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Lee, Youngseok,Lee, Yong,Lee, Jaejung,Bang, Sunhoe,Hyun, Seogang,Kang, Jongkyun,Hong, Sung-Tae,Bae, Eunkyung,Kaang, Bong-Kiun,Kim, Jaeseob Nature Pub. Co 2005 Nature genetics Vol.37 No.3
Several transient receptor potential channels were recently found to be activated by temperature stimuli in vitro. Their physiological and behavioral roles are largely unknown. From a temperature-preference behavior screen of 27,000 Drosophila melanogaster P-insertion mutants, we isolated a gene, named pyrexia (pyx), encoding a new transient receptor potential channel. Pyx was opened by temperatures above 40 °C in Xenopus laevis oocytes and HEK293T cells. It was ubiquitously expressed along the dendrites of a subset of peripheral nervous system neurons and was more permeable to K<SUP>+</SUP> than to Na<SUP>+</SUP>. Although some pyx alleles resulted in abnormal temperature preferences, pyx null flies did not have significantly different temperature preferences than wild-type flies. But 60% of pyx null flies were paralyzed within 3 min of exposure to 40 °C, whereas only 9% of wild-type flies were paralyzed by the same stimulus. From these findings, we propose that the primary in vivo role of Pyx is to protect flies from high-temperature stress.
Wong, Vanessa K,Baker, Stephen,Pickard, Derek J,Parkhill, Julian,Page, Andrew J,Feasey, Nicholas A,Kingsley, Robert A,Thomson, Nicholas R,Keane, Jacqueline A,Weill, Franç,ois-Xavier,Edwards, Dav Nature Pub. Co 2015 Nature genetics Vol.47 No.6
The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.
Yıldırım, Muhammed A,Goh, Kwang-Il,Cusick, Michael E,Barabá,si, Albert-Lá,szló,Vidal, Marc Nature Pub. Co 2007 Nature biotechnology Vol.25 No.10
The global set of relationships between protein targets of all drugs and all disease-gene products in the human protein–protein interaction or 'interactome' network remains uncharacterized. We built a bipartite graph composed of US Food and Drug Administration–approved drugs and proteins linked by drug–target binary associations. The resulting network connects most drugs into a highly interlinked giant component, with strong local clustering of drugs of similar types according to Anatomical Therapeutic Chemical classification. Topological analyses of this network quantitatively showed an overabundance of 'follow-on' drugs, that is, drugs that target already targeted proteins. By including drugs currently under investigation, we identified a trend toward more functionally diverse targets improving polypharmacology. To analyze the relationships between drug targets and disease-gene products, we measured the shortest distance between both sets of proteins in current models of the human interactome network. Significant differences in distance were found between etiological and palliative drugs. A recent trend toward more rational drug design was observed.
A common coding variant in CASP8 is associated with breast cancer risk
Cox, Angela,Dunning, Alison M,Garcia-Closas, Montserrat,Balasubramanian, Sabapathy,Reed, Malcolm W R,Pooley, Karen A,Scollen, Serena,Baynes, Caroline,Ponder, Bruce A J,Chanock, Stephen,Lissowska, Jola Nature Pub. Co 2007 Nature genetics Vol.39 No.3
The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 −202 C → A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3′ UTR A → G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9–15 studies, comprising 11,391–18,290 cases and 14,753–22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85–0.94) and 0.74 (95% c.i.: 0.62–0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P<SUB>trend</SUB> = 1.1 × 10<SUP>−7</SUP>) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02–1.13) and 1.16 (95% c.i.: 1.08–1.25), respectively; P<SUB>trend</SUB> = 2.8 × 10<SUP>−5</SUP>). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.
Choudhury, Aaheli Roy,Ju, Zhenyu,Djojosubroto, Meta W,Schienke, Andrea,Lechel, Andre,Schaetzlein, Sonja,Jiang, Hong,Stepczynska, Anna,Wang, Chunfang,Buer, Jan,Lee, Han-Woong,von Zglinicki, Thomas,Gans Nature Pub. Co 2007 Nature genetics Vol.39 No.1
Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1–5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.
Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer
Sakamoto, Hiromi,Yoshimura, Kimio,Saeki, Norihisa,Katai, Hitoshi,Shimoda, Tadakazu,Matsuno, Yoshihiro,Saito, Daizo,Sugimura, Haruhiko,Tanioka, Fumihiko,Kato, Shunji,Matsukura, Norio,Matsuda, Noriko,Na Nature Pub. Co 2008 Nature genetics Vol.40 No.6
Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38–1.89, P = 1.11 × 10<SUP>−9</SUP>). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r<SUP>2</SUP> = 0.995, D′ = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56–2.33, P = 8.01 × 10<SUP>−11</SUP>). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.
A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia
Yang, Suk-Kyun,Hong, Myunghee,Baek, Jiwon,Choi, Hyunchul,Zhao, Wanting,Jung, Yusun,Haritunians, Talin,Ye, Byong Duk,Kim, Kyung-Jo,Park, Sang Hyoung,Park, Soo-Kyung,Yang, Dong-Hoon,Dubinsky, Marla,Lee, Nature Pub. Co 2014 Nature genetics Vol.46 No.9
Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; P<SUB>combined</SUB> = 4.88 × 10<SUP>−94</SUP>). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10<SUP>−4</SUP>). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.
General rules for functional microRNA targeting
Kim, Doyeon,Sung, You Me,Park, Jinman,Kim, Sukjun,Kim, Jongkyu,Park, Junhee,Ha, Haeok,Bae, Jung Yoon,Kim, SoHui,Baek, Daehyun Nature Pub. Co 2016 Nature genetics Vol.48 No.12
<P>The functional rules for microRNA (miRNA) targeting remain controversial despite their biological importance because only a small fraction of distinct interactions, called site types, have been examined among an astronomical number of site types that can occur between miRNAs and their target mRNAs. To systematically discover functional site types and to evaluate the contradicting rules reported previously, we used large-scale transcriptome data and statistically examined whether each of approximately 2 billion site types is enriched in differentially downregulated mRNAs responding to overexpressed miRNAs. Accordingly, we identified seven non-canonical functional site types, most of which are novel, in addition to four canonical site types, while also removing numerous false positives reported by previous studies. Extensive experimental validation and significantly elevated 3' UTR sequence conservation indicate that these non-canonical site types may have biologically relevant roles. Our expanded catalog of functional site types suggests that the gene regulatory network controlled by miRNAs may be far more complex than currently understood.</P>
Minke whale genome and aquatic adaptation in cetaceans
Yim, Hyung-Soon,Cho, Yun Sung,Guang, Xuanmin,Kang, Sung Gyun,Jeong, Jae-Yeon,Cha, Sun-Shin,Oh, Hyun-Myung,Lee, Jae-Hak,Yang, Eun Chan,Kwon, Kae Kyoung,Kim, Yun Jae,Kim, Tae Wan,Kim, Wonduck,Jeon, Jeon Nature Pub. Co 2014 Nature genetics Vol.46 No.1
The shift from terrestrial to aquatic life by whales was a substantial evolutionary event. Here we report the whole-genome sequencing and de novo assembly of the minke whale genome, as well as the whole-genome sequences of three minke whales, a fin whale, a bottlenose dolphin and a finless porpoise. Our comparative genomic analysis identified an expansion in the whale lineage of gene families associated with stress-responsive proteins and anaerobic metabolism, whereas gene families related to body hair and sensory receptors were contracted. Our analysis also identified whale-specific mutations in genes encoding antioxidants and enzymes controlling blood pressure and salt concentration. Overall the whale-genome sequences exhibited distinct features that are associated with the physiological and morphological changes needed for life in an aquatic environment, marked by resistance to physiological stresses caused by a lack of oxygen, increased amounts of reactive oxygen species and high salt levels.
A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases
Zhao, Jian,Ma, Jianyang,Deng, Yun,Kelly, Jennifer A,Kim, Kwangwoo,Bang, So-Young,Lee, Hye-Soon,Li, Quan-Zhen,Wakeland, Edward K,Qiu, Rong,Liu, Mengru,Guo, Jianping,Li, Zhanguo,Tan, Wenfeng,Rasmussen, Nature Pub. Co 2017 Nature genetics Vol.49 No.3
<P>Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type 1 interferon signatures. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the lmmunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production(2), predisposes to SLE (odds ratio (OR) = 3.47 in Asians (P-meta = 3.1 x 10(-104)), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjogren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.</P>