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Latest Articles Include:

• Twelve lords a-leaping
  - Nat Genet 41(9):953 (2009)
  The UK House of Lords Science and Technology Committee reports that genomic medicine is already in practice but needs a coordinated set of infrastructural and training systems to allow the healthcare system to cope.
• CLCN2 variants in idiopathic generalized epilepsy
  Kleefuss-Lie A Friedl W Cichon S Haug K Warnstedt M Alekov A Sander T Ramirez A Poser B Maljevic S Hebeisen S Kubisch C Rebstock J Horvath S Hallmann K Dullinger JS Rau B Haverkamp F Beyenburg S Schulz H Janz D Giese B Müller-Newen G Propping P Elger CE Fahlke C Lerche H - Nat Genet 41(9):954-955 (2009)
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• Inherited susceptibility to pediatric acute lymphoblastic leukemia
  Levine RL - Nat Genet 41(9):957-958 (2009)
  Although genome-wide analyses have identified somatic alterations contributing to the pathogenesis of pediatric acute lymphoblastic leukemia (ALL), few studies have identified germline variants conferring risk of this disease. Two reports now provide the first genome-wide glimpse into the role of inherited alleles in ALL pathogenesis.
• Closing the gap between genotype and phenotype
  Gregersen PK - Nat Genet 41(9):958-959 (2009)
  Making causative connections between genotypic and phenotypic variation is a major challenge for geneticists engaged in the study of human disease. A study drawing this connection for a type 1 diabetes risk locus now demonstrates the importance of focusing on specific quantitative traits and studying them in normal subjects.
• An uphill battle toward pluripotency
  Graf T - Nat Genet 41(9):960-961 (2009)
  The discovery that a cocktail of transcription factors can reprogram somatic cells into induced pluripotent stem (iPS) cells keeps revealing new secrets of cell fate specification. A new study with hematopoietic cells shows that progenitor cells are far more susceptible than differentiated cells to reprogramming.
• Research Highlights
  - Nat Genet 41(9):962 (2009)
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• Genomic privacy and limits of individual detection in a pool
  Sankararaman S Obozinski G Jordan MI Halperin E - Nat Genet 41(9):965-967 (2009)
  Recent studies have demonstrated that statistical methods can be used to detect the presence of a single individual within a study group based on summary data reported from genome-wide association studies (GWAS). We present an analytical and empirical study of the statistical power of such methods. We thereby aim to provide quantitative guidelines for researchers wishing to make a limited number of SNPs available publicly without compromising subjects' privacy.
• Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells
  Eminli S Foudi A Stadtfeld M Maherali N Ahfeldt T Mostoslavsky G Hock H Hochedlinger K - Nat Genet 41(9):968-976 (2009)
  The reprogramming of somatic cells into induced pluripotent stem (iPS) cells upon overexpression of the transcription factors Oct4, Sox2, Klf4 and cMyc is inefficient. It has been assumed that the somatic differentiation state provides a barrier for efficient reprogramming; however, direct evidence for this notion is lacking. Here, we tested the potential of mouse hematopoietic cells at different stages of differentiation to be reprogrammed into iPS cells. We show that hematopoietic stem and progenitor cells give rise to iPS cells up to 300 times more efficiently than terminally differentiated B and T cells do, yielding reprogramming efficiencies of up to 28%. Our data provide evidence that the differentiation stage of the starting cell has a critical influence on the efficiency of reprogramming into iPS cells. Moreover, we identify hematopoietic progenitors as an attractive cell type for applications of iPS cell technology in research and therapy.
• Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak
  Suriben R Kivimäe S Fisher DA Moon RT Cheyette BN - Nat Genet 41(9):977-985 (2009)
  Mice homozygous for mutations in Dact1 (also called Dapper or Frodo) phenocopy human malformations involving the spine, genitourinary system and distal digestive tract. We traced this phenotype to disrupted germ-layer morphogenesis at the primitive streak. Notably, heterozygous mutation of Vangl2, a transmembrane component of the planar cell polarity (PCP) pathway, rescued recessive Dact1 phenotypes, whereas loss of Dact1 reciprocally rescued semidominant Vangl2 phenotypes. We show that Dact1, an intracellular protein, forms a complex with Vangl2. In Dact1 mutants, Vangl2 was increased at the primitive streak, where cells ordinarily undergo an epithelial–mesenchymal transition. This is associated with abnormal E-cadherin distribution and changes in biochemical measures of the PCP pathway. We conclude that Dact1 contributes to morphogenesis at the primitive streak by regulating Vangl2 upstream of cell adhesion and the PCP pathway.
• Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer
  Amundadottir L Kraft P Stolzenberg-Solomon RZ Fuchs CS Petersen GM Arslan AA Bueno-de-Mesquita HB Gross M Helzlsouer K Jacobs EJ LaCroix A Zheng W Albanes D Bamlet W Berg CD Berrino F Bingham S Buring JE Bracci PM Canzian F Clavel-Chapelon F Clipp S Cotterchio M de Andrade M Duell EJ Fox JW Gallinger S Gaziano JM Giovannucci EL Goggins M González CA Hallmans G Hankinson SE Hassan M Holly EA Hunter DJ Hutchinson A Jackson R Jacobs KB Jenab M Kaaks R Klein AP Kooperberg C Kurtz RC Li D Lynch SM Mandelson M McWilliams RR Mendelsohn JB Michaud DS Olson SH Overvad K Patel AV Peeters PH Rajkovic A Riboli E Risch HA Shu XO Thomas G Tobias GS Trichopoulos D Van Den Eeden SK Virtamo J Wactawski-Wende J Wolpin BM Yu H Yu K Zeleniuch-Jacquotte A Chanock SJ Hartge P Hoover RN - Nat Genet 41(9):986-990 (2009)
  We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 10-8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.
• Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer
  Wu X Ye Y Kiemeney LA Sulem P Rafnar T Matullo G Seminara D Yoshida T Saeki N Andrew AS Dinney CP Czerniak B Zhang ZF Kiltie AE Bishop DT Vineis P Porru S Buntinx F Kellen E Zeegers MP Kumar R Rudnai P Gurzau E Koppova K Mayordomo JI Sanchez M Saez B Lindblom A de Verdier P Steineck G Mills GB Schned A Guarrera S Polidoro S Chang SC Lin J Chang DW Hale KS Majewski T Grossman HB Thorlacius S Thorsteinsdottir U Aben KK Witjes JA Stefansson K Amos CI Karagas MR Gu J - Nat Genet 41(9):991-995 (2009)
  We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 10-10 and the allelic odds ratio was 1.15 (95% confidence interval 1.10–1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
• A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2
  Song H Ramus SJ Tyrer J Bolton KL Gentry-Maharaj A Wozniak E Anton-Culver H Chang-Claude J Cramer DW DiCioccio R Dörk T Goode EL Goodman MT Schildkraut JM Sellers T Baglietto L Beckmann MW Beesley J Blaakaer J Carney ME Chanock S Chen Z Cunningham JM Dicks E Doherty JA Dürst M Ekici AB Fenstermacher D Fridley BL Giles G Gore ME De Vivo I Hillemanns P Hogdall C Hogdall E Iversen ES Jacobs IJ Jakubowska A Li D Lissowska J Lubiński J Lurie G McGuire V McLaughlin J Medrek K Moorman PG Moysich K Narod S Phelan C Pye C Risch H Runnebaum IB Severi G Southey M Stram DO Thiel FC Terry KL Tsai YY Tworoger SS Van Den Berg DJ Vierkant RA Wang-Gohrke S Webb PM Wilkens LR Wu AH Yang H Brewster W Ziogas A Australian Cancer (Ovarian) Study Australian Ovarian Cancer Study Group Ovarian Cancer Association Consortium Houlston R Tomlinson I Whittemore AS Rossing MA Ponder BA Pearce CL Ness RB Menon U Kjaer SK Gronwald J Garcia-Closas M Fasching PA Easton DF Chenevix-Trench G Berchuck A Pharoah PD Gayther SA - Nat Genet 41(9):996-1000 (2009)
  Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk1. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and 2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10-8). The most significant SNP (rs3814113; P = 2.5 10-17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 10-19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 10-21).
• Germline genomic variants associated with childhood acute lymphoblastic leukemia
  Treviño LR Yang W French D Hunger SP Carroll WL Devidas M Willman C Neale G Downing J Raimondi SC Pui CH Evans WE Relling MV - Nat Genet 41(9):1001-1005 (2009)
  Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 10-5) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 10-15, odds ratio (OR) = 1.91; rs10994982, P = 5.7 10-9, OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 10-5, OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n = 124 children with ALL; P = 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes.
• Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia
  Papaemmanuil E Hosking FJ Vijayakrishnan J Price A Olver B Sheridan E Kinsey SE Lightfoot T Roman E Irving JA Allan JM Tomlinson IP Taylor M Greaves M Houlston RS - Nat Genet 41(9):1006-1010 (2009)
  To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 10-19), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 10-19) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 10-7). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.
• Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource
  Dendrou CA Plagnol V Fung E Yang JH Downes K Cooper JD Nutland S Coleman G Himsworth M Hardy M Burren O Healy B Walker NM Koch K Ouwehand WH Bradley JR Wareham NJ Todd JA Wicker LS - Nat Genet 41(9):1011-1015 (2009)
  Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases1. However, identifying causal genes within an associated region remains a major challenge1, 2. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis2, 3, 4. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectab! le normal donors from whom fresh, primary cells can be analyzed.
• Mutations in PYCR1 cause cutis laxa with progeroid features
  Reversade B Escande-Beillard N Dimopoulou A Fischer B Chng SC Li Y Shboul M Tham PY Kayserili H Al-Gazali L Shahwan M Brancati F Lee H O'Connor BD Schmidt-von Kegler M Merriman B Nelson SF Masri A Alkazaleh F Guerra D Ferrari P Nanda A Rajab A Markie D Gray M Nelson J Grix A Sommer A Savarirayan R Janecke AR Steichen E Sillence D Hausser I Budde B Nürnberg G Nürnberg P Seemann P Kunkel D Zambruno G Dallapiccola B Schuelke M Robertson S Hamamy H Wollnik B Van Maldergem L Mundlos S Kornak U - Nat Genet 41(9):1016-1021 (2009)
  Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation1, 2, 3. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.
• Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair
  Cordeddu V Di Schiavi E Pennacchio LA Ma'ayan A Sarkozy A Fodale V Cecchetti S Cardinale A Martin J Schackwitz W Lipzen A Zampino G Mazzanti L Digilio MC Martinelli S Flex E Lepri F Bartholdi D Kutsche K Ferrero GB Anichini C Selicorni A Rossi C Tenconi R Zenker M Merlo D Dallapiccola B Iyengar R Bazzicalupo P Gelb BD Tartaglia M - Nat Genet 41(9):1022-1026 (2009)
  N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue1, 2. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat–containing protein that positively modulates RAS-MAPK signal flow3, 4, 5, 6, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721)7 shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2S2Gin vitro enhanced MAPK activation in a cell type–specific fashion. Induction of SHOC2S2G in Caenorhabditis elegans engendered protru! ding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.
• INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse
  Jacoby M Cox JJ Gayral S Hampshire DJ Ayub M Blockmans M Pernot E Kisseleva MV Compère P Schiffmann SN Gergely F Riley JH Pérez-Morga D Woods CG Schurmans S - Nat Genet 41(9):1027-1031 (2009)
  The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing1, 2, 3. Here, we report that mice deficient for the lipid 5-phosphatase Inpp5e develop a multiorgan disorder associated with structural defects of the primary cilium. In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. Inpp5e inactivation did not impair ciliary assembly but altered the stability of pre-established cilia after serum addition. Blocking phosphoinositide 3-kinase (PI3K) activity or ciliary platelet-derived growth factor receptor (PDGFR) restored ciliary stability. In human INPP5E, we identified a mutation affecting INPP5E ciliary localization and cilium stability in a family with MORM syndrome, a condition related to Bardet-Biedl syndrome. Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ! ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction.
• Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies
  Bielas SL Silhavy JL Brancati F Kisseleva MV Al-Gazali L Sztriha L Bayoumi RA Zaki MS Abdel-Aleem A Rosti RO Kayserili H Swistun D Scott LC Bertini E Boltshauser E Fazzi E Travaglini L Field SJ Gayral S Jacoby M Schurmans S Dallapiccola B Majerus PW Valente EM Gleeson JG - Nat Genet 41(9):1032-1036 (2009)
  Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly2 and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data ! link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.
• FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation
  Aldinger KA Lehmann OJ Hudgins L Chizhikov VV Bassuk AG Ades LC Krantz ID Dobyns WB Millen KJ - Nat Genet 41(9):1037-1042 (2009)
  Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus1, 2. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alon! e causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.
• Retraction: Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies
  Haug K Warnstedt M Alekov AK Sander T Ramírez A Poser B Maljevic S Hebeisen S Kubisch C Rebstock J Horvath S Hallmann K Dullinger JS Rau B Haverkamp F Beyenburg S Schulz H Janz D Giese B Müller-Newen G Propping P Elger CE Fahlke C Lerche H Heils A - Nat Genet 41(9):1043 (2009)
  Introduction Nat. Genet. 33, 527–532 (2003); published online 3 March 2003 Re-examination of the families and the molecular genetic data by a neurologist and a geneticist who were not involved in the original study has revealed major differences from the published data in two of the three published pedigrees (presented in Figs. 1a,b of the original publication). The number of clinically affected individuals was much lower than was previously reported, and large parts of the pedigree structures and epilepsy phenotypes are different. Most importantly, re-examination revealed the existence of several asymptomatic mutation carriers, refuting the complete co-segregation of the two mutations with the clinical phenotypes that was originally reported. A detailed description of these differences, including the clinical phenotypes and the genetic reanalysis, is provided in the related Correspondence in this issue1. We sincerely regret our failure to recognize that important family data were false before the original manuscript was published, and we apologize for any inconvenience that may have arisen as a result of our report. A. Heils did not agree to coauthor this retraction.