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Latest Articles Include:

• Online Methods
  - Nat Genet 41(7):763 (2009)
  Most of our readers access our articles online, in formats that deal well with increasingly complex research methods and the growing requirement for increased precision of citation. These considerations have now led us to publish Methods online.
• High marks for GWAS
  - Nat Genet 41(7):765-766 (2009)
  Two genome-wide association studies for testicular cancer report associations at three new loci, including two candidate genes previously implicated in testicular development, KITLG (ligand for the receptor tyrosine kinase) and SPRY4 (sprouty 4). These studies are notable for the high effect sizes detected and the biological plausibility of the candidate genes.
• TET2 mutations in myelodysplasia and myeloid malignancies
  - Nat Genet 41(7):766-767 (2009)
  The genetic basis of myelodysplasia has long been enigmatic, with few common targets of mutation known. A new study reports common mutations in the TET2 gene in myelodysplasia and related myeloid malignancies, suggesting that TET2 has an important role in hematopoiesis and in the pathogenesis of this disease.
• Tumors line up for a letdown
  - Nat Genet 41(7):768-769 (2009)
  MicroRNAs (miRNAs) and the pathways that regulate their expression have critical functions during normal development. A new study demonstrates that select cancer cells have appropriated one developmental mechanism of miRNA regulation, the inhibition of let-7 biogenesis by the Lin-28 and Lin-28B RNA binding proteins, to rid themselves of an antitumorigenic miRNA.
• Research highlights
  - Nat Genet 41(7):770 (2009)
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• RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection
  - Nat Genet 41(7):773-775 (2009)
  Congenital cytomegalovirus brain infection without symptoms at birth can cause a static encephalopathy with characteristic patterns of brain abnormalities. Here we show that loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to cystic leukoencephalopathy, an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype. Congenital cytomegalovirus infection and RNASET2 deficiency may both interfere with brain development and myelination through angiogenesis or RNA metabolism.
• Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci
  - Nat Genet 41(7):776-782 (2009)
  We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 10-11), IRF8 (P = 3.73 10-9) and CD6 (P = 3.79 10-9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.
• Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia
  Chen Y Hu Y Zhang H Peng C Li S - Nat Genet 41(7):783-792 (2009)
  Targeting of cancer stem cells is believed to be essential for curative therapy of cancers, but supporting evidence is limited. Few selective target genes in cancer stem cells have been identified. Here we identify the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in BCR-ABL–induced chronic myeloid leukemia (CML). In the absence of Alox5, BCR-ABL failed to induce CML in mice. This Alox5 deficiency caused impairment of the function of LSCs but not normal hematopoietic stem cells (HSCs) through affecting differentiation, cell division and survival of long-term LSCs (LT-LSCs), consequently causing a depletion of LSCs and a failure of CML development. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly by affecting LT-LSCs, and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the! function of these stem cells.
• Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis
  - Nat Genet 41(7):793-799 (2009)
  Although many vertebrate organs, such as kidneys, lungs and liver, are composed of epithelial tubules, little is known of the mechanisms that establish the length or diameter of these tubules. In the kidney, defects in the establishment or maintenance of tubule diameter are associated with one of the most common inherited human disorders, polycystic kidney disease. Here we show that attenuation of Wnt9b signaling during kidney morphogenesis affects the planar cell polarity of the epithelium and leads to tubules with significantly increased diameter. Although previous studies showed that polarized cell divisions maintain the diameter of postnatal kidney tubules, we find that cell divisions are randomly oriented during embryonic development. Our data suggest that diameter is established during early morphogenetic stages by convergent extension processes and maintained by polarized cell divisions. Wnt9b, signaling through the non-canonical Rho/Jnk branch of the Wnt pathwa! y, is necessary for both of these processes.
• The establishment of gene silencing at single-cell resolution
  - Nat Genet 41(7):800-806 (2009)
  The establishment of silencing in Saccharomyces cerevisiae is similar to heterochromatin formation in multicellular eukaryotes. Previous batch culture studies determined that the de novo establishment of silencing initiates during S phase and continues for up to five cell divisions for completion. To track silencing phenotypically, we developed an assay that introduces Sir3 protein into individual sir3 mutant cells synchronously and then detects the onset of silencing with single-cell resolution. Silencing was completed within the first one to two cell divisions in most cells queried. Moreover, we uncovered unexpected complexity in the contributions of a histone acetyltransferase (Sas2), two histone methytransferases (Dot1 and Set1) and one histone demethylase (Jhd2) to the dynamics of silencing. Our findings showed that removal of methyl modifications at H3K4 and H3K79 were important steps in silent chromatin formation and that Jhd2 and Set1 had competing roles in the! process.
• A genome-wide association study of testicular germ cell tumor
  - Nat Genet 41(7):807-810 (2009)
  We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19–1.58), P = 3 10-13), chromosome 6 (OR = 1.50 (95% CI = 1.28–1.75), P = 10-13) and chromosome 12 (OR = 2.55 (95% CI = 2.05–3.19), P = 10-31). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.
• Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer
  - Nat Genet 41(7):811-815 (2009)
  Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 10-8 in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29–4.13; OR = 3.07, 95% CI = 2.29–4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 10-6 in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14–1.64; OR = 1.39, 95% CI = 1.16–1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as g! enes involved in TGCT susceptibility.
• HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin
  - Nat Genet 41(7):816-819 (2009)
  Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 10-33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 10-19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 10-8). These findings provide new insights into the mechanism of! flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
• REL, encoding a member of the NF-B family of transcription factors, is a newly defined risk locus for rheumatoid arthritis
  - Nat Genet 41(7):820-823 (2009)
  We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 10-10). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 10-14) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 10-11) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 10-9) and BLK (rs2736340; OR = 1.19; P = 5.69 10-9). c-Rel is an NF-B family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ1, 2.
• Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20
  - Nat Genet 41(7):824-828 (2009)
  To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13–14 (rs703842, P = 5.4 10-11; rs10876994, P = 2.7 10-10; rs12368653, P = 1.0 10-7) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 10-7; rs1569723, P = 2.9 10-7). Both loci are also associated with other autoimmune diseases1, 2, 3, 4, 5. We also replicated several known MS associations (HLA-DR15, P = 7.0 10-184; CD58, P = 9.6 10-8; EVI5-RPL5, P = 2.5 10-6; IL2RA, P = 7.4 10-6; CLEC16A, P = 1.1 10-4; IL7R, P = 1.3 10-3; TYK2, P = 3.5 10-3) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
• Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response
  - Nat Genet 41(7):829-832 (2009)
  Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
• Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome
  - Nat Genet 41(7):833-837 (2009)
  Defects in mitochondrial translation are among the most common causes of mitochondrial disease1, but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast Saccharomyces cerevisiae, all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5' UTRs and mediate translation2. As mammalian mitochondrial mRNAs do not have significant 5' UTRs3, alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44, encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable de! gree of structural similarity with bacterial homologs4, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.
• Acquired mutations in TET2 are common in myelodysplastic syndromes
  - Nat Genet 41(7):838-842 (2009)
  Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders1. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array–based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34+ progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We con! clude that TET2 is the most frequently mutated gene in MDS known so far.
• Lin28 promotes transformation and is associated with advanced human malignancies
  - Nat Genet 41(7):843-848 (2009)
  Multiple members of the let-7 family of miRNAs are often repressed in human cancers1, 2, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc3, 4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature miRNAs5, 6, 7, 8, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency 15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates act! ivation of LIN28 and LIN28B with poor clinical prognosis.
• The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans
  - Nat Genet 41(7):849-853 (2009)
  We recently proposed a DNA replication–based mechanism of fork stalling and template switching (FoSTeS) to explain the complex genomic rearrangements associated with a dysmyelinating central nervous system disorder in humans1. The FoSTeS mechanism has been further generalized and molecular mechanistic details have been provided in the microhomology-mediated break-induced replication (MMBIR) model that may underlie many structural variations in genomes from all domains of life2. Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR. Furthermore, we show that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. The FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis3 and exon shuffling4, suggesting an important role in both g! enome and single-gene evolution.
• Kif1b is essential for mRNA localization in oligodendrocytes and development of myelinated axons
  - Nat Genet 41(7):854-858 (2009)
  The kinesin motor protein Kif1b has previously been implicated in the axonal transport of mitochondria and synaptic vesicles1, 2. More recently, KIF1B has been associated with susceptibility to multiple sclerosis (MS)3. Here we show that Kif1b is required for the localization of mbp (myelin basic protein) mRNA to processes of myelinating oligodendrocytes in zebrafish. We observe the ectopic appearance of myelin-like membrane in kif1b mutants, coincident with the ectopic localization of myelin proteins in kif1b mutant oligodendrocyte cell bodies. These observations suggest that oligodendrocytes localize certain mRNA molecules, namely those encoding small basic proteins such as MBP, to prevent aberrant effects of these proteins elsewhere in the cell. We also find that Kif1b is required for outgrowth of some of the longest axons in the peripheral and central nervous systems. Our data demonstrate previously unknown functions of kif1b in vivo and provide insights into its p! ossible roles in MS.
• Corrigendum: Tiny RNAs associated with transcription start sites in animals
  - Nat Genet 41(7):859 (2009)
  Introduction Nat. Genet. 41, 572–578 (2009); published online 19 April 2009; corrected after print 26 June 2009 In the version of this article initially published, some author affiliations were incorrectly stated. The error has been corrected in the HTML and PDF versions of the article.
• Erratum: Narcolepsy is strongly associated with the T-cell receptor alpha locus
  - Nat Genet 41(7):859 (2009)
  Introduction Nat. Genet. 41, 708–711 (2009); published online 3 May 2009; corrected after print 26 June 2009 In the version of this article initially published, Seung-Chul Hong was incorrectly listed as Sheng Seung-Chul Hong. The error has been corrected in the HTML and PDF versions of the article.