Hot off the presses! Jan 01

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Latest Articles Include:

• Integrating with integrity
  - Nature genetics 42(1):1 (2010)
  Data worthy of integration with the results of other researchers need to be prepared to explicit export standards, linked to appropriate metadata and offered with field-specific caveats for use. Data exchange may need to be taught and discussed in handshaking workshops.
• No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy
  - Nature genetics 42(1):3 (2010)
  We note the retraction of a paper published in Nature Genetics in 2003, which had reported that mutations in CLCN2 (NCBI Reference Sequence NC_000003.11), the gene encoding the chloride channel ClC-2, were associated with several subtypes of idiopathic generalized epilepsy1.
• Reassessing the abundance of H3K9me2 chromatin domains in embryonic stem cells
  - Nature genetics 42(1):4 (2010)
  In a recent study in Nature Genetics, Wen et al.1 reported the intriguing observation that the human and mouse genomes are organized into large histone H3 lysine 9–dimethylated (H3K9me2) chromatin blocks in various cell types. One of the main conclusions drawn by the authors is that such large domains are minimally present to absent in undifferentiated embryonic stem (ES) cells but arise upon differentiation.
• Reply to "Reassessing the abundance of H3K9me2 chromatin domains in embryonic stem cells"
  - Nature genetics 42(1):5-6 (2010)
  Filion and van Steensel claim that the differentiation-related large organized chromatin K9 modifications (LOCKs) we reported1 are not supported by our microarray data. We disagree, but also note that our conclusions regarding LOCKs were not based on array data alone but also on the many validations and functional experiments described in the paper, including real-time PCR validation, conservation of LOCKs, and genetic knockout of the histone methyltransferase G9a in ES cells and this knockout's influence on gene expression.
• Evolutionary flux of canonical microRNAs and mirtrons in Drosophila
  - Nature genetics 42(1):6-9 (2010)
  Next-generation sequencing technologies generate vast catalogs of short RNA sequences from which to mine microRNAs (miRNAs), which are ~21–24-nucleotide regulatory RNAs derived from RNase III–mediated cleavages of hairpin transcripts. However, such data must be vetted to appropriately categorize miRNA precursors and interpret their evolution.
• Reply to "Evolutionary flux of canonical microRNAs and mirtrons in Drosophila"
  - Nature genetics 42(1):9-10 (2010)
  It has been known for some time that there are many weakly expressed and fast-evolving microRNAs (miRNAs)1, 2, 3, 4, 5, 6. After analyzing more than 100,000 reads of small RNAs obtained from Drosophila heads, we suggested that most of these miRNAs were born and then died with the evolutionary dynamics of neutrally evolving sequences7.
• Exome sequencing makes medical genomics a reality
  - Nature genetics 42(1):13-14 (2010)
  Massively parallel sequencing of the exomes of four individuals with Miller syndrome, combined with filtering to exclude benign and unrelated variants, has identified causative mutations in DHODH. This approach will accelerate discovery of the genetic bases of hundreds of other rare mendelian disorders.
• Lung function and airway diseases
  - Nature genetics 42(1):14-16 (2010)
  Two studies report genome-wide association studies for lung function, using cross-sectional spirometric measurements in healthy individuals. They identify six genetic loci newly associated to natural variation in lung function, which may have implications for the related airway diseases of asthma and chronic obstructive pulmonary disease.
• Getting connected in the globin interactome
  - Nature genetics 42(1):16-17 (2010)
  A new study provides compelling evidence that transcriptional regulation and three-dimensional genomic architecture are linked. The alpha- and beta-globin loci associate with hundreds of active genes across the genome at transcription factories in erythroid cells, and specialized Klf1-containing transcription factories mediate the association of Klf1-regulated genes.
• Research highlights
  - Nature genetics 42(1):19 (2010)
  
• Variant in PNPLA3 is associated with alcoholic liver disease
  Tian C Stokowski RP Kershenobich D Ballinger DG Hinds DA - Nature genetics 42(1):21-23 (2010)
  Two genome-wide association studies (GWAS) have described associations of variants in PNPLA3 with nonalcoholic fatty liver and plasma liver enzyme levels. We investigated the contributions of these variants to liver disease in Mestizo subjects with a history of alcohol dependence. We found that rs738409 in PNPLA3 is strongly associated with alcoholic liver disease and clinically evident alcoholic cirrhosis (unadjusted OR= 2.25, P=1.7 × 10−10; ancestry-adjusted OR=1.79, P=1.9 × 10−5).
• Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate
  Mangold E Ludwig KU Birnbaum S Baluardo C Ferrian M Herms S Reutter H de Assis NA Chawa TA Mattheisen M Steffens M Barth S Kluck N Paul A Becker J Lauster C Schmidt G Braumann B Scheer M Reich RH Hemprich A Pötzsch S Blaumeiser B Moebus S Krawczak M Schreiber S Meitinger T Wichmann HE Steegers-Theunissen RP Kramer FJ Cichon S Propping P Wienker TF Knapp M Rubini M Mossey PA Hoffmann P Nöthen MM - Nature genetics 42(1):24-26 (2010)
  We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10−8, relative risk in homozygotes = 1.84, 95% CI 1.34–2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10−8, relative risk in homozygotes = 2.17, 95% CI 1.32–3.56).
• A restricted spectrum of NRAS mutations causes Noonan syndrome
  Cirstea IC Kutsche K Dvorsky R Gremer L Carta C Horn D Roberts AE Lepri F Merbitz-Zahradnik T König R Kratz CP Pantaleoni F Dentici ML Joshi VA Kucherlapati RS Mazzanti L Mundlos S Patton MA Silengo MC Rossi C Zampino G Digilio C Stuppia L Seemanova E Pennacchio LA Gelb BD Dallapiccola B Wittinghofer A Ahmadian MR Tartaglia M Zenker M - Nature genetics 42(1):27-29 (2010)
  Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.
• Exome sequencing identifies the cause of a mendelian disorder
  Ng SB Buckingham KJ Lee C Bigham AW Tabor HK Dent KM Huff CD Shannon PT Jabs EW Nickerson DA Shendure J Bamshad MJ - Nature genetics 42(1):30-35 (2010)
  We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40× and sufficient depth to call variants at ~97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.
• Genome-wide association study identifies five loci associated with lung function
  Repapi E Sayers I Wain LV Burton PR Johnson T Obeidat M Zhao JH Ramasamy A Zhai G Vitart V Huffman JE Igl W Albrecht E Deloukas P Henderson J Granell R McArdle WL Rudnicka AR Wellcome Trust Case Control Consortium Barroso I Loos RJ Wareham NJ Mustelin L Rantanen T Surakka I Imboden M Wichmann HE Grkovic I Jankovic S Zgaga L Hartikainen AL Peltonen L Gyllensten U Johansson A Zaboli G Campbell H Wild SH Wilson JF Gläser S Homuth G Völzke H Mangino M Soranzo N Spector TD Polašek O Rudan I Wright AF Heliövaara M Ripatti S Pouta A Naluai AT Olin AC Torén K Cooper MN James AL Palmer LJ Hingorani AD Wannamethee SG Whincup PH Smith GD Ebrahim S McKeever TM Pavord ID Macleod AK Morris AD Porteous DJ Cooper C Dennison E Shaheen S Karrasch S Schnabel E Schulz H Grallert H Bouatia-Naji N Delplanque J Froguel P Blakey JD The NSHD Respiratory Study Team Britton JR Morris RW Holloway JW Lawlor DA Hui J Nyberg F Jarvelin MR Jackson C Kähönen M Kaprio J Probst-Hensch NM Koch B Hayward C Evans DM Elliott P Strachan DP Hall IP Tobin MD - Nature genetics 42(1):36-44 (2010)
  Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung t! issue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
• Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function
  Hancock DB Eijgelsheim M Wilk JB Gharib SA Loehr LR Marciante KD Franceschini N van Durme YM Chen TH Barr RG Schabath MB Couper DJ Brusselle GG Psaty BM van Duijn CM Rotter JI Uitterlinden AG Hofman A Punjabi NM Rivadeneira F Morrison AC Enright PL North KE Heckbert SR Lumley T Stricker BH O'Connor GT London SJ - Nature genetics 42(1):45-52 (2010)
  Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV1/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV1 (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 × 10−8) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
• Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells
  Schoenfelder S Sexton T Chakalova L Cope NF Horton A Andrews S Kurukuti S Mitchell JA Umlauf D Dimitrova DS Eskiw CH Luo Y Wei CL Ruan Y Bieker JJ Fraser P - Nature genetics 42(1):53-61 (2010)
  The discovery of interchromosomal interactions in higher eukaryotes points to a functional interplay between genome architecture and gene expression, challenging the view of transcription as a one-dimensional process. However, the extent of interchromosomal interactions and the underlying mechanisms are unknown. Here we present the first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues. Our results show that the active globin genes associate with hundreds of other transcribed genes, revealing extensive and preferential intra- and interchromosomal transcription interactomes. We show that the transcription factor Klf1 mediates preferential co-associations of Klf1-regulated genes at a limited number of specialized transcription factories. Our results establish a new gene expression paradigm, implying that active co-regulated genes and their regulatory factors cooperate to create specialized nuclear hot spots optimized ! for efficient and coordinated transcriptional control.
• Geographical genomics of human leukocyte gene expression variation in southern Morocco
  Idaghdour Y Czika W Shianna KV Lee SH Visscher PM Martin HC Miclaus K Jadallah SJ Goldstein DB Wolfinger RD Gibson G - Nature genetics 42(1):62-67 (2010)
  Studies of the genetics of gene expression can identify expression SNPs (eSNPs) that explain variation in transcript abundance. Here we address the robustness of eSNP associations to environmental geography and population structure in a comparison of 194 Arab and Amazigh individuals from a city and two villages in southern Morocco. Gene expression differed between pairs of locations for up to a third of all transcripts, with notable enrichment of transcripts involved in ribosomal biosynthesis and oxidative phosphorylation. Robust associations were observed in the leukocyte samples: cis eSNPs (P < 10−08) were identified for 346 genes, and trans eSNPs (P < 10−11) for 10 genes. All of these associations were consistent both across the three sample locations and after controlling for ancestry and relatedness. No evidence of large-effect trans-acting mediators of the pervasive environmental influence was found; instead, genetic and environmental factors acted in a large! ly additive manner.
• The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes
  Wallace C Smyth DJ Maisuria-Armer M Walker NM Todd JA Clayton DG - Nature genetics 42(1):68-71 (2010)
  Genome-wide association (GWA) studies to map common disease susceptibility loci have been hugely successful, with over 300 reproducibly associated loci reported to date1. However, these studies have not yet provided convincing evidence for any susceptibility locus subject to parent-of-origin effects. Using imputation to extend existing GWA datasets2, 3, 4, we have obtained robust evidence at rs941576 for paternally inherited risk of type 1 diabetes (T1D; ratio of allelic effects for paternal versus maternal transmissions = 0.75; 95% confidence interval (CI) = 0.71–0.79). This marker is in the imprinted region of chromosome 14q32.2, which contains the functional candidate gene DLK1. Our meta-analysis also provided support at genome-wide significance for a T1D locus at chromosome 19p13.2. The highest association was at marker rs2304256 (odds ratio (OR) = 0.86; 95%CI = 0.82–0.90) in the TYK2 gene, which has previously been associated with systemic lupus erythematosus5! and multiple sclerosis6.
• Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis
  Brown EJ Schlöndorff JS Becker DJ Tsukaguchi H Uscinski AL Higgs HN Henderson JM Pollak MR - Nature genetics 42(1):72-76 (2010)
  Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified that, when mutated, lead to inherited FSGS and/or the related nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal-dominant FSGS susceptibility on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues. The observation that alterations in this podocyte-expressed formin cause FSGS e! mphasizes the importance of fine regulation of actin polymerization in podocyte function.
• Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies
  Veeriah S Taylor BS Meng S Fang F Yilmaz E Vivanco I Janakiraman M Schultz N Hanrahan AJ Pao W Ladanyi M Sander C Heguy A Holland EC Paty PB Mischel PS Liau L Cloughesy TF Mellinghoff IK Solit DB Chan TA - Nature genetics 42(1):77-82 (2010)
  Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease1, 2, 3. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altere! d in non-neuronal somatic cells.
• Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/− mice
  Wang H Bauzon F Ji P Xu X Sun D Locker J Sellers RS Nakayama K Nakayama KI Cobrinik D Zhu L - Nature genetics 42(1):83-88 (2010)
  Heterozygosity of the retinoblastoma gene Rb1 elicits tumorigenesis in susceptible tissues following spontaneous loss of the remaining functional allele. Inactivation of previously studied retinoblastoma protein (pRb) targets partially inhibited tumorigenesis in Rb1+/− mice1, 2, 3, 4, 5, 6. Here we report that inactivation of pRb target Skp2 (refs. 7,8) completely prevents spontaneous tumorigenesis in Rb1+/− mice. Targeted Rb1 deletion in melanotrophs ablates the entire pituitary intermediate lobe when Skp2 is inactivated. Skp2 inactivation does not inhibit aberrant proliferation of Rb1-deleted melanotrophs but induces their apoptotic death. Eliminating p27 phosphorylation on T187 in p27T187A knock-in mice reproduces the effects of Skp2 knockout, identifying p27 ubiquitination by SCFSkp2 ubiquitin ligase as the underlying mechanism for Skp2's essential tumorigenic role in this setting. RB1-deficient human retinoblastoma cells also undergo apoptosis after Skp2 knock! down; and ectopic expression of p27, especially the p27T187A mutant, induces apoptosis. These results reveal that Skp2 becomes an essential survival gene when susceptible cells incur Rb1 deficiency.
• Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin
  Martínez-Estrada OM Lettice LA Essafi A Guadix JA Slight J Velecela V Hall E Reichmann J Devenney PS Hohenstein P Hosen N Hill RE Muñoz-Chapuli R Hastie ND - Nature genetics 42(1):89-93 (2010)
  The epicardial epithelial-mesenchymal transition (EMT) is hypothesized to generate cardiovascular progenitor cells that differentiate into various cell types, including coronary smooth muscle and endothelial cells, perivascular and cardiac interstitial fibroblasts and cardiomyocytes. Here we show that an epicardial-specific knockout of the gene encoding Wilms' tumor-1 (Wt1) leads to a reduction in mesenchymal progenitor cells and their derivatives. We show that Wt1 is essential for repression of the epithelial phenotype in epicardial cells and during embryonic stem cell differentiation through direct transcriptional regulation of the genes encoding Snail (Snai1) and E-cadherin (Cdh1), two of the major mediators of EMT. Some mesodermal lineages do not form in Wt1-null embryoid bodies, but this effect is rescued by the expression of Snai1, underscoring the importance of EMT in generating these differentiated cells. These new insights into the molecular mechanisms regulat! ing cardiovascular progenitor cells and EMT will shed light on the pathogenesis of heart diseases and may help the development of cell-based therapies.