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  • 1
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    Global landscape of HIV-human protein complexes (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-12-23
    Description: Human immunodeficiency virus (HIV) has a small genome and therefore relies heavily on the host cellular machinery to replicate. Identifying which host proteins and complexes come into physical contact with the viral proteins is crucial for a comprehensive understanding of how HIV rewires the host's cellular machinery during the course of infection. Here we report the use of affinity tagging and purification mass spectrometry to determine systematically the physical interactions of all 18 HIV-1 proteins and polyproteins with host proteins in two different human cell lines (HEK293 and Jurkat). Using a quantitative scoring system that we call MiST, we identified with high confidence 497 HIV-human protein-protein interactions involving 435 individual human proteins, with approximately 40% of the interactions being identified in both cell types. We found that the host proteins hijacked by HIV, especially those found interacting in both cell types, are highly conserved across primates. We uncovered a number of host complexes targeted by viral proteins, including the finding that HIV protease cleaves eIF3d, a subunit of eukaryotic translation initiation factor 3. This host protein is one of eleven identified in this analysis that act to inhibit HIV replication. This data set facilitates a more comprehensive and detailed understanding of how the host machinery is manipulated during the course of HIV infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310911/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310911/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jager, Stefanie -- Cimermancic, Peter -- Gulbahce, Natali -- Johnson, Jeffrey R -- McGovern, Kathryn E -- Clarke, Starlynn C -- Shales, Michael -- Mercenne, Gaelle -- Pache, Lars -- Li, Kathy -- Hernandez, Hilda -- Jang, Gwendolyn M -- Roth, Shoshannah L -- Akiva, Eyal -- Marlett, John -- Stephens, Melanie -- D'Orso, Ivan -- Fernandes, Jason -- Fahey, Marie -- Mahon, Cathal -- O'Donoghue, Anthony J -- Todorovic, Aleksandar -- Morris, John H -- Maltby, David A -- Alber, Tom -- Cagney, Gerard -- Bushman, Frederic D -- Young, John A -- Chanda, Sumit K -- Sundquist, Wesley I -- Kortemme, Tanja -- Hernandez, Ryan D -- Craik, Charles S -- Burlingame, Alma -- Sali, Andrej -- Frankel, Alan D -- Krogan, Nevan J -- P01 AI090935/AI/NIAID NIH HHS/ -- P01 AI090935-02/AI/NIAID NIH HHS/ -- P01 GM073732-05/GM/NIGMS NIH HHS/ -- P41 GM103481/GM/NIGMS NIH HHS/ -- P41 RR001081/RR/NCRR NIH HHS/ -- P41RR001614/RR/NCRR NIH HHS/ -- P50 GM081879/GM/NIGMS NIH HHS/ -- P50 GM081879-02/GM/NIGMS NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- P50 GM082250-05/GM/NIGMS NIH HHS/ -- P50GM081879/GM/NIGMS NIH HHS/ -- P50GM082545/GM/NIGMS NIH HHS/ -- U54 RR022220/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Dec 21;481(7381):365-70. doi: 10.1038/nature10719.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22190034" target="_blank"〉PubMed〈/a〉
    Keywords: Affinity Labels ; Amino Acid Sequence ; Conserved Sequence ; Eukaryotic Initiation Factor-3/chemistry/metabolism ; HEK293 Cells ; HIV Infections/metabolism/virology ; HIV Protease/metabolism ; HIV-1/*chemistry/*metabolism/physiology ; *Host-Pathogen Interactions ; Human Immunodeficiency Virus Proteins/analysis/chemistry/isolation & ; purification/*metabolism ; Humans ; Immunoprecipitation ; Jurkat Cells ; Mass Spectrometry ; Protein Binding ; Protein Interaction Mapping/*methods ; Protein Interaction Maps/*physiology ; Reproducibility of Results ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Understanding mechanisms underlying human gene expression variation with RNA sequencing (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-03-12
    Description: Understanding the genetic mechanisms underlying natural variation in gene expression is a central goal of both medical and evolutionary genetics, and studies of expression quantitative trait loci (eQTLs) have become an important tool for achieving this goal. Although all eQTL studies so far have assayed messenger RNA levels using expression microarrays, recent advances in RNA sequencing enable the analysis of transcript variation at unprecedented resolution. We sequenced RNA from 69 lymphoblastoid cell lines derived from unrelated Nigerian individuals that have been extensively genotyped by the International HapMap Project. By pooling data from all individuals, we generated a map of the transcriptional landscape of these cells, identifying extensive use of unannotated untranslated regions and more than 100 new putative protein-coding exons. Using the genotypes from the HapMap project, we identified more than a thousand genes at which genetic variation influences overall expression levels or splicing. We demonstrate that eQTLs near genes generally act by a mechanism involving allele-specific expression, and that variation that influences the inclusion of an exon is enriched within and near the consensus splice sites. Our results illustrate the power of high-throughput sequencing for the joint analysis of variation in transcription, splicing and allele-specific expression across individuals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089435/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089435/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pickrell, Joseph K -- Marioni, John C -- Pai, Athma A -- Degner, Jacob F -- Engelhardt, Barbara E -- Nkadori, Everlyne -- Veyrieras, Jean-Baptiste -- Stephens, Matthew -- Gilad, Yoav -- Pritchard, Jonathan K -- GM077959/GM/NIGMS NIH HHS/ -- MH084703-01/MH/NIMH NIH HHS/ -- R01 GM077959/GM/NIGMS NIH HHS/ -- R01 GM077959-05/GM/NIGMS NIH HHS/ -- R01 MH084703/MH/NIMH NIH HHS/ -- R01 MH084703-02/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Apr 1;464(7289):768-72. doi: 10.1038/nature08872. Epub 2010 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Human Genetics, The University of Chicago, Chicago 60637, USA. pickrell@uchicago.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20220758" target="_blank"〉PubMed〈/a〉
    Keywords: African Continental Ancestry Group/genetics ; Alleles ; Consensus Sequence/genetics ; DNA, Complementary/genetics ; Exons/genetics ; *Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Humans ; Nigeria ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; RNA Splice Sites/genetics ; RNA, Messenger/*analysis/*genetics ; Sequence Analysis, RNA ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Animal research: replacing the lab rat (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-03-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stephens, Martin -- England -- Nature. 2011 Mar 24;471(7339):449. doi: 10.1038/471449c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430764" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Experimentation ; Animal Use Alternatives/*trends ; Animals ; *Animals, Laboratory ; Rats
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    DNase I sensitivity QTLs are a major determinant of human expression variation (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-07
    Description: The mapping of expression quantitative trait loci (eQTLs) has emerged as an important tool for linking genetic variation to changes in gene regulation. However, it remains difficult to identify the causal variants underlying eQTLs, and little is known about the regulatory mechanisms by which they act. Here we show that genetic variants that modify chromatin accessibility and transcription factor binding are a major mechanism through which genetic variation leads to gene expression differences among humans. We used DNase I sequencing to measure chromatin accessibility in 70 Yoruba lymphoblastoid cell lines, for which genome-wide genotypes and estimates of gene expression levels are also available. We obtained a total of 2.7 billion uniquely mapped DNase I-sequencing (DNase-seq) reads, which allowed us to produce genome-wide maps of chromatin accessibility for each individual. We identified 8,902 locations at which the DNase-seq read depth correlated significantly with genotype at a nearby single nucleotide polymorphism or insertion/deletion (false discovery rate = 10%). We call such variants 'DNase I sensitivity quantitative trait loci' (dsQTLs). We found that dsQTLs are strongly enriched within inferred transcription factor binding sites and are frequently associated with allele-specific changes in transcription factor binding. A substantial fraction (16%) of dsQTLs are also associated with variation in the expression levels of nearby genes (that is, these loci are also classified as eQTLs). Conversely, we estimate that as many as 55% of eQTL single nucleotide polymorphisms are also dsQTLs. Our observations indicate that dsQTLs are highly abundant in the human genome and are likely to be important contributors to phenotypic variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501342/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Degner, Jacob F -- Pai, Athma A -- Pique-Regi, Roger -- Veyrieras, Jean-Baptiste -- Gaffney, Daniel J -- Pickrell, Joseph K -- De Leon, Sherryl -- Michelini, Katelyn -- Lewellen, Noah -- Crawford, Gregory E -- Stephens, Matthew -- Gilad, Yoav -- Pritchard, Jonathan K -- HG006123/HG/NHGRI NIH HHS/ -- MH084703/MH/NIMH NIH HHS/ -- MH090951/MH/NIMH NIH HHS/ -- R01 HG006123/HG/NHGRI NIH HHS/ -- R01 HG006123-01/HG/NHGRI NIH HHS/ -- R01 HG006123-02/HG/NHGRI NIH HHS/ -- R01 MH090951/MH/NIMH NIH HHS/ -- R01 MH090951-01/MH/NIMH NIH HHS/ -- R01 MH090951-02/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 5;482(7385):390-4. doi: 10.1038/nature10808.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22307276" target="_blank"〉PubMed〈/a〉
    Keywords: Chromatin/genetics/metabolism ; *DNA Footprinting ; Deoxyribonuclease I/*metabolism ; Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Genome, Human/genetics ; Humans ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/*genetics ; Sequence Analysis, DNA ; Transcription Factors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    A statin-dependent QTL for GATM expression is associated with statin-induced myopathy (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-09-03
    Description: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mangravite, Lara M -- Engelhardt, Barbara E -- Medina, Marisa W -- Smith, Joshua D -- Brown, Christopher D -- Chasman, Daniel I -- Mecham, Brigham H -- Howie, Bryan -- Shim, Heejung -- Naidoo, Devesh -- Feng, QiPing -- Rieder, Mark J -- Chen, Yii-Der I -- Rotter, Jerome I -- Ridker, Paul M -- Hopewell, Jemma C -- Parish, Sarah -- Armitage, Jane -- Collins, Rory -- Wilke, Russell A -- Nickerson, Deborah A -- Stephens, Matthew -- Krauss, Ronald M -- HG002585/HG/NHGRI NIH HHS/ -- K99/R00HG006265/HG/NHGRI NIH HHS/ -- MC_U137686853/Medical Research Council/United Kingdom -- P30 DK063491/DK/NIDDK NIH HHS/ -- R00 HG006265/HG/NHGRI NIH HHS/ -- R01 HG002585/HG/NHGRI NIH HHS/ -- R01 HL104133/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL69757/HL/NHLBI NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Oct 17;502(7471):377-80. doi: 10.1038/nature12508. Epub 2013 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sage Bionetworks, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. lara.mangravite@sagebase.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995691" target="_blank"〉PubMed〈/a〉
    Keywords: Amidinotransferases/deficiency/*genetics/metabolism ; Cell Line ; Cholesterol/deficiency/metabolism/pharmacology ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacology ; Lymphocytes/cytology/drug effects/metabolism ; Muscular Diseases/*chemically induced/genetics/metabolism ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/*genetics ; Simvastatin/*adverse effects/pharmacology ; Sterol Regulatory Element Binding Proteins/metabolism ; Transcription, Genetic/drug effects
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Mangravite et al. reply (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-09-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mangravite, Lara M -- Engelhardt, Barbara E -- Stephens, Matthew -- Krauss, Ronald M -- England -- Nature. 2014 Sep 18;513(7518):E3. doi: 10.1038/nature13630.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sage Bionetworks, Seattle, Washington 98109, USA. ; 1] Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA [2] Present address: Biostatistics and Bioinformatics Department and Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA. ; 1] Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA [2] Department of Statistics, University of Chicago, Chicago, Illinois 60637, USA. ; Children's Hospital Research Institute, Oakland, California 94609, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25230670" target="_blank"〉PubMed〈/a〉
    Keywords: Amidinotransferases/*genetics ; Gene Expression Regulation/*drug effects ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects ; Muscular Diseases/*chemically induced ; Quantitative Trait Loci/*genetics ; Simvastatin/*adverse effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Control of Reactivated Proterozoic Basement Structures on Sandstone-Hosted Pb-Zn Deposits along the Caledonian Front, Sweden: Evidence from Airborne Magnetic Data, Structural Analysis, and Ore-Grade Modeling (2014)
    Society of Economic Geologists (SEG)
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    Publication Date: 2014-11-26
    Description: Strata-bound, nonstratiform, epigenetic galena-sphalerite-cement mineralization in Ediacaran-Cambrian sandstone, including the previously mined deposits at Laisvall and Vassbo, occurs along the eastern erosional front of the Caledonian orogen in Sweden. The sandstone is part of an autochthonous siliciclastic sedimentary sequence that rests unconformably on top of Proterozoic crystalline basement beneath the Caledonian thrust nappes. Linear anomalies have been identified in high-resolution airborne magnetic data that correspond to geologic features in the Proterozoic basement. Furthermore, the Laisvall and Vassbo strata-bound Pb-Zn deposits are both spatially associated with areas of change in the trend of the magnetic lineaments. Magnetic anomalies, trending either N-S to NE-SW and WNW-ESE to NW-SE in the Laisvall area, and NNE-SSW to NNW-SSE and NW-SE to W-E in the Vassbo area, were identified. In the Laisvall area, some magnetic minima and edges along magnetic gradients can be correlated with faults in the Proterozoic basement. The reactivation of these basement structures is expressed in the Ediacaran-Cambrian sedimentary cover rocks as newly formed faults with Phanerozoic displacement. Along individual faults belonging to two sets (NE-SW to N-S and WNW-ESE to NW-SE), synsedimentary block movement has been recognized. The highest Pb and Zn grades in Laisvall delineate orebodies and orebody trends that follow these faults. Areas where the faults change strike contain some of the largest and richest orebodies. In the Vassbo area, the orebody footprint reflects a folded dolerite dike in the underlying Proterozoic basement. The dike, modeled on the basis of borehole data, is recognized by a magnetic maximum and an edge along a magnetic gradient. No faults have been mapped at the ground surface as being related to the location of dolerite dikes in the basement. However, it is considered that the basement dikes illustrate a structural control, emplacement either producing a local fracture network or being driven by preexisting basement structures. The main orebodies in both deposits display funnel-shape geometry, fault-rooted in Laisvall and located close to the hinges of the folded dolerite dike in the basement at Vassbo. Metal distribution patterns are similar in both deposits and are characterized by Pb-rich cores proximal to the basement-steered structures while Zn-rich shells are distal from these structures. The funnel-shaped ore geometry is interpreted to reflect a fault-rooted migration path and the metal precipitation mechanism. In both deposits, the highest Pb and Zn grades occur at the top of sandstone paleoaquifers. Similar mineralization footprints, variation in grades, and paleoaquifer settings were recognized in several carbonate-hosted Mississippi Valley-type (MVT) Zn-Pb deposits (e.g., San Vicente deposit, Peru; Topla-Mežica deposits, Slovenia). This geometry is suggestive of a sour gas trap that accumulated by density at the top of paleoaquifers. This gas could have provided H 2 S by thermogenic sulfate reduction to the metal-bearing fluids and triggered precipitation of Pb-Zn sulfides. The combined evidence from the airborne magnetic data, the structural analysis and the geometry of the orebodies, and metal distribution suggests that the basement faults reactivated during the Ediacaran-Cambrian sedimentation, acted at a later time as feeders for the metal-bearing fluids to fertile horizons for mineralization, and localized deformation during postsedimentary and postmineralization tectonics.
    Print ISSN: 0361-0128
    Topics: Geosciences
    Published by Society of Economic Geologists (SEG)
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