| 1. |
- Sodergren, Erica, et al.
(författare)
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The genome of the sea urchin Strongylocentrotus purpuratus.
- 2006
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 314:5801, s. 941-52
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Tidskriftsartikel (refereegranskat)abstract
- We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
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| 2. |
- Burke, R. D., et al.
(författare)
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A genomic view of the sea urchin nervous system
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 300:1, s. 434-460
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Tidskriftsartikel (refereegranskat)abstract
- The sequencing of the Strongylocentrotus purpuratus genome provides a unique opportunity to investigate the function and evolution of neural genes. The neurobiology of sea urchins is of particular interest because they have a close phylogenetic relationship with chordates, yet a distinctive pentaradiate body plan and unusual neural organization. Orthologues of transcription factors that regulate neurogenesis in other animals have been identified and several are expressed in neurogenic domains before gastrulation indicating that they may operate near the top of a conserved neural gene regulatory network. A family of genes encoding voltage-gated ion channels is present but, surprisingly, genes encoding gap junction proteins (connexins and pannexins) appear to be absent. Genes required for synapse formation and function have been identified and genes for synthesis and transport of neurotransmitters are present. There is a large family of G-protein-coupled receptors, including 874 rhodopsin-type receptors, 28 metabotropic glutamate-like receptors and a remarkably expanded group of 161 secretin receptor-like proteins. Absence of cannabinoid, lysophospholipid and melanocortin receptors indicates that this group may be unique to chordates. There are at least 37 putative G-protein-coupled peptide receptors and precursors for several neuropeptides and peptide hormones have been identified, including SALMFamides, NGFFFamide, a vasotocin-like peptide, glycoprotein hormones and insulin/insulin-like growth factors. Identification of a neurotrophin-like gene and Trk receptor in sea urchin indicates that this neural signaling system is not unique to chordates. Several hundred chemoreceptor genes have been predicted using several approaches, a number similar to that for other animals. Intriguingly, genes encoding homologues of rhodopsin, Pax6 and several other key mammalian retinal transcription factors are expressed in tube feet, suggesting tube feet function as photosensory organs. Analysis of the sea urchin genome presents a unique perspective on the evolutionary history of deuterostome nervous systems and reveals new approaches to investigate the development and neurobiology of sea urchins. (c) 2006 Elsevier Inc. All rights reserved.
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| 3. |
- Chen, Wei-Min, et al.
(författare)
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Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.
- 2008
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; Jun 2, s. 2620-2628
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
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| 4. |
- Garcia-Closas, Montserrat, et al.
(författare)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Tidskriftsartikel (refereegranskat)abstract
- A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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| 5. |
- Kamel, Ihab R., et al.
(författare)
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N-Methyl-D-Aspartate (NMDA) Antagonists-S(+)-ketamine, Dextrorphan, and Dextromethorphan-Act as Calcium Antagonists on Bovine Cerebral Arteries
- 2008
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Ingår i: Journal of Neurosurgical Anesthesiology. - 1537-1921. ; 20:4, s. 241-248
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Tidskriftsartikel (refereegranskat)abstract
- Ketamine an intravenous anesthetic and a major drug of abuse, is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Ketamine's enantiomer. S(+)-ketamine, acts stereoselectively on neuronal NMDA receptors. The purpose of this in vitro study was to compare the direct effects of S(+)-ketamine. 2 other noncompetitive NMDA receptor antagonists (dextrorphan and dextromethorphan), and the calcium entry blocker nimodipine on the cerebral vasculature, using bovine middle cerebral arterics as an experimental model. Arterial rings were mounted in isolated tissue chambers equipped with isometric tension transducers to obtain pharmacologic dose-response curves. In the absence of exogenous vasoconstrictor, the NMDA antagonists or nimodipine had negligible effects oil cerebral arterial tone. When rings were preconstricted with either potassium or the stable thromboxane A(2) mimetic U46619. the NMDA antagonists and nimodipine each produced dose-dependent relaxation. Prior endothelial stripping had no effect on subsequent drug-induced relaxation of K+-constricted rings. In Ca2+-deficient media containing either potassium or U46619. the NMDA antagonists and nimodipine each produced competitive inhibition of subsequent Ca2+ induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using (45)calcium (Ca-45) as a radioactive tracer. The NMDA antagonists and nimodipine each blocked potasium-stimulated or U46619-stilmulated Ca-45 uptake into arterial strips. These results indicate that S(+)-ketamine, dextrorphan, arteries by acting as calcium antagonists; they all inhibit Ca-45 uptake through both potential-operated (potassium) and receptor-operated (U46619) channels in cerebrovascular smooth muscle.
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| 6. |
- Prokopenko, Inga, et al.
(författare)
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Variants in MTNR1B influence fasting glucose levels
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
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Tidskriftsartikel (refereegranskat)abstract
- To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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| 7. |
- Zeggini, Eleftheria, et al.
(författare)
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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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