Nature Genetics

Genome-wide association study identifies multiple loci influencing human serum metabolite levels.

Publication Date: 2012 Jan 29 PMID: 22286219
Authors: Kettunen, J. - Tukiainen, T. - Sarin, A. P. - Ortega-Alonso, A. - Tikkanen, E. - Lyytikainen, L. P. - Kangas, A. J. - Soininen, P. - Wurtz, P. - Silander, K. - Dick, D. M. - Rose, R. J. - Savolainen, M. J. - Viikari, J. - Kahonen, M. - Lehtimaki, T. - Pietilainen, K. H. - Inouye, M. - McCarthy, M. I. - Jula, A. - Eriksson, J. - Raitakari, O. T. - Salomaa, V. - Kaprio, J. - Jarvelin, M. R. - Peltonen, L. - Perola, M. - Freimer, N. B. - Ala-Korpela, M. - Palotie, A. - Ripatti, S.
Journal: Nat Genet

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 x 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

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Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.

Publication Date: 2012 Jan 29 PMID: 22286218
Authors: Raychaudhuri, S. - Sandor, C. - Stahl, E. A. - Freudenberg, J. - Lee, H. S. - Jia, X. - Alfredsson, L. - Padyukov, L. - Klareskog, L. - Worthington, J. - Siminovitch, K. A. - Bae, S. C. - Plenge, R. M. - Gregersen, P. K. - de Bakker, P. I.
Journal: Nat Genet

The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRbeta1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPbeta1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.

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Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event.

Publication Date: 2012 Jan 29 PMID: 22286217
Authors: Golubchik, T. - Brueggemann, A. B. - Street, T. - Gertz, R. E. Jr - Spencer, C. C. - Ho, T. - Giannoulatou, E. - Link-Gelles, R. - Harding, R. M. - Beall, B. - Peto, T. E. - Moore, M. R. - Donnelly, P. - Crook, D. W. - Bowden, R.
Journal: Nat Genet

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age. The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination, showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.

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Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.

Publication Date: 2012 Jan 29 PMID: 22286216
Authors: Wu, G. - Broniscer, A. - McEachron, T. A. - Lu, C. - Paugh, B. S. - Becksfort, J. - Qu, C. - Ding, L. - Huether, R. - Parker, M. - Zhang, J. - Gajjar, A. - Dyer, M. A. - Mullighan, C. G. - Gilbertson, R. J. - Mardis, E. R. - Wilson, R. K. - Downing, J. R. - Ellison, D. W. - Zhang, J. - Baker, S. J.
Journal: Nat Genet

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.

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Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity.

Publication Date: 2012 Jan 29 PMID: 22286215
Authors: Andersen, E. C. - Gerke, J. P. - Shapiro, J. A. - Crissman, J. R. - Ghosh, R. - Bloom, J. S. - Felix, M. A. - Kruglyak, L.
Journal: Nat Genet

The nematode Caenorhabditis elegans is central to research in molecular, cell and developmental biology, but nearly all of this research has been conducted on a single strain of C. elegans. Little is known about the population genomic and evolutionary history of this species. We characterized C. elegans genetic variation using high-throughput selective sequencing of a worldwide collection of 200 wild strains and identified 41,188 SNPs. Notably, C. elegans genome variation is dominated by a set of commonly shared haplotypes on four of its six chromosomes, each spanning many megabases. Population genetic modeling showed that this pattern was generated by chromosome-scale selective sweeps that have reduced variation worldwide; at least one of these sweeps probably occurred in the last few hundred years. These sweeps, which we hypothesize to be a result of human activity, have drastically reshaped the global C. elegans population in the recent past.

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Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.

Publication Date: 2012 Jan 29 PMID: 22286214
Authors: Bonnefond, A. - Clement, N. - Fawcett, K. - Yengo, L. - Vaillant, E. - Guillaume, J. L. - Dechaume, A. - Payne, F. - Roussel, R. - Czernichow, S. - Hercberg, S. - Hadjadj, S. - Balkau, B. - Marre, M. - Lantieri, O. - Langenberg, C. - Bouatia-Naji, N. - Charpentier, G. - Vaxillaire, M. - Rocheleau, G. - Wareham, N. J. - Sladek, R. - McCarthy, M. I. - Dina, C. - Barroso, I. - Jockers, R. - Froguel, P.
Journal: Nat Genet

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT(2)) increase type 2 diabetes (T2D) risk. Although the strongest association signal was highly significant (P < 1 x 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of approximately 1.10-1.15). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 x 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 x 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 x 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk.

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Developing predictive molecular maps of human disease through community-based modeling.

Publication Date: 2012 PMID: 22281773
Authors: Derry, J. M. - Mangravite, L. M. - Suver, C. - Furia, M. D. - Henderson, D. - Schildwachter, X. - Bot, B. - Izant, J. - Sieberts, S. K. - Kellen, M. R. - Friend, S. H.
Journal: Nat Genet

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Toward interoperable bioscience data.

Publication Date: 2012 PMID: 22281772
Authors: Sansone, S. A. - Rocca-Serra, P. - Field, D. - Maguire, E. - Taylor, C. - Hofmann, O. - Fang, H. - Neumann, S. - Tong, W. - Amaral-Zettler, L. - Begley, K. - Booth, T. - Bougueleret, L. - Burns, G. - Chapman, B. - Clark, T. - Coleman, L. A. - Copeland, J. - Das, S. - de Daruvar, A. - de Matos, P. - Dix, I. - Edmunds, S. - Evelo, C. T. - Forster, M. J. - Gaudet, P. - Gilbert, J. - Goble, C. - Griffin, J. L. - Jacob, D. - Kleinjans, J. - Harland, L. - Haug, K. - Hermjakob, H. - Ho Sui, S. J. - Laederach, A. - Liang, S. - Marshall, S. - McGrath, A. - Merrill, E. - Reilly, D. - Roux, M. - Shamu, C. E. - Shang, C. A. - Steinbeck, C. - Trefethen, A. - Williams-Jones, B. - Wolstencroft, K. - Xenarios, I. - Hide, W.
Journal: Nat Genet

To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision.

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Gregarious locusts.

Publication Date: 2012 PMID: 22281771
Authors: Feliciano, P.
Journal: Nat Genet

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SIRT1 and anxiety.

Publication Date: 2012 PMID: 22281770
Authors: Feliciano, P.
Journal: Nat Genet

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Cardiac symptoms of Rett syndrome.

Publication Date: 2012 PMID: 22281769
Authors: Peng, W.
Journal: Nat Genet

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Genomics of endangered primates.

Publication Date: 2012 PMID: 22281768
Authors: Bahcall, O.
Journal: Nat Genet

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DICER1 in ovarian cancers.

Publication Date: 2012 PMID: 22281767
Authors: Vogan, K.
Journal: Nat Genet

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The persistence of a silent memory.

Publication Date: 2012 PMID: 22281766
Authors: Zaratiegui, M. - Martienssen, R.
Journal: Nat Genet

One of the most striking properties of RNA interference (RNAi) in Caenorhabditis elegans is its persistence in offspring after the triggering double-stranded RNA (dsRNA) has disappeared. A new study reveals that a heterochromatic silencing mark is deposited around the targets of RNAi and is transmitted through generations. These results show that RNAi can induce stable and heritable chromatin modifications in animals.

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The genome of a blood fluke associated with human cancer.

Publication Date: 2012 PMID: 22281765
Authors: Mitreva, M.
Journal: Nat Genet

The sequencing of the genome and transcriptome of Schistosoma haematobium, a highly prevalent blood fluke and human parasite with a proven link to malignant bladder cancer, marks the 160(th) anniversary of its discovery as the first schistosome known to infect humans. Comparative genomic analyses of S. haematobium and the more prevalent human-schistosomiasis pathogens (Schistosoma mansoni and Schistosoma japonicum) identified both shared and distinct genomic features.

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Arabidopsis thaliana as a model for the genetics of local adaptation.

Publication Date: 2012 PMID: 22281764
Authors: Gaut, B.
Journal: Nat Genet

A new study reports SNP genotypes of over 1,300 Arabidopsis thaliana accessions from throughout Eurasia, providing a resource for genome-wide association studies and studies of local adaptation. The extensive data are also used to identify targets of natural selection and to describe genome-wide patterns of recombination.

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A digital examination of medicine.

Publication Date: 2012 PMID: 22281763
Authors: Green, H. A.
Journal: Nat Genet

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The authorship network of genome-wide association studies.

Publication Date: 2012 PMID: 22281762
Authors: Bulik-Sullivan, B. K. - Sullivan, P. F.
Journal: Nat Genet

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It's not about the data.

Publication Date: 2012 PMID: 22281761
Authors:
Journal: Nat Genet

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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

Publication Date: 2012 Jan 22 PMID: 22267201
Authors: Stolk, L. - Perry, J. R. - Chasman, D. I. - He, C. - Mangino, M. - Sulem, P. - Barbalic, M. - Broer, L. - Byrne, E. M. - Ernst, F. - Esko, T. - Franceschini, N. - Gudbjartsson, D. F. - Hottenga, J. J. - Kraft, P. - McArdle, P. F. - Porcu, E. - Shin, S. Y. - Smith, A. V. - van Wingerden, S. - Zhai, G. - Zhuang, W. V. - Albrecht, E. - Alizadeh, B. Z. - Aspelund, T. - Bandinelli, S. - Lauc, L. B. - Beckmann, J. S. - Boban, M. - Boerwinkle, E. - Broekmans, F. J. - Burri, A. - Campbell, H. - Chanock, S. J. - Chen, C. - Cornelis, M. C. - Corre, T. - Coviello, A. D. - d'Adamo, P. - Davies, G. - de Faire, U. - de Geus, E. J. - Deary, I. J. - Dedoussis, G. V. - Deloukas, P. - Ebrahim, S. - Eiriksdottir, G. - Emilsson, V. - Eriksson, J. G. - Fauser, B. C. - Ferreli, L. - Ferrucci, L. - Fischer, K. - Folsom, A. R. - Garcia, M. E. - Gasparini, P. - Gieger, C. - Glazer, N. - Grobbee, D. E. - Hall, P. - Haller, T. - Hankinson, S. E. - Hass, M. - Hayward, C. - Heath, A. C. - Hofman, A. - Ingelsson, E. - Janssens, A. C. - Johnson, A. D. - Karasik, D. - Kardia, S. L. - Keyzer, J. - Kiel, D. P. - Kolcic, I. - Kutalik, Z. - Lahti, J. - Lai, S. - Laisk, T. - Laven, J. S. - Lawlor, D. A. - Liu, J. - Lopez, L. M. - Louwers, Y. V. - Magnusson, P. K. - Marongiu, M. - Martin, N. G. - Klaric, I. M. - Masciullo, C. - McKnight, B. - Medland, S. E. - Melzer, D. - Mooser, V. - Navarro, P. - Newman, A. B. - Nyholt, D. R. - Onland-Moret, N. C. - Palotie, A. - Pare, G. - Parker, A. N. - Pedersen, N. L. - Peeters, P. H. - Pistis, G. - Plump, A. S. - Polasek, O. - Pop, V. J. - Psaty, B. M. - Raikkonen, K. - Rehnberg, E. - Rotter, J. I. - Rudan, I. - Sala, C. - Salumets, A. - Scuteri, A. - Singleton, A. - Smith, J. A. - Snieder, H. - Soranzo, N. - Stacey, S. N. - Starr, J. M. - Stathopoulou, M. G. - Stirrups, K. - Stolk, R. P. - Styrkarsdottir, U. - Sun, Y. V. - Tenesa, A. - Thorand, B. - Toniolo, D. - Tryggvadottir, L. - Tsui, K. - Ulivi, S. - van Dam, R. M. - van der Schouw, Y. T. - van Gils, C. H. - van Nierop, P. - Vink, J. M. - Visscher, P. M. - Voorhuis, M. - Waeber, G. - Wallaschofski, H. - Wichmann, H. E. - Widen, E. - Wijnands-van Gent, C. J. - Willemsen, G. - Wilson, J. F. - Wolffenbuttel, B. H. - Wright, A. F. - Yerges-Armstrong, L. M. - Zemunik, T. - Zgaga, L. - Zillikens, M. C. - Zygmunt, M. - Study, T. L. - Arnold, A. M. - Boomsma, D. I. - Buring, J. E. - Crisponi, L. - Demerath, E. W. - Gudnason, V. - Harris, T. B. - Hu, F. B. - Hunter, D. J. - Launer, L. J. - Metspalu, A. - Montgomery, G. W. - Oostra, B. A. - Ridker, P. M. - Sanna, S. - Schlessinger, D. - Spector, T. D. - Stefansson, K. - Streeten, E. A. - Thorsteinsdottir, U. - Uda, M. - Uitterlinden, A. G. - van Duijn, C. M. - Volzke, H. - Murray, A. - Murabito, J. M. - Visser, J. A. - Lunetta, K. L.
Journal: Nat Genet

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

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Discovery of common variants associated with low TSH levels and thyroid cancer risk.

Publication Date: 2012 Jan 22 PMID: 22267200
Authors: Gudmundsson, J. - Sulem, P. - Gudbjartsson, D. F. - Jonasson, J. G. - Masson, G. - He, H. - Jonasdottir, A. - Sigurdsson, A. - Stacey, S. N. - Johannsdottir, H. - Th Helgadottir, H. - Li, W. - Nagy, R. - Ringel, M. D. - Kloos, R. T. - de Visser, M. C. - Plantinga, T. S. - den Heijer, M. - Aguillo, E. - Panadero, A. - Prats, E. - Garcia-Castano, A. - De Juan, A. - Rivera, F. - Walters, G. B. - Bjarnason, H. - Tryggvadottir, L. - Eyjolfsson, G. I. - Bjornsdottir, U. S. - Holm, H. - Olafsson, I. - Kristjansson, K. - Kristvinsson, H. - T Magnusson, O. - Thorleifsson, G. - Gulcher, J. R. - Kong, A. - Kiemeney, L. A. - Jonsson, T. - Hjartarson, H. - Mayordomo, J. I. - Netea-Maier, R. T. - de la Chapelle, A. - Hrafnkelsson, J. - Thorsteinsdottir, U. - Rafnar, T. - Stefansson, K.
Journal: Nat Genet

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 x 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 x 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 x 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 x 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 x 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.

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Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.

Publication Date: 2012 Jan 22 PMID: 22267199
Authors: Delgado-Olguin, P. - Huang, Y. - Li, X. - Christodoulou, D. - Seidman, C. E. - Seidman, J. G. - Tarakhovsky, A. - Bruneau, B. G.
Journal: Nat Genet

Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown. The Polycomb histone methyltransferase Ezh2 stabilizes transcription by depositing repressive marks during development that persist into adulthood, but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor gene Six1, which functions in cardiac progenitor cells but is stably silenced upon cardiac differentiation. Deletion of Ezh2 in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable gene expression and homeostasis in the postnatal heart. Our results suggest that epigenetic dysregulation in embryonic progenitor cells is a predisposing factor for adult disease and dysregulated stress responses.

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Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.

Publication Date: 2012 Jan 22 PMID: 22267198
Authors: Anderson, B. H. - Kasher, P. R. - Mayer, J. - Szynkiewicz, M. - Jenkinson, E. M. - Bhaskar, S. S. - Urquhart, J. E. - Daly, S. B. - Dickerson, J. E. - O'Sullivan, J. - Leibundgut, E. O. - Muter, J. - Abdel-Salem, G. M. - Babul-Hirji, R. - Baxter, P. - Berger, A. - Bonafe, L. - Brunstom-Hernandez, J. E. - Buckard, J. A. - Chitayat, D. - Chong, W. K. - Cordelli, D. M. - Ferreira, P. - Fluss, J. - Forrest, E. H. - Franzoni, E. - Garone, C. - Hammans, S. R. - Houge, G. - Hughes, I. - Jacquemont, S. - Jeannet, P. Y. - Jefferson, R. J. - Kumar, R. - Kutschke, G. - Lundberg, S. - Lourenco, C. M. - Mehta, R. - Naidu, S. - Nischal, K. K. - Nunes, L. - Ounap, K. - Philippart, M. - Prabhakar, P. - Risen, S. R. - Schiffmann, R. - Soh, C. - Stephenson, J. B. - Stewart, H. - Stone, J. - Tolmie, J. L. - van der Knaap, M. S. - Vieira, J. P. - Vilain, C. N. - Wakeling, E. L. - Wermenbol, V. - Whitney, A. - Lovell, S. C. - Meyer, S. - Livingston, J. H. - Baerlocher, G. M. - Black, G. C. - Rice, G. I. - Crow, Y. J.
Journal: Nat Genet

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous gammaH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the alpha-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-alpha primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

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Genome-wide association analysis identifies three new breast cancer susceptibility loci.

Publication Date: 2012 Jan 22 PMID: 22267197
Authors: Ghoussaini, M. - Fletcher, O. - Michailidou, K. - Turnbull, C. - Schmidt, M. K. - Dicks, E. - Dennis, J. - Wang, Q. - Humphreys, M. K. - Luccarini, C. - Baynes, C. - Conroy, D. - Maranian, M. - Ahmed, S. - Driver, K. - Johnson, N. - Orr, N. - Dos Santos Silva, I. - Waisfisz, Q. - Meijers-Heijboer, H. - Uitterlinden, A. G. - Rivadeneira, F. - Hall, P. - Czene, K. - Irwanto, A. - Liu, J. - Nevanlinna, H. - Aittomaki, K. - Blomqvist, C. - Meindl, A. - Schmutzler, R. K. - Muller-Myhsok, B. - Lichtner, P. - Chang-Claude, J. - Hein, R. - Nickels, S. - Flesch-Janys, D. - Tsimiklis, H. - Makalic, E. - Schmidt, D. - Bui, M. - Hopper, J. L. - Apicella, C. - Park, D. J. - Southey, M. - Hunter, D. J. - Chanock, S. J. - Broeks, A. - Verhoef, S. - Hogervorst, F. B. - Fasching, P. A. - Lux, M. P. - Beckmann, M. W. - Ekici, A. B. - Sawyer, E. - Tomlinson, I. - Kerin, M. - Marme, F. - Schneeweiss, A. - Sohn, C. - Burwinkel, B. - Guenel, P. - Truong, T. - Cordina-Duverger, E. - Menegaux, F. - Bojesen, S. E. - Nordestgaard, B. G. - Nielsen, S. F. - Flyger, H. - Milne, R. L. - Alonso, M. R. - Gonzalez-Neira, A. - Benitez, J. - Anton-Culver, H. - Ziogas, A. - Bernstein, L. - Dur, C. C. - Brenner, H. - Muller, H. - Arndt, V. - Stegmaier, C. - Justenhoven, C. - Brauch, H. - Bruning, T. - Wang-Gohrke, S. - Eilber, U. - Dork, T. - Schurmann, P. - Bremer, M. - Hillemanns, P. - Bogdanova, N. V. - Antonenkova, N. N. - Rogov, Y. I. - Karstens, J. H. - Bermisheva, M. - Prokofieva, D. - Khusnutdinova, E. - Lindblom, A. - Margolin, S. - Mannermaa, A. - Kataja, V. - Kosma, V. M. - Hartikainen, J. M. - Lambrechts, D. - Yesilyurt, B. T. - Floris, G. - Leunen, K. - Manoukian, S. - Bonanni, B. - Fortuzzi, S. - Peterlongo, P. - Couch, F. J. - Wang, X. - Stevens, K. - Lee, A. - Giles, G. G. - Baglietto, L. - Severi, G. - McLean, C. - Alnaes, G. G. - Kristensen, V. - Borrensen-Dale, A. L. - John, E. M. - Miron, A. - Winqvist, R. - Pylkas, K. - Jukkola-Vuorinen, A. - Kauppila, S. - Andrulis, I. L. - Glendon, G. - Mulligan, A. M. - Devilee, P. - van Asperen, C. J. - Tollenaar, R. A. - Seynaeve, C. - Figueroa, J. D. - Garcia-Closas, M. - Brinton, L. - Lissowska, J. - Hooning, M. J. - Hollestelle, A. - Oldenburg, R. A. - van den Ouweland, A. M. - Cox, A. - Reed, M. W. - Shah, M. - Jakubowska, A. - Lubinski, J. - Jaworska, K. - Durda, K. - Jones, M. - Schoemaker, M. - Ashworth, A. - Swerdlow, A. - Beesley, J. - Chen, X. - Muir, K. R. - Lophatananon, A. - Rattanamongkongul, S. - Chaiwerawattana, A. - Kang, D. - Yoo, K. Y. - Noh, D. Y. - Shen, C. Y. - Yu, J. C. - Wu, P. E. - Hsiung, C. N. - Perkins, A. - Swann, R. - Velentzis, L. - Eccles, D. M. - Tapper, W. J. - Gerty, S. M. - Graham, N. J. - Ponder, B. A. - Chenevix-Trench, G. - Pharoah, P. D. - Lathrop, M. - Dunning, A. M. - Rahman, N. - Peto, J. - Easton, D. F.
Journal: Nat Genet

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in approximately 70,000 cases and approximately 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

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Whole-genome sequence of Schistosoma haematobium.

Publication Date: 2012 PMID: 22246508
Authors: Young, N. D. - Jex, A. R. - Li, B. - Liu, S. - Yang, L. - Xiong, Z. - Li, Y. - Cantacessi, C. - Hall, R. S. - Xu, X. - Chen, F. - Wu, X. - Zerlotini, A. - Oliveira, G. - Hofmann, A. - Zhang, G. - Fang, X. - Kang, Y. - Campbell, B. E. - Loukas, A. - Ranganathan, S. - Rollinson, D. - Rinaldi, G. - Brindley, P. J. - Yang, H. - Wang, J. - Wang, J. - Gasser, R. B.
Journal: Nat Genet

Schistosomiasis is a neglected tropical disease caused by blood flukes (genus Schistosoma; schistosomes) and affecting 200 million people worldwide. No vaccines are available, and treatment relies on one drug, praziquantel. Schistosoma haematobium has come into the spotlight as a major cause of urogenital disease, as an agent linked to bladder cancer and as a predisposing factor for HIV/AIDS. The parasite is transmitted to humans from freshwater snails. Worms dwell in blood vessels and release eggs that become embedded in the bladder wall to elicit chronic immune-mediated disease and induce squamous cell carcinoma. Here we sequenced the 385-Mb genome of S. haematobium using Illumina-based technology at 74-fold coverage and compared it to sequences from related parasites. We included genome annotation based on function, gene ontology, networking and pathway mapping. This genome now provides an unprecedented resource for many fundamental research areas and shows great promise for the design of new disease interventions.

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ABCG2 null alleles define the Jr(a-) blood group phenotype.

Publication Date: 2012 PMID: 22246507
Authors: Zelinski, T. - Coghlan, G. - Liu, X. Q. - Reid, M. E.
Journal: Nat Genet

The high-incidence erythrocyte blood group antigen Jr(a) has been known in transfusion medicine for over 40 years. To identify the gene encoding Jr(a), we performed SNP analysis of genomic DNA from six Jr(a-) individuals. All individuals shared a homozygous region of 397,000 bp at chromosome 4q22.1 that contained the gene ABCG2, and DNA sequence analysis showed that ABCG2 null alleles define the Jr(a-) phenotype.

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ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis.

Publication Date: 2012 PMID: 22246506
Authors: Helias, V. - Saison, C. - Ballif, B. A. - Peyrard, T. - Takahashi, J. - Takahashi, H. - Tanaka, M. - Deybach, J. C. - Puy, H. - Le Gall, M. - Sureau, C. - Pham, B. N. - Le Pennec, P. Y. - Tani, Y. - Cartron, J. P. - Arnaud, L.
Journal: Nat Genet

The human ATP-binding cassette (ABC) transporter ABCB6 has been described as a mitochondrial porphyrin transporter essential for heme biosynthesis, but it is also suspected to contribute to anticancer drug resistance, as do other ABC transporters located at the plasma membrane. We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells, and we established that ABCB6 encodes a new blood group system (Langereis, Lan). Targeted sequencing of ABCB6 in 12 unrelated individuals of the Lan(-) blood type identified 10 different ABCB6 null mutations. This is the first report of deficient alleles of this human ABC transporter gene. Of note, Lan(-) (ABCB6(-/-)) individuals do not suffer any clinical consequences, although their deficiency in ABCB6 may place them at risk when determining drug dosage.

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Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior.

Publication Date: 2012 PMID: 22246505
Authors: Saison, C. - Helias, V. - Ballif, B. A. - Peyrard, T. - Puy, H. - Miyazaki, T. - Perrot, S. - Vayssier-Taussat, M. - Waldner, M. - Le Pennec, P. Y. - Cartron, J. P. - Arnaud, L.
Journal: Nat Genet

The breast cancer resistance protein, also known as ABCG2, is one of the most highly studied ATP-binding cassette (ABC) transporters because of its ability to confer multidrug resistance. The lack of information on the physiological role of ABCG2 in humans severely limits cancer chemotherapeutic approaches targeting this transporter. We report here that ABCG2 comprises the molecular basis of a new blood group system (Junior, Jr) and that individuals of the Jr(a-) blood type have inherited two null alleles of ABCG2. We identified five frameshift and three nonsense mutations in ABCG2. We also show that the prevalence of the Jr(a-) blood type in the Japanese and European Gypsy populations is related to the p.Gln126* and p.Arg236* protein alterations, respectively. The identification of ABCG2(-/-) (Jr(a-)) individuals who appear phenotypically normal is an essential step toward targeting ABCG2 in cancer and also in understanding the physiological and pharmacological roles of this promiscuous transporter in humans.

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PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.

Publication Date: 2012 PMID: 22246504
Authors: Grall, A. - Guaguere, E. - Planchais, S. - Grond, S. - Bourrat, E. - Hausser, I. - Hitte, C. - Le Gallo, M. - Derbois, C. - Kim, G. J. - Lagoutte, L. - Degorce-Rubiales, F. - Radner, F. P. - Thomas, A. - Kury, S. - Bensignor, E. - Fontaine, J. - Pin, D. - Zimmermann, R. - Zechner, R. - Lathrop, M. - Galibert, F. - Andre, C. - Fischer, J.
Journal: Nat Genet

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.

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CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium.

Publication Date: 2012 PMID: 22246503
Authors: Lee, J. E. - Silhavy, J. L. - Zaki, M. S. - Schroth, J. - Bielas, S. L. - Marsh, S. E. - Olvera, J. - Brancati, F. - Iannicelli, M. - Ikegami, K. - Schlossman, A. M. - Merriman, B. - Attie-Bitach, T. - Logan, C. V. - Glass, I. A. - Cluckey, A. - Louie, C. M. - Lee, J. H. - Raynes, H. R. - Rapin, I. - Castroviejo, I. P. - Setou, M. - Barbot, C. - Boltshauser, E. - Nelson, S. F. - Hildebrandt, F. - Johnson, C. A. - Doherty, D. A. - Valente, E. M. - Gleeson, J. G.
Journal: Nat Genet

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.

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Genomic and metabolic prediction of complex heterotic traits in hybrid maize.

Publication Date: 2012 PMID: 22246502
Authors: Riedelsheimer, C. - Czedik-Eysenberg, A. - Grieder, C. - Lisec, J. - Technow, F. - Sulpice, R. - Altmann, T. - Stitt, M. - Willmitzer, L. - Melchinger, A. E.
Journal: Nat Genet

Maize is both an exciting model organism in plant genetics and also the most important crop worldwide for food, animal feed and bioenergy production. Recent genome-wide association and metabolic profiling studies aimed to resolve quantitative traits to their causal genetic loci and key metabolic regulators. Here we present a complementary approach that exploits large-scale genomic and metabolic information to predict complex, highly polygenic traits in hybrid testcrosses. We crossed 285 diverse Dent inbred lines from worldwide sources with two testers and predicted their combining abilities for seven biomass- and bioenergy-related traits using 56,110 SNPs and 130 metabolites. Whole-genome and metabolic prediction models were built by fitting effects for all SNPs or metabolites. Prediction accuracies ranged from 0.72 to 0.81 for SNPs and from 0.60 to 0.80 for metabolites, allowing a reliable screening of large collections of diverse inbred lines for their potential to create superior hybrids.

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Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development.

Publication Date: 2012 PMID: 22231485
Authors: Bonn, S. - Zinzen, R. P. - Girardot, C. - Gustafson, E. H. - Perez-Gonzalez, A. - Delhomme, N. - Ghavi-Helm, Y. - Wilczynski, B. - Riddell, A. - Furlong, E. E.
Journal: Nat Genet

Chromatin modifications are associated with many aspects of gene expression, yet their role in cellular transitions during development remains elusive. Here, we use a new approach to obtain cell type-specific information on chromatin state and RNA polymerase II (Pol II) occupancy within the multicellular Drosophila melanogaster embryo. We directly assessed the relationship between chromatin modifications and the spatio-temporal activity of enhancers. Rather than having a unique chromatin state, active developmental enhancers show heterogeneous histone modifications and Pol II occupancy. Despite this complexity, combined chromatin signatures and Pol II presence are sufficient to predict enhancer activity de novo. Pol II recruitment is highly predictive of the timing of enhancer activity and seems dependent on the timing and location of transcription factor binding. Chromatin modifications typically demarcate large regulatory regions encompassing multiple enhancers, whereas local changes in nucleosome positioning and Pol II occupancy delineate single active enhancers. This cell type-specific view identifies dynamic enhancer usage, an essential step in deciphering developmental networks.

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Genome-wide patterns of genetic variation in worldwide Arabidopsis thaliana accessions from the RegMap panel.

Publication Date: 2012 PMID: 22231484
Authors: Horton, M. W. - Hancock, A. M. - Huang, Y. S. - Toomajian, C. - Atwell, S. - Auton, A. - Muliyati, N. W. - Platt, A. - Sperone, F. G. - Vilhjalmsson, B. J. - Nordborg, M. - Borevitz, J. O. - Bergelson, J.
Journal: Nat Genet

Arabidopsis thaliana is native to Eurasia and is naturalized across the world. Its ability to be easily propagated and its high phenotypic variability make it an ideal model system for functional, ecological and evolutionary genetics. To date, analyses of the natural genetic variation of A. thaliana have involved small numbers of individual plants or genetic markers. Here we genotype 1,307 worldwide accessions, including several regional samples, using a 250K SNP chip. This allowed us to produce a high-resolution description of the global pattern of genetic variation. We applied three complementary selection tests and identified new targets of selection. Further, we characterized the pattern of historical recombination in A. thaliana and observed an enrichment of hotspots in its intergenic regions and repetitive DNA, which is consistent with the pattern that is observed for humans but which is strikingly different from that observed in other plant species. We have made the seeds we used to produce this Regional Mapping (RegMap) panel publicly available. This panel comprises one of the largest genomic mapping resources currently available for global natural isolates of a non-human species.

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De novo assembly and genotyping of variants using colored de Bruijn graphs.

Publication Date: 2012 PMID: 22231483
Authors: Iqbal, Z. - Caccamo, M. - Turner, I. - Flicek, P. - McVean, G.
Journal: Nat Genet

Detecting genetic variants that are highly divergent from a reference sequence remains a major challenge in genome sequencing. We introduce de novo assembly algorithms using colored de Bruijn graphs for detecting and genotyping simple and complex genetic variants in an individual or population. We provide an efficient software implementation, Cortex, the first de novo assembler capable of assembling multiple eukaryotic genomes simultaneously. Four applications of Cortex are presented. First, we detect and validate both simple and complex structural variations in a high-coverage human genome. Second, we identify more than 3 Mb of sequence absent from the human reference genome, in pooled low-coverage population sequence data from the 1000 Genomes Project. Third, we show how population information from ten chimpanzees enables accurate variant calls without a reference sequence. Last, we estimate classical human leukocyte antigen (HLA) genotypes at HLA-B, the most variable gene in the human genome.

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Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint.

Publication Date: 2012 PMID: 22231482
Authors: Gu, S. G. - Pak, J. - Guang, S. - Maniar, J. M. - Kennedy, S. - Fire, A.
Journal: Nat Genet

Exogenous double-stranded RNA (dsRNA) has been shown to exert homology-dependent effects at the level of both target mRNA stability and chromatin structure. Using C. elegans undergoing RNAi as an animal model, we have investigated the generality, scope and longevity of dsRNA-targeted chromatin effects and their dependence on components of the RNAi machinery. Using high-resolution genome-wide chromatin profiling, we found that a diverse set of genes can be induced to acquire locus-specific enrichment of histone H3 lysine 9 trimethylation (H3K9me3), with modification footprints extending several kilobases from the site of dsRNA homology and with locus specificity sufficient to distinguish the targeted locus from the other 20,000 genes in the C. elegans genome. Genetic analysis of the response indicated that factors responsible for secondary siRNA production during RNAi were required for effective targeting of chromatin. Temporal analysis revealed that H3K9me3, once triggered by dsRNA, can be maintained in the absence of dsRNA for at least two generations before being lost. These results implicate dsRNA-triggered chromatin modification in C. elegans as a programmable and locus-specific response defining a metastable state that can persist through generational boundaries.

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Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome.

Publication Date: 2012 PMID: 22231481
Authors: Samaco, R. C. - Mandel-Brehm, C. - McGraw, C. M. - Shaw, C. A. - McGill, B. E. - Zoghbi, H. Y.
Journal: Nat Genet

Genomic duplications spanning Xq28 are associated with a spectrum of phenotypes, including anxiety and autism. The minimal region shared among affected individuals includes MECP2 and IRAK1, although it is unclear which gene when overexpressed causes anxiety and social behavior deficits. We report that doubling MECP2 levels causes heightened anxiety and autism-like features in mice and alters the expression of genes that influence anxiety and social behavior, such as Crh and Oprm1. To test the hypothesis that alterations in these two genes contribute to heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) that have reduced Crh and Oprm1 expression. In MECP2-TG1 animals, reducing the levels of Crh or its receptor, Crhr1, suppressed anxiety-like behavior; in contrast, reducing Oprm1 expression improved abnormal social behavior. These data indicate that increased MeCP2 levels affect molecular pathways underlying anxiety and social behavior and provide new insight into potential therapies for MECP2-related disorders.

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