10.1038/ng.2930 A new study explores the ancient oral microbiome from the well-preserved dental calculus samples of four human individuals who lived during medieval times, using a suite of genomic, proteomic and microscopic approaches. The authors investigate the evolution of dental pathogens by reconstructing the genome of the periodontal pathogen Tannerella forsythia and also identify antibiotic resistance genes, bacterial virulence factors and host immune defense proteins. See also: Article by Warinner et al. Zinc transport and diabetes risk   pp323 - 324 Ewan Pearson doi:10.1038/ng.2934 Genome-wide association studies have previously identified variants in SLC30A8, encoding the zinc transporter ZnT8, associated with diabetes risk. A rare variant association study has now established the direction of effect, surprisingly showing that loss-of-function mutations in SLC30A8 are protective against diabetes. See also: Letter by Flannick et al. Genetics JOBS of the week Post-doctoral Fellow (CLessard) - Genetics and Genomics of Autoimmune Diseases Oklahoma Medical Research Foundation (OMRF) Postdoctoral Research Fellow Genetics of Common Complex Diseases University of British Columbia Postdoctoral Researcher in Plant Genomics Databases / Bioinformatics University of Connecticut (UConn) Bioinformatics Post-Doc in Melanoma Genomics University of Colorado Anschutz Medical Campus Postdoctoral Scholar Position – mRNA processing & gene expression in stem cells University of California - Irvine More Science jobs from Genetics EVENT Drosophila Genetics and Genomics 27.07.14 Cambridge, UK More science events from Research Highlights Top Promoter silencing by CGG repeats | Inflammatory syndrome ADA2 deficiency | Two pathways for courtship behavior | eQTL mapping for innate immunity | PRKCI and SOX2 drive lung cancer Brief Communication Top Mutations in TJP2 cause progressive cholestatic liver disease   pp326 - 328 Melissa Sambrotta, Sandra Strautnieks, Efterpi Papouli, Peter Rushton, Barnaby E Clark, David A Parry, Clare V Logan, Lucy J Newbury, Binita M Kamath, Simon Ling, Tassos Grammatikopoulos, Bart E Wagner, John C Magee, Ronald J Sokol, Giorgina Mieli-Vergani, University of Washington Center for Mendelian Genomics, Joshua D Smith, Colin A Johnson, Patricia McClean, Michael A Simpson, A S Knisely, Laura N Bull & Richard J Thompson doi:10.1038/ng.2918 Richard Thompson, Melissa Sambrotta and colleagues show that biallelic mutations in TJP2 cause severe cholestatic liver disease. Their findings suggest that loss of TJP2 protein disrupts the structural integrity of tight junctions in liver tissue, resulting in progressive liver damage. Advertisement Droplet Digital™ PCR gives scientists the power to be certain of their results. See how this technology is helping HIV therapies progress from probable to proven. Watch the video>   Articles Top Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma   pp329 - 335 Jay Gunawardana, Fong Chun Chan, Adèle Telenius, Bruce Woolcock, Robert Kridel, King L Tan, Susana Ben-Neriah, Anja Mottok, Raymond S Lim, Merrill Boyle, Sanja Rogic, Lisa M Rimsza, Chrystelle Guiter, Karen Leroy, Philippe Gaulard, Corinne Haioun, Marco A Marra, Kerry J Savage, Joseph M Connors, Sohrab P Shah, Randy D Gascoyne & Christian Steidl doi:10.1038/ng.2900 Christian Steidl and colleagues identify recurrent somatic mutations in the PTPN1 gene in primary mediastinal B cell lymphoma and Hodgkin lymphoma. They show that mutant PTPN1 leads to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Pathogens and host immunity in the ancient human oral cavity   pp336 - 344 Christina Warinner, João F Matias Rodrigues, Rounak Vyas, Christian Trachsel, Natallia Shved, Jonas Grossmann, Anita Radini, Y Hancock, Raul Y Tito, Sarah Fiddyment, Camilla Speller, Jessica Hendy, Sophy Charlton, Hans Ulrich Luder, Domingo C Salazar-García, Elisabeth Eppler, Roger Seiler, Lars H Hansen, José Alfredo Samaniego Castruita, Simon Barkow-Oesterreicher, Kai Yik Teoh, Christian D Kelstrup, Jesper V Olsen, Paolo Nanni, Toshihisa Kawai, Eske Willerslev, Christian von Mering, Cecil M Lewis Jr, Matthew J Collins, M Thomas P Gilbert, Frank Rühli & Enrico Cappellini doi:10.1038/ng.2906 Christina Warinner and colleagues report a high-resolution characterization of the oral microbiome isolated from the dental tissues of adult skeletons dating to 1100 CE and showing evidence of periodontal disease. They show the long-term carriage of a diverse range of opportunistic pathogens in the oral cavity and reconstruct the genome of the periodontal pathogen Tannerella forsythia. See also: News and Views by Metcalf et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk   pp345 - 351 Oddgeir L Holmen, He Zhang, Yanbo Fan, Daniel H Hovelson, Ellen M Schmidt, Wei Zhou, Yanhong Guo, Ji Zhang, Arnulf Langhammer, Maja-Lisa Løchen, Santhi K Ganesh, Lars Vatten, Frank Skorpen, Håvard Dalen, Jifeng Zhang, Subramaniam Pennathur, Jin Chen, Carl Platou, Ellisiv B Mathiesen, Tom Wilsgaard, Inger Njølstad, Michael Boehnke, Y Eugene Chen, Gonçalo R Abecasis, Kristian Hveem & Cristen J Willer doi:10.1038/ng.2926 Cristen Willer, Kristian Hveem and colleagues use an exome array to identify a coding variant in TM6SF2 that is associated with total cholesterol levels. They further show that transient overexpression of TM6SF2 or knockdown of Tm6sf2 in mice alters serum lipid profiles, implicating TM6SF2 as a causal regulator of lipid traits. Letters Top Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease   pp352 - 356 Julia Kozlitina, Eriks Smagris, Stefan Stender, Børge G Nordestgaard, Heather H Zhou, Anne Tybjærg-Hansen, Thomas F Vogt, Helen H Hobbs & Jonathan C Cohen doi:10.1038/ng.2901 Helen Hobbs, Jonathan Cohen and colleagues identify a nonsynonymous variant in TM6SF2 associated with susceptibility to nonalcoholic fatty acid liver disease. They further show that knockdown of Tm6sf2 in mice results in increased liver triglyceride content and reduced very-low-density lipoprotein (VLDL) secretion, suggesting that impaired TM6SF2 function contributes causally to disease risk. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes   pp357 - 363 Jason Flannick, Gudmar Thorleifsson, Nicola L Beer, Suzanne B R Jacobs, Niels Grarup, Noël P Burtt, Anubha Mahajan, Christian Fuchsberger, Gil Atzmon, Rafn Benediktsson, John Blangero, Don W Bowden, Ivan Brandslund, Julia Brosnan, Frank Burslem, John Chambers, Yoon Shin Cho, Cramer Christensen, Desirée A Douglas, Ravindranath Duggirala, Zachary Dymek, Yossi Farjoun, Timothy Fennell, Pierre Fontanillas, Tom Forsén, Stacey Gabriel, Benjamin Glaser, Daniel F Gudbjartsson, Craig Hanis, Torben Hansen, Astradur B Hreidarsson, Kristian Hveem, Erik Ingelsson, Bo Isomaa, Stefan Johansson, Torben Jørgensen, Marit Eika Jørgensen, Sekar Kathiresan, Augustine Kong, Jaspal Kooner, Jasmina Kravic, Markku Laakso, Jong-Young Lee, Lars Lind, Cecilia M Lindgren, Allan Linneberg, Gisli Masson, Thomas Meitinger, Karen L Mohlke, Anders Molven, Andrew P Morris, Shobha Potluri, Rainer Rauramaa, Rasmus Ribel-Madsen, Ann-Marie Richard, Tim Rolph, Veikko Salomaa, Ayellet V Segrè, Hanna Skärstrand, Valgerdur Steinthorsdottir, Heather M Stringham, Patrick Sulem, E Shyong Tai, Yik Ying Teo, Tanya Teslovich, Unnur Thorsteinsdottir, Jeff K Trimmer, Tiinamaija Tuomi, Jaakko Tuomilehto, Fariba Vaziri-Sani, Benjamin F Voight, James G Wilson, Michael Boehnke, Mark I McCarthy, Pål R Njølstad, Oluf Pedersen, Go-T2D Consortium, T2D-GENES Consortium, Leif Groop, David R Cox, Kari Stefansson & David Altshuler doi:10.1038/ng.2915 David Altshuler and colleagues report genotyping or sequencing of ~150,000 individuals from several population-based cohorts, identifying 12 rare protein-truncating variants in SLC30A8, encoding a pancreatic islet zinc transporter. Carriers of these rare protein-truncating variants in SLC30A8 show reduced risk of type 2 diabetes and reduced glucose levels. See also: News and Views by Pearson An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia   pp364 - 370 Birgit Knoechel, Justine E Roderick, Kaylyn E Williamson, Jiang Zhu, Jens G Lohr, Matthew J Cotton, Shawn M Gillespie, Daniel Fernandez, Manching Ku, Hongfang Wang, Federica Piccioni, Serena J Silver, Mohit Jain, Daniel Pearson, Michael J Kluk, Christopher J Ott, Leonard D Shultz, Michael A Brehm, Dale L Greiner, Alejandro Gutierrez, Kimberly Stegmaier, Andrew L Kung, David E Root, James E Bradner, Jon C Aster, Michelle A Kelliher & Bradley E Bernstein doi:10.1038/ng.2913 Michelle Kelliher, Bradley Bernstein and colleagues identify T cell acute lymphoblastic leukemia cells that are resistant to γ-secretase inhibitor treatment and characterize the epigenetic mechanism of resistance. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma   pp371 - 375 Hae Yong Yoo, Min Kyung Sung, Seung Ho Lee, Sangok Kim, Haeseung Lee, Seongjin Park, Sang Cheol Kim, Byungwook Lee, Kyoohyoung Rho, Jong-Eun Lee, Kwang-Hwi Cho, Wankyu Kim, Hyunjung Ju, Jaesang Kim, Seok Jin Kim, Won Seog Kim, Sanghyuk Lee & Young Hyeh Ko doi:10.1038/ng.2916 Sanghyuk Lee, Young Hyeh Ko and colleagues report exome and transcriptome sequences for angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, and identify a recurrent somatic mutation in RHOA. See also: News and Views by Cools Recurrent PTPRB and PLCG1 mutations in angiosarcoma   pp376 - 379 Sam Behjati, Patrick S Tarpey, Helen Sheldon, Inigo Martincorena, Peter Van Loo, Gunes Gundem, David C Wedge, Manasa Ramakrishna, Susanna L Cooke, Nischalan Pillay, Hans Kristian M Vollan, Elli Papaemmanuil, Hans Koss, Tom D Bunney, Claire Hardy, Olivia R Joseph, Sancha Martin, Laura Mudie, Adam Butler, Jon W Teague, Meena Patil, Graham Steers, Yu Cao, Curtis Gumbs, Davis Ingram, Alexander J Lazar, Latasha Little, Harshad Mahadeshwar, Alexei Protopopov, Ghadah A Al Sannaa, Sahil Seth, Xingzhi Song, Jiabin Tang, Jianhua Zhang, Vinod Ravi, Keila E Torres, Bhavisha Khatri, Dina Halai, Ioannis Roxanis, Daniel Baumhoer, Roberto Tirabosco, M Fernanda Amary, Chris Boshoff, Ultan McDermott, Matilda Katan, Michael R Stratton, P Andrew Futreal, Adrienne M Flanagan, Adrian Harris & Peter J Campbell doi:10.1038/ng.2921 Peter Campbell and colleagues identify PLCG1 and PTPRB as new driver genes for angiosarcoma through whole-exome sequencing of tumor samples. They find somatic PTPRB mutations in 10 of 39 cases and PLCG1 mutations in 3 of 34 cases, along with mutations in known cancer-related genes. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP   pp380 - 384 Céline Helsmoortel, Anneke T Vulto-van Silfhout, Bradley P Coe, Geert Vandeweyer, Liesbeth Rooms, Jenneke van den Ende, Janneke H M Schuurs-Hoeijmakers, Carlo L Marcelis, Marjolein H Willemsen, Lisenka E L M Vissers, Helger G Yntema, Madhura Bakshi, Meredith Wilson, Kali T Witherspoon, Helena Malmgren, Ann Nordgren, Göran Annerén, Marco Fichera, Paolo Bosco, Corrado Romano, Bert B A de Vries, Tjitske Kleefstra, R Frank Kooy, Evan E Eichler & Nathalie Van der Aa doi:10.1038/ng.2899 Frank Kooy, Nathalie Van der Aa and colleagues report that de novo mutations in ADNP cause a syndrome characterized by autism, intellectual disability and facial dysmorphisms. ADNP encodes a transcription factor that interacts with components of the SWI/SNF chromatin remodeling complex. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability   pp385 - 388 Katrina Tatton-Brown, Sheila Seal, Elise Ruark, Jenny Harmer, Emma Ramsay, Silvana del Vecchio Duarte, Anna Zachariou, Sandra Hanks, Eleanor O'Brien, Lise Aksglaede, Diana Baralle, Tabib Dabir, Blanca Gener, David Goudie, Tessa Homfray, Ajith Kumar, Daniela T Pilz, Angelo Selicorni, I Karen Temple, Lionel Van Maldergem, Naomi Yachelevich, Childhood Overgrowth Consortium, Robert van Montfort & Nazneen Rahman doi:10.1038/ng.2917 Nazneen Rahman, Katrina Tatton-Brown and colleagues identify de novo mutations in the DNA methyltransferase gene DNMT3A as the cause of a new overgrowth syndrome. Shared features of this syndrome include a distinctive facial appearance, intellectual disability and greater height. Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant   pp389 - 392 Jahda H Hill, Zhe Chen and Hong Xu doi:10.1038/ng.2920 Hong Xu and colleagues demonstrate reduced germline replication and selection against the transmission of mitochondria encoding a temperature-sensitive cytochrome c oxidase subunit. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster   pp393 - 397 Hansong Ma, Hong Xu and Patrick H O'Farrell doi:10.1038/ng.2919 Patrick H O'Farrell and colleagues show not only that deleterious variants are selected against but that complementing mutant mitochondria are selected at characteristic stable ratios. Chalk5 encodes a vacuolar H+-translocating pyrophosphatase influencing grain chalkiness in rice   pp398 - 404 Yibo Li, Chuchuan Fan, Yongzhong Xing, Peng Yun, Lijun Luo, Bao Yan, Bo Peng, Weibo Xie, Gongwei Wang, Xianghua Li, Jinghua Xiao, Caiguo Xu & Yuqing He doi:10.1038/ng.2923 Yuqing He and colleagues show that Chalk5, a major quantitative trait locus for grain chalkiness in rice, encodes a vacuolar pyrophosphatase with H+ translocation activity. They find that elevated expression of Chalk5 disturbs the endomembrane trafficking system in developing seeds, leading to an accumulation of vesicle-like structures and increased chalkiness. Direct measurement of transcription factor dissociation excludes a simple operator occupancy model for gene regulation   pp405 - 408 Petter Hammar, Mats Walldén, David Fange, Fredrik Persson, Özden Baltekin, Gustaf Ullman, Prune Leroy & Johan Elf doi:10.1038/ng.2905 Johan Elf and colleagues developed a single-molecule chase assay to measure the time a single transcription factor is bound at a specific chromosomal operator site, which they use to examine the dynamics of binding of the Lac repressor dimer at the native lac operator in Escherichia coli. Their findings do not support the simple operator occupancy model and suggest a role for non-equilibrium transcription factor kinetics in E. coli gene regulation. Technical Report Top Ancestry estimation and control of population stratification for sequence-based association studies   pp409 - 415 Chaolong Wang, Xiaowei Zhan, Jennifer Bragg-Gresham, Hyun Min Kang, Dwight Stambolian, Emily Y Chew, Kari E Branham, John Heckenlively, The FUSION Study, Robert Fulton, Richard K Wilson, Elaine R Mardis, Xihong Lin, Anand Swaroop, Sebastian Zöllner & Gonçalo R Abecasis doi:10.1038/ng.2924 Goncalo Abecasis, Chaolong Wang and colleagues report a new statistical method, implemented in a publicly available software program LASER, to estimate an individual's genetic ancestry directly from off-target sequence reads from targeted sequencing experiments, making use of a reference panel. Their simulations and testing on real data sets show accurate inference of worldwide continental ancestry with whole-genome shotgun coverage as low as 0.001× and of fine-scale ancestry within Europe with coverage as low as 0.1×. 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