| 1. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 2. |
- Birney, Ewan, et al.
(författare)
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Prepublication data sharing
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7261, s. 168-170
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Tidskriftsartikel (refereegranskat)abstract
- Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.
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| 3. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 4. |
- de Jong, F. A., et al.
(författare)
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Irinotecan-induced diarrhea : functional significance of the polymorphic ABCC2 transporter protein
- 2007
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 81:1, s. 42-49
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Tidskriftsartikel (refereegranskat)abstract
- Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04–0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49–7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.
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| 5. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 6. |
- Gilbert, T., et al.
(författare)
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DNA from Pre-Clovis Human Coprolites in Oregon, North America
- 2008
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 320:5877, s. 786-789
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Tidskriftsartikel (refereegranskat)abstract
- The timing of the first human migration into the Americas and its relation to the appearance of the Clovis technological complex in North America at about 11,000 to 10,800 radiocarbon years before the present ( C-14 years B. P.) remains contentious. We establish that humans were present at Paisley 5 Mile Point Caves, in south- central Oregon, by 12,300 C-14 years B. P., through the recovery of human mitochondrial DNA ( mtDNA) from coprolites, directly dated by accelerator mass spectrometry. The mtDNA corresponds to Native American founding haplogroups A2 and B2. The dates of the coprolites are > 1000 C-14 years earlier than currently accepted dates for the Clovis complex.
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| 7. |
- Worrillow, Lisa, et al.
(författare)
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Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma
- 2008
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 45:3, s. 142-146
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position-93, rs1800734) modifies the risk of cancer after methylating chemotherapy. Methods: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. Results: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. Conclusions: These data support the hypothesis that the common polymorphism at position - 93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
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| 8. |
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| 9. |
- Grundberg, Elin, et al.
(författare)
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Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells
- 2008
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 33:3, s. 301-11
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Tidskriftsartikel (refereegranskat)abstract
- Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.
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| 10. |
- Hill, Timothy, et al.
(författare)
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Small molecule inhibitors of dynamin I GTPase activity : development of dimeric tyrphostins.
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:24
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Tidskriftsartikel (refereegranskat)abstract
- Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a microM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 microM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low microM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50= 5.1 +/- 0.6 microM), its 3,4,5-trihydroxy congener (10) (IC50= 1.7 +/- 0.2 microM), and the corresponding 3-methyl ether (11) (IC50= 9 +/- 3 microM). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50's of 1.7 +/- 0.2, 1.7 +/- 0.2, and 5 +/- 1 microM, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50's of 42 +/- 3, 38 +/- 2, and 61 +/- 2 microM, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.
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