Hot off the presses! Aug 27 Neuron

The Aug 27 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Location Matters: Synaptotagmin Helps Place Vesicles Near Calcium Channels
  McNeil BD Wu LG - Neuron 63(4):419-421 (2009)
  Positioning releasable vesicles near voltage-gated calcium channels may ensure transmitter release upon calcium influx. Disruption of vesicle positioning may underlie short-term synaptic depression. However, how this positioning is achieved is unclear. In this issue of Neuron, Young and Neher find that synaptotagmin 2 helps to align readily releasable vesicles near calcium channels at nerve terminals.
• Imagining the Possibilities: Ripples, Routes, and Reactivation
  Knierim JJ - Neuron 63(4):421-423 (2009)
  Hippocampal place cells fire selectively when a rat occupies a particular location. Under certain conditions, the cells briefly represent trajectories along locations away from the rat's current location. New results lend important insight into this phenomenon and demonstrate spatiotemporally coherent, cognitive representations that are independent of current sensory input.
• Harnessing Chaos in Recurrent Neural Networks
  Buonomano DV - Neuron 63(4):423-425 (2009)
  In this issue of Neuron, Sussillo and Abbott describe a new learning rule that helps harness the computational power of recurrent neural networks.
• The Neurobiological Basis of Posttraumatic Stress Disorder and Its Treatment
  - Neuron 63(4):426-428 (2009)
  
• Supraresolution Imaging in Brain Slices using Stimulated-Emission Depletion Two-Photon Laser Scanning Microscopy
  Ding JB Takasaki KT Sabatini BL - Neuron 63(4):429-437 (2009)
  Two-photon laser scanning microscopy (2PLSM) has allowed unprecedented fluorescence imaging of neuronal structure and function within neural tissue. However, the resolution of this approach is poor compared to that of conventional confocal microscopy. Here, we demonstrate supraresolution 2PLSM within brain slices. Imaging beyond the diffraction limit is accomplished by using near-infrared (NIR) lasers for both pulsed two-photon excitation and continuous wave stimulated emission depletion (STED). Furthermore, we demonstrate that Alexa Fluor 594, a bright fluorophore commonly used for both live cell and fixed tissue fluorescence imaging, is suitable for STED 2PLSM. STED 2PLSM supraresolution microscopy achieves approximately 3-fold improvement in resolution in the radial direction over conventional 2PLSM, revealing greater detail in the structure of dendritic spines located 100 microns below the surface of brain slices. Further improvements in resolution are theoreticall! y achievable, suggesting that STED 2PLSM will permit nanoscale imaging of neuronal structures located in relatively intact brain tissue.
• Spontaneous Generation of Prion Infectivity in Fatal Familial Insomnia Knockin Mice
  Jackson WS Borkowski AW Faas H Steele AD King OD Watson N Jasanoff A Lindquist S - Neuron 63(4):438-450 (2009)
  A crucial tenet of the prion hypothesis is that misfolding of the prion protein (PrP) induced by mutations associated with familial prion disease is, in an otherwise normal mammalian brain, sufficient to generate the infectious agent. Yet this has never been demonstrated. We engineered knockin mice to express a PrP mutation associated with a distinct human prion disease, fatal familial insomnia (FFI). An additional substitution created a strong transmission barrier against pre-existing prions. The mice spontaneously developed a disease distinct from that of other mouse prion models and highly reminiscent of FFI. Unique pathology was transmitted from FFI mice to mice expressing wild-type PrP sharing the same transmission barrier. FFI mice were highly resistant to infection by pre-existing prions, confirming infectivity did not arise from contaminating agents. Thus, a single amino acid change in PrP is sufficient to induce a distinct neurodegenerative disease and the spo! ntaneous generation of prion infectivity.
• Distinct Temporal Requirements for the Homeobox Gene Gsx2 in Specifying Striatal and Olfactory Bulb Neuronal Fates
  Waclaw RR Wang B Pei Z Ehrman LA Campbell K - Neuron 63(4):451-465 (2009)
  The homeobox gene Gsx2 (formerly Gsh2) is known to be required for striatal and olfactory bulb neurogenesis; however, its specific role in the specification of these two neuronal subtypes remains unclear. To address this, we have employed a temporally regulated gain-of-function approach in transgenic mice and found that misexpression of Gsx2 at early stages of telencephalic neurogenesis favors the specification of striatal projection neuron identity over that of olfactory bulb interneurons. In contrast, delayed activation of the Gsx2 transgene until later stages exclusively promotes olfactory bulb interneuron identity. In a complementary approach, we have conditionally inactivated Gsx2 in a temporally progressive manner. Unlike germline Gsx2 mutants, which exhibit severe alterations in both striatal and olfactory bulb neurogenesis at birth, the conditional mutants exhibited defects restricted to olfactory bulb interneurons. These results demonstrate that Gsx2 specifies! striatal projection neuron and olfactory bulb interneuron identity at distinct time points during telencephalic neurogenesis.
• The Cell-Intrinsic Requirement of Sox6 for Cortical Interneuron Development
  Batista-Brito R Rossignol E Hjerling-Leffler J Denaxa M Wegner M Lefebvre V Pachnis V Fishell G - Neuron 63(4):466-481 (2009)
  We describe the role of Sox6 in cortical interneuron development, from a cellular to a behavioral level. We identify Sox6 as a protein expressed continuously within MGE-derived cortical interneurons from postmitotic progenitor stages into adulthood. Both its expression pattern and null phenotype suggests that Sox6 gene function is closely linked to that of Lhx6. In both Lhx6 and Sox6 null animals, the expression of PV and SST and the position of both basket and Martinotti neurons are abnormal. We find that Sox6 functions downstream ofLhx6. Electrophysiological analysis of Sox6 mutant cortical interneurons revealed that basket cells, even when mispositioned, retain characteristic but immature fast-spiking physiological features. Our data suggest that Sox6 is not required for the specification of MGE-derived cortical interneurons. It is, however, necessary for their normal positioning and maturation. As a consequence, the specific removal of Sox6 from this population res! ults in a severe epileptic encephalopathy.
• Synaptotagmin Has an Essential Function in Synaptic Vesicle Positioning for Synchronous Release in Addition to Its Role as a Calcium Sensor
  Young SM Neher E - Neuron 63(4):482-496 (2009)
  A multitude of synaptic proteins interact at the active zones of nerve terminals to achieve the high temporal precision of neurotransmitter release in synchrony with action potentials. Though synaptotagmin has been recognized as the Ca2+ sensor for synchronous release, it may have additional roles of action. We address this question at the calyx of Held, a giant presynaptic terminal, that allows biophysical dissection of multiple roles of molecules in synaptic transmission. Using high-level expression recombinant adenoviruses, in conjunction with a stereotactic surgery in postnatal day 1 rats, we overcame the previous inability to moleculary perturb the calyx by overexpression of a mutated synaptotagmin. We report that this mutation leaves intrinsic Ca2+ sensitivity of vesicles intact while it destabilizes the readily releasable pool of vesicles and loosens the tight coupling between Ca2+ influx and release, most likely by interfering with the correct positioning of ve! sicles with respect to Ca2+ channels.
• Hippocampal Replay of Extended Experience
  Davidson TJ Kloosterman F Wilson MA - Neuron 63(4):497-507 (2009)
  During pauses in exploration, ensembles of place cells in the rat hippocampus re-express firing sequences corresponding to recent spatial experience. Such "replay" co-occurs with ripple events: short-lasting (50–120 ms), high-frequency (200 Hz) oscillations that are associated with increased hippocampal-cortical communication. In previous studies, rats exploring small environments showed replay anchored to the rat's current location and compressed in time into a single ripple event. Here, we show, using a neural decoding approach, that firing sequences corresponding to long runs through a large environment are replayed with high fidelity and that such replay can begin at remote locations on the track. Extended replay proceeds at a characteristic virtual speed of 8 m/s and remains coherent across trains of ripple events. These results suggest that extended replay is composed of chains of shorter subsequences, which may reflect a strategy for the storage and flexib! le expression of memories of prolonged experience.
• Direct Activation of Sparse, Distributed Populations of Cortical Neurons by Electrical Microstimulation
  Histed MH Bonin V Reid RC - Neuron 63(4):508-522 (2009)
  For over a century, electrical microstimulation has been the most direct method for causally linking brain function with behavior. Despite this long history, it is still unclear how the activity of neural populations is affected by stimulation. For example, there is still no consensus on where activated cells lie or on the extent to which neural processes such as passing axons near the electrode are also activated. Past studies of this question have proven difficult because microstimulation interferes with electrophysiological recordings, which in any case provide only coarse information about the location of activated cells. We used two-photon calcium imaging, an optical method, to circumvent these hurdles. We found that microstimulation sparsely activates neurons around the electrode, sometimes as far as millimeters away, even at low currents. Our results indicate that the pattern of activated neurons likely arises from the direct activation of axons in a volume tens! of microns in diameter.
• MT Neurons Combine Visual Motion with a Smooth Eye Movement Signal to Code Depth-Sign from Motion Parallax
  Nadler JW Nawrot M Angelaki DE DeAngelis GC - Neuron 63(4):523-532 (2009)
  The capacity to perceive depth is critical for an observer to interact with his or her surroundings. During observer movement, information about depth can be extracted from the resulting patterns of image motion on the retina (motion parallax). Without extraretinal signals related to observer movement, however, depth-sign (near versus far) from motion parallax can be ambiguous. We previously demonstrated that MT neurons combine visual motion with extraretinal signals to code depth-sign from motion parallax in the absence of other depth cues. In that study, head translations were always accompanied by compensatory tracking eye movements, allowing at least two potential sources of extraretinal input. We now show that smooth eye movement signals provide the critical extraretinal input to MT neurons for computing depth-sign from motion parallax. Our findings demonstrate a powerful modulation of MT activity by eye movements, as predicted by human studies of depth perception! from motion parallax.
• Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia
  Eippert F Bingel U Schoell ED Yacubian J Klinger R Lorenz J Büchel C - Neuron 63(4):533-543 (2009)
  Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-mo! dulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.
• Generating Coherent Patterns of Activity from Chaotic Neural Networks
  Sussillo D Abbott LF - Neuron 63(4):544-557 (2009)
  Neural circuits display complex activity patterns both spontaneously and when responding to a stimulus or generating a motor output. How are these two forms of activity related? We develop a procedure called FORCE learning for modifying synaptic strengths either external to or within a model neural network to change chaotic spontaneous activity into a wide variety of desired activity patterns. FORCE learning works even though the networks we train are spontaneously chaotic and we leave feedback loops intact and unclamped during learning. Using this approach, we construct networks that produce a wide variety of complex output patterns, input-output transformations that require memory, multiple outputs that can be switched by control inputs, and motor patterns matching human motion capture data. Our results reproduce data on premovement activity in motor and premotor cortex, and suggest that synaptic plasticity may be a more rapid and powerful modulator of network activi! ty than generally appreciated.

Hot off the presses! Sep 01 Nat Genet

The Sep 01 issue of the Nat Genet is now up on Pubget (About Nat Genet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

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)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Genetics Select this option to purchase a personal subscription to Nature Genetics.
• 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)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Genetics Select this option to purchase a personal subscription to Nature Genetics.
• 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.

Hot off the presses! Sep 01 Nat Methods

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Latest Articles Include:

• Metagenomics versus Moore's law
  - Nat Methods 6(9):623 (2009)
  Metagenomics sprang from advances in sequencing technology, and continued improvements are providing data in quantities unimaginable a few years ago. But without concerted efforts, the amount of data will quickly outpace the ability of scientists to analyze it.
• CASD-NMR: critical assessment of automated structure determination by NMR
  - Nat Methods 6(9):625-626 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Methods Select this option to purchase a personal subscription to Nature Methods.
• Targeting ancient DNA
  - Nat Methods 6(9):629 (2009)
  A method that allows precise capture of Neanderthal genome sequences will permit detailed comparison of modern and ancient humans.
• Tethered together
  - Nat Methods 6(9):630-631 (2009)
  Researchers describe a genetic approach to identify the native components responsible for forming molecular transport junctions between the mitochondria and the endoplasmic reticulum.
• Location, location, location
  - Nat Methods 6(9):630-631 (2009)
  A strategy for selectively disabling activated neurons helps researchers to characterize brain circuitry controlling addiction-related behaviors.
• News in brief
  - Nat Methods 6(9):631 (2009)
  
• Reading between the lines
  - Nat Methods 6(9):632 (2009)
  A phenotype prediction tool helps 'fill in the blanks' for expression microarrays, extending their predictive power and uncovering once-hidden biases.
• Stopping intracellular leakage with chemistry
  - Nat Methods 6(9):634 (2009)
  Researchers develop a strategy to improve the intracellular retention of fluorescent probes and thus their imaging sensitivity.
• Google 'EarthWorm'
  - Nat Methods 6(9):635-636 (2009)
  A three-dimensional digital atlas allows cell-by-cell navigation of Caenorhabditis elegans.
• The 'rare biosphere': a reality check
  - Nat Methods 6(9):636-637 (2009)
  Methods for error correction and classification of metagenomic datasets suggest that the rare biosphere is not as large as previously assumed.
• Accurate determination of microbial diversity from 454 pyrosequencing data
  - Nat Methods 6(9):639-641 (2009)
  We present an algorithm, PyroNoise, that clusters the flowgrams of 454 pyrosequencing reads using a distance measure that models sequencing noise. This infers the true sequences in a collection of amplicons. We pyrosequenced a known mixture of microbial 16S rDNA sequences extracted from a lake and found that without noise reduction the number of operational taxonomic units is overestimated but using PyroNoise it can be accurately calculated.
• Modular scanning FCS quantifies receptor-ligand interactions in living multicellular organisms
  Ries J Yu SR Burkhardt M Brand M Schwille P - Nat Methods 6(9):643-645 (2009)
  Analysis of receptor-ligand interactions in vivo is key to biology but poses a considerable challenge to quantitative microscopy. Here we combine static-volume, two-focus and dual-color scanning fluorescence correlation spectroscopy to solve this task at cellular resolution in complex biological environments. We quantified the mobility of fibroblast growth factor receptors Fgfr1 and Fgfr4 in cell membranes of living zebrafish embryos and determined their in vivo binding affinities to their ligand Fgf8.
• Digital transcriptome profiling using selective hexamer priming for cDNA synthesis
  - Nat Methods 6(9):647-649 (2009)
  We developed a procedure for the preparation of whole transcriptome cDNA libraries depleted of ribosomal RNA from only 1 g of total RNA. The method relies on a collection of short, computationally selected oligonucleotides, called 'not-so-random' (NSR) primers, to obtain full-length, strand-specific representation of nonribosomal RNA transcripts. In this study we validated the technique by profiling human whole brain and universal human reference RNA using ultra-high-throughput sequencing.
• Crystallographic ab initio protein structure solution below atomic resolution
  - Nat Methods 6(9):651-653 (2009)
  Ab initio macromolecular phasing has been so far limited to small proteins diffracting at atomic resolution (beyond 1.2 Å) unless heavy atoms are present. We describe a general ab initio phasing method for 2 Å data, based on combination of localizing model fragments such as small á-helices with Phaser and density modification with SHELXE. We implemented this approach in the program Arcimboldo to solve a 222-amino-acid structure at 1.95 Å.
• Isolation of deletion alleles by G4 DNA-induced mutagenesis
  - Nat Methods 6(9):655-657 (2009)
  Metazoan genomes contain thousands of sequence tracts that match the guanine-quadruplex (G4) DNA signature G3NxG3NxG3NxG3, a motif that is intrinsically mutagenic, probably because it can form secondary structures during DNA replication. Here we show how and to what extent this feature can be used to generate deletion alleles of many Caenorhabditis elegans genes.
• ErythRED, a hESC line enabling identification of erythroid cells
  - Nat Methods 6(9):659-662 (2009)
  A human embryonic stem cell (hESC) line that enabled globin-expressing cells to be easily recognized would facilitate optimization of erythroid differentiation in vitro and aid in the identification of hESC-derived erythroid cells in transplanted animals. We describe a genetically modified hESC line, ErythRED, in which expression of RFP, controlled by regulatory sequences from the human -globin locus control region, is restricted to maturing erythroid cells.
• A customized and versatile high-density genotyping array for the mouse
  - Nat Methods 6(9):663-666 (2009)
  We designed a high-density mouse genotyping array containing 623,124 single-nucleotide polymorphisms that captures the known genetic variation present in the laboratory mouse. The array also contains 916,269 invariant genomic probes targeted to functional elements and regions known to harbor segmental duplications. The array opens the door to the characterization of genetic diversity, copy-number variation, allele-specific gene expression and DNA methylation, and will extend the successes of human genome-wide association studies to the mouse.
• A 3D digital atlas of C. elegans and its application to single-cell analyses
  - Nat Methods 6(9):667-672 (2009)
  We built a digital nuclear atlas of the newly hatched, first larval stage (L1) of the wild-type hermaphrodite of Caenorhabditis elegans at single-cell resolution from confocal image stacks of 15 individual worms. The atlas quantifies the stereotypy of nuclear locations and provides other statistics on the spatial patterns of the 357 nuclei that could be faithfully segmented and annotated out of the 558 present at this developmental stage. We then developed an automated approach to assign cell names to each nucleus in a three-dimensional image of an L1 worm. We achieved 86% accuracy in identifying the 357 nuclei automatically. This computational method will allow high-throughput single-cell analyses of the post-embryonic worm, such as gene expression analysis, or ablation or stimulation of cells under computer control in a high-throughput functional screen.
• Phymm and PhymmBL: metagenomic phylogenetic classification with interpolated Markov models
  Brady A Salzberg SL - Nat Methods 6(9):673-676 (2009)
  Metagenomics projects collect DNA from uncharacterized environments that may contain thousands of species per sample. One main challenge facing metagenomic analysis is phylogenetic classification of raw sequence reads into groups representing the same or similar taxa, a prerequisite for genome assembly and for analyzing the biological diversity of a sample. New sequencing technologies have made metagenomics easier, by making sequencing faster, and more difficult, by producing shorter reads than previous technologies. Classifying sequences from reads as short as 100 base pairs has until now been relatively inaccurate, requiring researchers to use older, long-read technologies. We present Phymm, a classifier for metagenomic data, that has been trained on 539 complete, curated genomes and can accurately classify reads as short as 100 base pairs, a substantial improvement over previous composition-based classification methods. We also describe how combining Phymm with sequ! ence alignment algorithms improves accuracy.
• BreakDancer: an algorithm for high-resolution mapping of genomic structural variation
  - Nat Methods 6(9):677-681 (2009)
  Detection and characterization of genomic structural variation are important for understanding the landscape of genetic variation in human populations and in complex diseases such as cancer. Recent studies demonstrate the feasibility of detecting structural variation using next-generation, short-insert, paired-end sequencing reads. However, the utility of these reads is not entirely clear, nor are the analysis methods with which accurate detection can be achieved. The algorithm BreakDancer predicts a wide variety of structural variants including insertion-deletions (indels), inversions and translocations. We examined BreakDancer's performance in simulation, in comparison with other methods and in analyses of a sample from an individual with acute myeloid leukemia and of samples from the 1,000 Genomes trio individuals. BreakDancer sensitively and accurately detected indels ranging from 10 base pairs to 1 megabase pair that are difficult to detect via a single convention! al approach.
• Microfluidics: the great divide
  - Nat Methods 6(9):683-686 (2009)
  Although many intricate microfluidic devices have been created in academic laboratories around the world, far fewer have been commercialized for wider use. But several efforts are underway to bridge this divide.