Nature Genetics 41, 763 (2009). doi:10.1038/ng0709-763

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Nature Genetics 41, 765 (2009). doi:10.1038/ng0709-765

Author: Stephen Chanock

Two genome-wide association studies for testicular cancer report associations at three new loci, including two candidate genes previously implicated in testicular development, KITLG (ligand for the receptor tyrosine kinase) and SPRY4 (sprouty 4). These studies are notable for the high effect sizes detected and the biological plausibility of the candidate genes.

Nature Genetics 41, 766 (2009). doi:10.1038/ng0709-766

Author: Charles G Mullighan

The genetic basis of myelodysplasia has long been enigmatic, with few common targets of mutation known. A new study reports common mutations in the TET2 gene in myelodysplasia and related myeloid malignancies, suggesting that TET2 has an important role in hematopoiesis and in the pathogenesis of this disease.

Nature Genetics 41, 768 (2009). doi:10.1038/ng0709-768

Author: Joshua T Mendell

MicroRNAs (miRNAs) and the pathways that regulate their expression have critical functions during normal development. A new study demonstrates that select cancer cells have appropriated one developmental mechanism of miRNA regulation, the inhibition of let-7 biogenesis by the Lin-28 and Lin-28B RNA binding proteins, to rid themselves of an antitumorigenic miRNA.

Nature Genetics 41, 773 (2009). doi:10.1038/ng.398

Authors: Marco Henneke, Simone Diekmann, Andreas Ohlenbusch, Jens Kaiser, Volkher Engelbrecht, Alfried Kohlschütter, Ralph Krätzner, Marcos Madruga-Garrido, Michèle Mayer, Lennart Opitz, Diana Rodriguez, Franz Rüschendorf, Johannes Schumacher, Holger Thiele, Sven Thoms, Robert Steinfeld, Peter Nürnberg & Jutta Gärtner

Congenital cytomegalovirus brain infection without symptoms at birth can cause a static encephalopathy with characteristic patterns of brain abnormalities. Here we show that loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to cystic leukoencephalopathy, an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype. Congenital cytomegalovirus infection and RNASET2 deficiency may both interfere with brain development and myelination through angiogenesis or RNA metabolism.

Nature Genetics 41, 776 (2009). doi:10.1038/ng.401

Authors: Philip L De Jager, Xiaoming Jia, Joanne Wang, Paul I W de Bakker, Linda Ottoboni, Neelum T Aggarwal, Laura Piccio, Soumya Raychaudhuri, Dong Tran, Cristin Aubin, Rebeccah Briskin, Susan Romano, Sergio E Baranzini, Jacob L McCauley, Margaret A Pericak-Vance, Jonathan L Haines, Rachel A Gibson, Yvonne Naeglin, Bernard Uitdehaag, Paul M Matthews, Ludwig Kappos, Chris Polman, Wendy L McArdle, David P Strachan, Denis Evans, Anne H Cross, Mark J Daly, Alastair Compston, Stephen J Sawcer, Howard L Weiner, Stephen L Hauser, David A Hafler & Jorge R Oksenberg

Nature Genetics 41, 783 (2009). doi:10.1038/ng.389

Authors: Yaoyu Chen, Yiguo Hu, Haojian Zhang, Cong Peng & Shaoguang Li

Nature Genetics 41, 793 (2009). doi:10.1038/ng.400

Authors: Courtney M Karner, Rani Chirumamilla, Shigehisa Aoki, Peter Igarashi, John B Wallingford & Thomas J Carroll

Nature Genetics 41, 800 (2009). doi:10.1038/ng.402

Authors: Erin A Osborne, Sandrine Dudoit & Jasper Rine

Nature Genetics 41, 807 (2009). doi:10.1038/ng.394

Authors: Elizabeth A Rapley, Clare Turnbull, Ali Amin Al Olama, Emmanouil T Dermitzakis, Rachel Linger, Robert A Huddart, Anthony Renwick, Deborah Hughes, Sarah Hines, Sheila Seal, Jonathan Morrison, Jeremie Nsengimana, Panagiotis Deloukas, Nazneen Rahman, D Timothy Bishop, Douglas F Easton & Michael R Stratton

We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19–1.58), P = 3 × 10−13), chromosome 6 (OR = 1.50 (95% CI = 1.28–1.75), P = 10−13) and chromosome 12 (OR = 2.55 (95% CI = 2.05–3.19), P = 10−31). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.

Nature Genetics 41, 811 (2009). doi:10.1038/ng.393

Authors: Peter A Kanetsky, Nandita Mitra, Saran Vardhanabhuti, Mingyao Li, David J Vaughn, Richard Letrero, Stephanie L Ciosek, David R Doody, Lauren M Smith, JoEllen Weaver, Anthony Albano, Chu Chen, Jacqueline R Starr, Daniel J Rader, Andrew K Godwin, Muredach P Reilly, Hakon Hakonarson, Stephen M Schwartz & Katherine L Nathanson

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P

Nature Genetics 41, 816 (2009). doi:10.1038/ng.379

Authors: Ann K Daly, Peter T Donaldson, Pallav Bhatnagar, Yufeng Shen, Itsik Pe'er, Aris Floratos, Mark J Daly, David B Goldstein, Sally John, Matthew R Nelson, Julia Graham, B Kevin Park, John F Dillon, William Bernal, Heather J Cordell, Munir Pirmohamed, Guruprasad P Aithal & Christopher P Day

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

Nature Genetics 41, 820 (2009). doi:10.1038/ng.395

Authors: Peter K Gregersen, Chistopher I Amos, Annette T Lee, Yue Lu, Elaine F Remmers, Daniel L Kastner, Michael F Seldin, Lindsey A Criswell, Robert M Plenge, V Michael Holers, Ted R Mikuls, Tuulikki Sokka, Larry W Moreland, S Louis Bridges, Gang Xie, Ann B Begovich & Katherine A Siminovitch

Nature Genetics 41, 824 (2009). doi:10.1038/ng.396

Authors:

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13–14 (rs703842, P = 5.4 × 10−11; rs10876994, P = 2.7 × 10−10; rs12368653, P = 1.0 × 10−7) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 × 10−7; rs1569723, P = 2.9 × 10−7). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 × 10−184; CD58, P = 9.6 × 10−8; EVI5-RPL5, P = 2.5 × 10−6; IL2RA, P = 7.4 × 10−6; CLEC16A, P = 1.1 × 10−4; IL7R, P = 1.3 × 10−3; TYK2, P = 3.5 × 10−3) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Nature Genetics 41, 829 (2009). doi:10.1038/ng.373

Authors: Gillian I Rice, Jacquelyn Bond, Aruna Asipu, Rebecca L Brunette, Iain W Manfield, Ian M Carr, Jonathan C Fuller, Richard M Jackson, Teresa Lamb, Tracy A Briggs, Manir Ali, Hannah Gornall, Lydia R Couthard, Alec Aeby, Simon P Attard-Montalto, Enrico Bertini, Christine Bodemer, Knut Brockmann, Louise A Brueton, Peter C Corry, Isabelle Desguerre, Elisa Fazzi, Angels Garcia Cazorla, Blanca Gener, Ben C J Hamel, Arvid Heiberg, Matthew Hunter, Marjo S van der Knaap, Ram Kumar, Lieven Lagae, Pierre G Landrieu, Charles M Lourenco, Daphna Marom, Michael F McDermott, William van der Merwe, Simona Orcesi, Julie S Prendiville, Magnhild Rasmussen, Stavit A Shalev, Doriette M Soler, Marwan Shinawi, Ronen Spiegel, Tiong Y Tan, Adeline Vanderver, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, Pierre Lebon, Daniel B Stetson, David T Bonthron & Yanick J Crow

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

Nature Genetics 41, 833 (2009). doi:10.1038/ng.390

Authors: Woranontee Weraarpachai, Hana Antonicka, Florin Sasarman, Jürgen Seeger, Bertold Schrank, Jill E Kolesar, Hanns Lochmüller, Mario Chevrette, Brett A Kaufman, Rita Horvath & Eric A Shoubridge

Defects in mitochondrial translation are among the most common causes of mitochondrial disease, but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast Saccharomyces cerevisiae, all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5′ UTRs and mediate translation. As mammalian mitochondrial mRNAs do not have significant 5′ UTRs, alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44, encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable degree of structural similarity with bacterial homologs, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.

Nature Genetics 41, 838 (2009). doi:10.1038/ng.391

Authors: Saskia M C Langemeijer, Roland P Kuiper, Marieke Berends, Ruth Knops, Mariam G Aslanyan, Marion Massop, Ellen Stevens-Linders, Patricia van Hoogen, Ad Geurts van Kessel, Reinier A P Raymakers, Eveline J Kamping, Gregor E Verhoef, Estelle Verburgh, Anne Hagemeijer, Peter Vandenberghe, Theo de Witte, Bert A van der Reijden & Joop H Jansen

Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array–based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34+ progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.

Nature Genetics 41, 843 (2009). doi:10.1038/ng.392

Authors: Srinivas R Viswanathan, John T Powers, William Einhorn, Yujin Hoshida, Tony L Ng, Sara Toffanin, Maureen O'Sullivan, Jun Lu, Letha A Phillips, Victoria L Lockhart, Samar P Shah, Pradeep S Tanwar, Craig H Mermel, Rameen Beroukhim, Mohammad Azam, Jose Teixeira, Matthew Meyerson, Timothy P Hughes, Josep M Llovet, Jerald Radich, Charles G Mullighan, Todd R Golub, Poul H Sorensen & George Q Daley

Multiple members of the let-7 family of miRNAs are often repressed in human cancers, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature miRNAs, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.

Nature Genetics 41, 849 (2009). doi:10.1038/ng.399

Authors: Feng Zhang, Mehrdad Khajavi, Anne M Connolly, Charles F Towne, Sat Dev Batish & James R Lupski

We recently proposed a DNA replication–based mechanism of fork stalling and template switching (FoSTeS) to explain the complex genomic rearrangements associated with a dysmyelinating central nervous system disorder in humans. The FoSTeS mechanism has been further generalized and molecular mechanistic details have been provided in the microhomology-mediated break-induced replication (MMBIR) model that may underlie many structural variations in genomes from all domains of life. Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR. Furthermore, we show that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. The FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis and exon shuffling, suggesting an important role in both genome and single-gene evolution.

Nature Genetics 41, 854 (2009). doi:10.1038/ng.376

Authors: David A Lyons, Stephen G Naylor, Anja Scholze & William S Talbot

The kinesin motor protein Kif1b has previously been implicated in the axonal transport of mitochondria and synaptic vesicles. More recently, KIF1B has been associated with susceptibility to multiple sclerosis (MS). Here we show that Kif1b is required for the localization of mbp (myelin basic protein) mRNA to processes of myelinating oligodendrocytes in zebrafish. We observe the ectopic appearance of myelin-like membrane in kif1b mutants, coincident with the ectopic localization of myelin proteins in kif1b mutant oligodendrocyte cell bodies. These observations suggest that oligodendrocytes localize certain mRNA molecules, namely those encoding small basic proteins such as MBP, to prevent aberrant effects of these proteins elsewhere in the cell. We also find that Kif1b is required for outgrowth of some of the longest axons in the peripheral and central nervous systems. Our data demonstrate previously unknown functions of kif1b in vivo and provide insights into its possible roles in MS.