Nature Genetics 40, 929 (2008). doi:10.1038/ng0808-929

In association with the Wellcome Trust, we are pleased to announce the second Genomics of Common Diseases conference to be held September 6–9, 2008, in Cambridge, MA, USA.

Nature Genetics 40, 939 (2008). doi:10.1038/ng0808-939

Authors: Colleen M McBride, Sharon Hensley Alford, Robert J Reid, Eric B Larson, Andreas D Baxevanis & Lawrence C Brody

Colleen McBride and colleagues argue that progress on a multifaceted research agenda is necessary to reap the full benefits and avoid the potential pitfalls of the emerging area of personalized genomics. They also outline one element of this agenda, the Multiplex Initiative, which has been underway since 2006.

Nature Genetics 40, 932 (2008). doi:10.1038/ng0808-932

Authors: Marisa S Bartolomei, Sebastien Vigneau & Michael J O'Neill

The linked maternally expressed H19 and paternally expressed Igf2 genes use a CTCF-dependent DNA methylation–sensitive insulator to govern their allele-specific imprinting patterns. Contrary to expectations, a new study shows that the noncoding H19 RNA has a marsupial ortholog and that key features of the locus are similar, indicating that the imprinting regulation of this locus is conserved among therian mammals.

Nature Genetics 40, 934 (2008). doi:10.1038/ng0808-934

Authors: Elizabeth K Bikoff & Elizabeth J Robertson

Developmentally regulated expression of the transcriptional repressor Prdm1 (Blimp1) in the early mammalian embryo controls global epigenetic changes required for specification of primordial germ cells. A new study demonstrates that a close family member, Prdm14, similarly activated in response to Bmp and Smad signals, also has an essential role during establishment of the germ cell lineage.

Nature Genetics 40, 935 (2008). doi:10.1038/ng0808-935

Author: Thomas R Gingeras

Pervasive genome-wide transcription is widespread in eukaryotic cells, but key features of the transcriptome have yet to be fully characterized. A new study using antibody-based detection of RNA-DNA duplexes on tiling arrays now reveals a complex, strand-specific transcriptional world in fission yeast.

Nature Genetics 40, 931 (2008). doi:10.1038/ng0808-931

Authors: Philip J Mason & Monica Bessler

A new study of pigmentation in mice has revealed a surprising link between dark skin and defects in ribosomal proteins. The demonstration that this phenotype is mediated via cell-specific stabilization of p53 suggests insights into the pathogenesis of human diseases such as Diamond-Blackfan anemia caused by similar defects in ribosomal proteins.

Nature Genetics 40, 943 (2008). doi:10.1038/ng.177

Authors: Michael Benzinou, John W M Creemers, Helene Choquet, Stephane Lobbens, Christian Dina, Emmanuelle Durand, Audrey Guerardel, Philippe Boutin, Beatrice Jouret, Barbara Heude, Beverley Balkau, Jean Tichet, Michel Marre, Natascha Potoczna, Fritz Horber, Catherine Le Stunff, Sebastien Czernichow, Annelli Sandbaek, Torsten Lauritzen, Knut Borch-Johnsen, Gitte Andersen, Wieland Kiess, Antje Körner, Peter Kovacs, Peter Jacobson, Lena M S Carlsson, Andrew J Walley, Torben Jørgensen, Torben Hansen, Oluf Pedersen, David Meyre & Philippe Froguel

Nature Genetics 40, 949 (2008). doi:10.1038/ng.187

Authors: Deborah J G Mackay, Jonathan L A Callaway, Sophie M Marks, Helen E White, Carlo L Acerini, Susanne E Boonen, Pinar Dayanikli, Helen V Firth, Judith A Goodship, Andreas P Haemers, Johanne M D Hahnemann, Olga Kordonouri, Ahmed F Masoud, Elsebet Oestergaard, John Storr, Sian Ellard, Andrew T Hattersley, David O Robinson & I Karen Temple

We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

Nature Genetics 40, 952 (2008). doi:10.1038/ng.164

Authors: Michal Pravenec, Paul C Churchill, Monique C Churchill, Ondrej Viklicky, Ludmila Kazdova, Timothy J Aitman, Enrico Petretto, Norbert Hubner, Caroline A Wallace, Heike Zimdahl, Vaclav Zidek, Vladimir Landa, Joseph Dunbar, Anil Bidani, Karen Griffin, Nathan Qi, Martina Maxova, Vladimir Kren, Petr Mlejnek, Jiaming Wang & Theodore W Kurtz

To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension.

Nature Genetics 40, 946 (2008). doi:10.1038/ng.190

Authors: Barbara Schormair, David Kemlink, Darina Roeske, Gertrud Eckstein, Lan Xiong, Peter Lichtner, Stephan Ripke, Claudia Trenkwalder, Alexander Zimprich, Karin Stiasny-Kolster, Wolfgang Oertel, Cornelius G Bachmann, Walter Paulus, Birgit Högl, Birgit Frauscher, Viola Gschliesser, Werner Poewe, Ines Peglau, Pavel Vodicka, Jana Vávrová, Karel Sonka, Sona Nevsimalova, Jacques Montplaisir, Gustavo Turecki, Guy Rouleau, Christian Gieger, Thomas Illig, H-Erich Wichmann, Florian Holsboer, Bertram Müller-Myhsok, Thomas Meitinger & Juliane Winkelmann

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23–24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5′ UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, Pnominal/λ corrected = 5.91 × 10−10, odds ratio (OR) = 1.44; rs1975197, Pnominal/λ corrected = 5.81 × 10−9, OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

Nature Genetics 40, 955 (2008). doi:10.1038/ng.175

Authors: Jeffrey C Barrett, Sarah Hansoul, Dan L Nicolae, Judy H Cho, Richard H Duerr, John D Rioux, Steven R Brant, Mark S Silverberg, Kent D Taylor, M Michael Barmada, Alain Bitton, Themistocles Dassopoulos, Lisa Wu Datta, Todd Green, Anne M Griffiths, Emily O Kistner, Michael T Murtha, Miguel D Regueiro, Jerome I Rotter, L Philip Schumm, A Hillary Steinhart, Stephan R Targan, Ramnik J Xavier, Cécile Libioulle, Cynthia Sandor, Mark Lathrop, Jacques Belaiche, Olivier Dewit, Ivo Gut, Simon Heath, Debby Laukens, Myriam Mni, Paul Rutgeerts, André Van Gossum, Diana Zelenika, Denis Franchimont, Jean-Pierre Hugot, Martine de Vos, Severine Vermeire, Edouard Louis, Lon R Cardon, Carl A Anderson, Hazel Drummond, Elaine Nimmo, Tariq Ahmad, Natalie J Prescott, Clive M Onnie, Sheila A Fisher, Jonathan Marchini, Jilur Ghori, Suzannah Bumpstead, Rhian Gwilliam, Mark Tremelling, Panos Deloukas, John Mansfield, Derek Jewell, Jack Satsangi, Christopher G Mathew, Miles Parkes, Michel Georges & Mark J Daly

Nature Genetics 40, 977 (2008). doi:10.1038/ng.196

Authors: Natalie Dutrow, David A Nix, Derick Holt, Brett Milash, Brian Dalley, Erick Westbroek, Timothy J Parnell & Bradley R Cairns

Nature Genetics 40, 987 (2008). doi:10.1038/ng.195

Authors: Kathryn E Holt, Julian Parkhill, Camila J Mazzoni, Philippe Roumagnac, François-Xavier Weill, Ian Goodhead, Richard Rance, Stephen Baker, Duncan J Maskell, John Wain, Christiane Dolecek, Mark Achtman & Gordon Dougan

Nature Genetics 40, 963 (2008). doi:10.1038/ng.188

Authors: Kelly A McGowan, Jun Z Li, Christopher Y Park, Veronica Beaudry, Holly K Tabor, Amit J Sabnis, Weibin Zhang, Helmut Fuchs, Martin Hrabé de Angelis, Richard M Myers, Laura D Attardi & Gregory S Barsh

Nature Genetics 40, 971 (2008). doi:10.1038/ng.168

Authors: Guillaume Smits, Andrew J Mungall, Sam Griffiths-Jones, Paul Smith, Delphine Beury, Lucy Matthews, Jane Rogers, Andrew J Pask, Geoff Shaw, John L VandeBerg, John R McCarrey, Marilyn B Renfree, Wolf Reik & Ian Dunham

Nature Genetics 40, 994 (2008). doi:10.1038/ng.176

Authors: Yoshinari Miyamoto, Dongquan Shi, Masahiro Nakajima, Kouichi Ozaki, Akihiro Sudo, Akihiro Kotani, Atsumasa Uchida, Toshihiro Tanaka, Naoshi Fukui, Tatsuhiko Tsunoda, Atsushi Takahashi, Yusuke Nakamura, Qing Jiang & Shiro Ikegawa

Susceptibility to osteoarthritis, the most common human arthritis, is known to be influenced by genetic factors. Through a genome-wide association study using ∼100,000 SNPs, we have identified a previously unknown gene on chromosome 3p24.3, DVWA, which is associated with susceptibility to knee osteoarthritis. Expressed specifically in cartilage, DVWA encodes a 276-amino-acid protein with two regions corresponding to the von Willebrand factor type A domain (VWA domain). Several DVWA SNPs are significantly associated with knee osteoarthritis in two independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and a Han Chinese case-control cohort (combined P = 7.3 × 10−11). DVWA protein binds to β-tubulin, and the binding is influenced by two highly associated missense SNPs (rs11718863 and rs7639618) located in the VWA domain. The Tyr169-Cys260 isoform of DVWA, which is overrepresented in knee osteoarthritis, showed weaker interaction. Our findings reveal a new paradigm for study of osteoarthritis etiology and pathogenesis.

Nature Genetics 40, 999 (2008). doi:10.1038/ng.166

Authors: Matthew J Rock, Jean Prenen, Vincent A Funari, Tara L Funari, Barry Merriman, Stanley F Nelson, Ralph S Lachman, William R Wilcox, Soraya Reyno, Roberto Quadrelli, Alicia Vaglio, Grzegorz Owsianik, Annelies Janssens, Thomas Voets, Shiro Ikegawa, Toshiro Nagai, David L Rimoin, Bernd Nilius & Daniel H Cohn

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1–12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4α-phorbol 12,13-didecanoate (4αPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.

Nature Genetics 40, 1004 (2008). doi:10.1038/ng.185

Authors: Gerli Rosengren Pielberg, Anna Golovko, Elisabeth Sundström, Ino Curik, Johan Lennartsson, Monika H Seltenhammer, Thomas Druml, Matthew Binns, Carolyn Fitzsimmons, Gabriella Lindgren, Kaj Sandberg, Roswitha Baumung, Monika Vetterlein, Sara Strömberg, Manfred Grabherr, Claire Wade, Kerstin Lindblad-Toh, Fredrik Pontén, Carl-Henrik Heldin, Johann Sölkner & Leif Andersson

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.

Nature Genetics 40, 1010 (2008). doi:10.1038/ng.179

Authors: Sakura Saburi, Ian Hester, Evelyne Fischer, Marco Pontoglio, Vera Eremina, Manfred Gessler, Sue E Quaggin, Robert Harrison, Richard Mount & Helen McNeill

Tissue organization in Drosophila is regulated by the core planar cell polarity (PCP) proteins Frizzled, Dishevelled, Prickle, Van Gogh and Flamingo. Core PCP proteins are conserved in mammals and function in mammalian tissue organization. Recent studies have identified another group of Drosophila PCP proteins, consisting of the protocadherins Fat and Dachsous (Ds) and the transmembrane protein Four-jointed (Fj). In Drosophila, Fat represses fj transcription, and Ds represses Fat activity in PCP. Here we show that Fat4 is an essential gene that has a key role in vertebrate PCP. Loss of Fat4 disrupts oriented cell divisions and tubule elongation during kidney development, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 and Fjx1 in cyst formation. In addition, Fat4 represses Fjx1 expression, indicating that Fat signaling is conserved. Together, these data suggest that Fat4 regulates vertebrate PCP and that loss of PCP signaling may underlie some cystic diseases in humans.

Nature Genetics 40, 1023 (2008). doi:10.1038/ng.169

Authors: Ayahiko Shomura, Takeshi Izawa, Kaworu Ebana, Takeshi Ebitani, Hiromi Kanegae, Saeko Konishi & Masahiro Yano

The domestication of crops involves a complex process of selection in plant evolution and is associated with changes in the DNA regulating agronomically important traits. Here we report the cloning of a newly identified QTL, qSW5 (QTL for seed width on chromosome 5), involved in the determination of grain width in rice. Through fine mapping, complementation testing and association analysis, we found that a deletion in qSW5 resulted in a significant increase in sink size owing to an increase in cell number in the outer glume of the rice flower; this trait might have been selected by ancient humans to increase yield of rice grains. In addition, we mapped two other defective functional nucleotide polymorphisms of rice domestication-related genes with genome-wide RFLP polymorphisms of various rice landraces. These analyses show that the qSW5 deletion had an important historical role in artificial selection, propagation of cultivation and natural crossings in rice domestication, and shed light on how the rice genome was domesticated.

Nature Genetics 40, 1016 (2008). doi:10.1038/ng.186

Authors: Masashi Yamaji, Yoshiyuki Seki, Kazuki Kurimoto, Yukihiro Yabuta, Mihoko Yuasa, Mayo Shigeta, Kaori Yamanaka, Yasuhide Ohinata & Mitinori Saitou

Specification of germ cell fate is fundamental in development and heredity. Recent evidence indicates that in mice, specification of primordial germ cells (PGCs), the common source of both oocytes and spermatozoa, occurs through the integration of three key events: repression of the somatic program, reacquisition of potential pluripotency and ensuing genome-wide epigenetic reprogramming. Here we provide genetic evidence that Prdm14, a PR domain–containing transcriptional regulator with exclusive expression in the germ cell lineage and pluripotent cell lines, is critical in two of these events, the reacquisition of potential pluripotency and successful epigenetic reprogramming. In Prdm14 mutants, the failure of these two events manifests even in the presence of Prdm1 (also known as Blimp1), a key transcriptional regulator for PGC specification. Our combined evidence demonstrates that Prdm14 defines a previously unknown genetic pathway, initiating independently from Prdm1, for ensuring the launching of the mammalian germ cell lineage.