Cecilia Penedo

Genetics, Molecular Biology

38.15

Publications

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    ABSTRACT: Background: Sebaceous adenitis (SA) and Addison's disease (AD) increased rapidly in incidence among Standard Poodles after the mid-twentieth century. Previous attempts to identify specific genetic causes using genome wide association studies and interrogation of the dog leukocyte antigen (DLA) region have been non-productive. However, such studies led us to hypothesize that positive selection for desired phenotypic traits that arose in the mid-twentieth century led to intense inbreeding and the inadvertent amplification of AD and SA associated traits. Results: This hypothesis was tested with genetic studies of 761 Standard, Miniature, and Miniature/Standard Poodle crosses from the USA, Canada and Europe, coupled with extensive pedigree analysis of thousands more dogs. Genome-wide diversity across the world-wide population was measured using a panel of 33 short tandem repeat (STR) loci. Allele frequency data were also used to determine the internal relatedness of individual dogs within the population as a whole. Assays based on linkage between STR genomic loci and DLA genes were used to identify class I and II haplotypes and disease associations. Genetic diversity statistics based on genomic STR markers indicated that Standard Poodles from North America and Europe were closely related and reasonably diverse across the breed. However, genetic diversity statistics, internal relatedness, principal coordinate analysis, and DLA haplotype frequencies showed a marked imbalance with 30 % of the diversity in 70 % of the dogs. Standard Poodles with SA and AD were strongly linked to this inbred population, with dogs suffering with SA being the most inbred. No single strong association was found between STR defined DLA class I or II haplotypes and SA or AD in the breed as a whole, although certain haplotypes present in a minority of the population appeared to confer moderate degrees of risk or protection against either or both diseases. Dogs possessing minor DLA class I haplotypes were half as likely to develop SA or AD as dogs with common haplotypes. Miniature/Standard Poodle crosses being used for outcrossing were more genetically diverse than Standard Poodles and genetically distinguishable across the genome and in the DLA class I and II region. Conclusions: Ancestral genetic polymorphisms responsible for SA and AD entered Standard Poodles through separate lineages, AD earlier and SA later, and were increasingly fixed by a period of close linebreeding that was related to popular bloodlines from the mid-twentieth century. This event has become known as the midcentury bottleneck or MCB. Sustained positive selection resulted in a marked imbalance in genetic diversity across the genome and in the DLA class I and II region. Both SA and AD were concentrated among the most inbred dogs, with genetic outliers being relatively disease free. No specific genetic markers other than those reflecting the degree of inbreeding were consistently associated with either disease. Standard Poodles as a whole remain genetically diverse, but steps should be taken to rebalance diversity using genetic outliers and if necessary, outcrosses to phenotypically similar but genetically distinct breeds.
    Full-text · Article · Dec 2015
  • H M Holl · S A Brooks · S Archer · K Brown · J Malvick · M C T Penedo · R R Bellone
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    ABSTRACT: Leopard complex spotting (LP), the result of an incompletely dominant mutation in TRPM1, produces a collection of unique depigmentation patterns in the horse. Although the LP mutation allows for expression of the various patterns, other loci are responsible for modification of the extent of white. Pedigree analysis of families segregating for high levels of patterning indicated a single dominant gene, named Pattern-1 (PATN1), as a major modifier of LP. Linkage analysis in two half-sibling families segregating for PATN1 identified a 15-Mb region on ECA3p that warranted further investigation. Whole transcriptome sequencing of skin samples from horses with and without the PATN1 allele was performed to identify genic SNPs for fine mapping. Two Sequenom assays were utilized to genotype 192 individuals from five LP-carrying breeds. The initial panel highlighted a 1.6-Mb region without a clear candidate gene. In the second round of fine mapping, SNP ECA3:23 658 447T>G in the 3'-UTR of RING finger and WD repeat domain 3 (RFWD3) reached a significance level of P = 1.063 × 10(-39) . Sequencing of RFWD3 did not identify any coding polymorphisms specific to PATN1 horses. Genotyping of the RFWD3 3'-UTR SNP in 54 additional LP animals and 327 horses from nine breeds not segregating for LP further supported the association (P = 4.17 × 10(-115) ). This variant is a strong candidate for PATN1 and may be particularly useful for LP breeders to select for high levels of white patterning.
    No preview · Article · Nov 2015 · Animal Genetics
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    Michael S. Mooring · M. Cecilia T. Penedo

    Full-text · Dataset · Oct 2015
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    ABSTRACT: Within the United States (US), Peninsular bighorn sheep (Ovis canadensis nelsoni, PBS) are listed as federally endangered. Despite known metapopulation structure, little is known regarding functional connectivity across the international border with Mexico. Increasing threats to connectivity associated with highway expansion, renewable energy development, and completion of the US–Mexico border fence, led us to conduct a study of genetic variation and spatial structure. Blood and fecal samples were collected (n = 224) on both sides of the border from 1992 to 2013. Genetic data was obtained for 25 microsatellite loci and 515 base pairs of the mitochondrial DNA control region. Microsatellite diversity (observed heterozygosity = 0.56; allelic richness = 4.1; inbreeding coefficient = 0.01) was substantial despite past demographic declines. STRUCTURE analysis indicated the presence of three genetic populations, one of which spanned the international border. This pattern of genetic structure was supported by analysis of molecular variance for both microsatellites and mitochondrial DNA (P < 0.01), and low-moderate pairwise fixation indices (FST = 0.09–0.15; ΦST = 0.18–0.27) indicated substantial gene flow among populations. Migrant detection tests indicated natal dispersal occurred within both sexes, with no evidence of sex bias. Despite the severe reductions in population abundance which led to federal listing in the US, these data suggest PBS have retained substantial genetic variation and show little evidence of a recent genetic bottleneck. Patterns of genetic spatial structure indicate gene flow throughout the ranges is common, and construction of a US–Mexico border fence or wind energy infrastructure would disrupt connectivity of the metapopulation. Future conservation efforts should focus on identifying dispersal corridors and maintaining functional connectivity to facilitate recolonization of unoccupied habitat.
    Full-text · Article · Apr 2015 · Biological Conservation
  • Y H Choi · M C T Penedo · P Daftari · I C Velez · K Hinrichs
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    ABSTRACT: Preimplantation genetic diagnosis has great potential in the horse, but information on evaluation of equine embryo biopsy samples is limited. Blastocysts were biopsied using a Piezo drill and methods for whole-genome amplification (WGA) investigated. Results for 33 genetic loci were then compared between biopsy samples from in vitro-produced (IVP) and in vivo-recovered (VIV) blastocysts. Under the experimental conditions described, WGA using the Qiagen Repli-g Midi kit was more accurate than that using the Illustra Genomiphi V2 kit (98.2% vs 25.8%, respectively). Using WGA with the Qiagen kit, three biopsy samples were evaluated from each of eight IVP and 19 VIV blastocysts, some produced using semen from stallions carrying the genetic mutations associated with the diseases hereditary equine regional dermal asthenia (HERDA), hyperkalemic periodic paralysis (HYPP) or polysaccharide storage myopathy 1 (PSSM1). Three of 81 biopsy samples (3.7%) returned 95% overall accuracy in IVP and VIV embryos, and this technique is suitable for use in a clinical setting.
    No preview · Article · Mar 2015 · Reproduction Fertility and Development
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    Michael S. Mooring · M. Cecilia T. Penedo
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    ABSTRACT: Accurate measures of fitness are important for both basic research on sexual selection and applied conservation actions to promote genetic diversity. For polygynous mammals, good estimates of male reproductive success are often critically important, but especially difficult to obtain. Because the genetic contribution of males is impossible to directly measure in the field, investigators have developed surrogate measures of fitness based on behavioral observations. Such measures are founded on the assumption that observed mating success can reliably predict reproductive success, yet only a few studies have been in a position to validate the accuracy of this assumption. We studied the bison herd at Fort Niobrara National Wildlife Refuge for 8 years, conducting intensive behavioral observations on breeding behavior during the rut (2003-2009) and collecting tissue samples of calves born the following year (2004-2010) for genetic paternity analysis. Our results reveal 2 major trends also observed in other studies: Estimates of mating success were positively correlated with reproductive success when we pooled the entire herd across age classes or years. However, copulatory success did a poor job of predicting the actual number of offspring sired by individual males. For example, 44% of observed matings did not result in the birth of offspring, and 60% of the copulations that did produce a calf did not accurately predict the sire bull. Generalized linear mixed model analysis revealed that observation of mating by a given bull in itself had no predictive power regarding likelihood of paternity, whereas total copulations per season, dominance status, and age of bull or dam significantly influenced the probability of siring offspring. Although use of behavioral data was unable to predict the sire for particular cows, it did give insights into patterns of reproductive success that use of genetic data alone could not provide, such as the role of alternate mating strategies and sperm competition for male reproductive success. We conclude that both behavioral and genetic measures of fitness are needed to understand sexual selection and meet the challenges faced by species of conservation concern.
    Full-text · Article · Oct 2014 · Journal of Mammalogy
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    L C Gershony · M C T Penedo · B W Davis · W J Murphy · C R Helps · L A Lyons
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    ABSTRACT: Coat colours and patterns are highly variable in cats and are determined mainly by several genes with Mendelian inheritance. A 2-bp deletion in agouti signalling protein (ASIP) is associated with melanism in domestic cats. Bengal cats are hybrids between domestic cats and Asian leopard cats (Prionailurus bengalensis), and the charcoal coat colouration/pattern in Bengals presents as a possible incomplete melanism. The complete coding region of ASIP was directly sequenced in Asian leopard, domestic and Bengal cats. Twenty-seven variants were identified between domestic and leopard cats and were investigated in Bengals and Savannahs, a hybrid with servals (Leptailurus serval). The leopard cat ASIP haplotype was distinguished from domestic cat by four synonymous and four non-synonymous exonic SNPs, as well as 19 intronic variants, including a 42-bp deletion in intron 4. Fifty-six of 64 reported charcoal cats were compound heterozygotes at ASIP, with leopard cat agouti (A(P) (be) ) and domestic cat non-agouti (a) haplotypes. Twenty-four Bengals had an additional unique haplotype (A2) for exon 2 that was not identified in leopard cats, servals or jungle cats (Felis chaus). The compound heterozygote state suggests the leopard cat allele, in combination with the recessive non-agouti allele, influences Bengal markings, producing a darker, yet not completely melanistic coat. This is the first validation of a leopard cat allele segregating in the Bengal breed and likely affecting their overall pelage phenotype. Genetic testing services need to be aware of the possible segregation of wild felid alleles in all assays performed on hybrid cats.
    Full-text · Article · Aug 2014 · Animal Genetics
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    ABSTRACT: Background/Question/Methods Peninsular bighorn sheep (Ovis canadensis nelsoni, PBS) are a federally endangered metapopulation of desert bighorn sheep endemic to the Peninsular Ranges of southern California, extending to the U.S./Mexico border. This metapopulation declined to <300 animals prior to listing in 1999, and is currently managed within a series of recovery regions approximating ewe home range groups. The goal of this project was to examine genetic diversity and spatial structure within the metapopulation and determine the extent of gene flow among selected recovery regions. Genetic data was generated by amplifying 39 microsatellite loci and a 515 bp fragment of the mtDNA control region from blood samples collected from sheep (n= 165) captured in seven recovery regions from 1992 to 2013. Results/Conclusions STRUCTURE analysis of microsatellite genotypes clustered sheep into two distinct genetic groups (north vs. south). Significant pairwise FST estimates among sheep from seven recovery regions (0.03 to 0.12) generally supported the presence of two genetic groups, with the possibility of additional substructure in the north (pairwise FST = 0.03 to 0.04, amova P = 0.02). Mitochondrial DNA analyses revealed five distinct haplotypes and indicated a similar pattern of north vs. south population structure (pairwise ΦST = 0.27 to 0.50). Considerable microsatellite diversity was found within both northern and southern groups (mean HO = 0.496; allelic richness = 3.47; FIS = 0.02), comparable to published accounts for desert bighorn sheep in other regions. We identified first-generation migrants of both sexes using GENECLASS2, but significantly lower assignment indices (AIc) among rams (Mann-Whitney U-test: P < 0.01) suggested dispersal was primarily male biased. Despite past population declines and ongoing deterministic threats, PBS have retained substantial genetic variation and gene flow among regions. Future conservation efforts should not only focus on sustaining population numbers, but also maintaining functional connectivity so the recovering metapopulation can expand into available habitat throughout the Peninsular Ranges.
    No preview · Conference Paper · Aug 2014
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    Full-text · Dataset · Jan 2014
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    ABSTRACT: For centuries, domestic horses have represented an important means of transport and served as working and companion animals. Although their role in transportation is less important today, many horse breeds are still subject to intense selection based on their pattern of locomotion. A striking example of such a selected trait is the ability of a horse to perform additional gaits other than the common walk, trot and gallop. Those could be four-beat ambling gaits, which are particularly smooth and comfortable for the rider, or pace, used mainly in racing. Gaited horse breeds occur around the globe, suggesting that gaitedness is an old trait, selected for in many breeds. A recent study discovered that a nonsense mutation in DMRT3 has a major impact on gaitedness in horses and is present at a high frequency in gaited breeds and in horses bred for harness racing. Here, we report a study of the worldwide distribution of this mutation. We genotyped 4396 horses representing 141 horse breeds for the DMRT3 stop mutation. More than half (2749) of these horses also were genotyped for a SNP situated 32 kb upstream of the DMRT3 nonsense mutation because these two SNPs are in very strong linkage disequilibrium. We show that the DMRT3 mutation is present in 68 of the 141 genotyped horse breeds at a frequency ranging from 1% to 100%. We also show that the mutation is not limited to a geographical area, but is found worldwide. The breeds with a high frequency of the stop mutation (>50%) are either classified as gaited or bred for harness racing. Introduction Few animals have been of such great value to humans as horses when it comes to means of transportation. All over the world, horses have been used for everyday transporta-tion, in military settings, cattle herding and agricultural power, pulling carriages and carts, pleasure riding or racing. Over the centuries, horse populations and breeds
    Full-text · Dataset · Jan 2014
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    ABSTRACT: For centuries, domestic horses have represented an important means of transport and served as working and companion animals. Although their role in transportation is less important today, many horse breeds are still subject to intense selection based on their pattern of locomotion. A striking example of such a selected trait is the ability of a horse to perform additional gaits other than the common walk, trot and gallop. Those could be four-beat ambling gaits, which are particularly smooth and comfortable for the rider, or pace, used mainly in racing. Gaited horse breeds occur around the globe, suggesting that gaitedness is an old trait, selected for in many breeds. A recent study discovered that a nonsense mutation in DMRT3 has a major impact on gaitedness in horses and is present at a high frequency in gaited breeds and in horses bred for harness racing. Here, we report a study of the worldwide distribution of this mutation. We genotyped 4396 horses representing 141 horse breeds for the DMRT3 stop mutation. More than half (2749) of these horses also were genotyped for a SNP situated 32 kb upstream of the DMRT3 nonsense mutation because these two SNPs are in very strong linkage disequilibrium. We show that the DMRT3 mutation is present in 68 of the 141 genotyped horse breeds at a frequency ranging from 1% to 100%. We also show that the mutation is not limited to a geographical area, but is found worldwide. The breeds with a high frequency of the stop mutation (>50%) are either classified as gaited or bred for harness racing.
    Full-text · Article · Jan 2014 · Animal Genetics
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    Full-text · Dataset · Nov 2013
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    ABSTRACT: Determining the value of livestock breeds is essential to define conservation priorities, manage genetic diversity and allocate funds. Within- and between-breed genetic diversity need to be assessed to preserve the highest intra-specific variability. Information on genetic diversity and risk status is still lacking for many Creole cattle breeds from the Americas, despite their distinct evolutionary trajectories and adaptation to extreme environmental conditions. A comprehensive genetic analysis of 67 Iberoamerican cattle breeds was carried out with 19 FAO-recommended microsatellites to assess conservation priorities. Contributions to global diversity were investigated using alternative methods, with different weights given to the within- and between-breed components of genetic diversity. Information on Iberoamerican plus 15 worldwide cattle breeds was used to investigate the contribution of geographical breed groups to global genetic diversity. Overall, Creole cattle breeds showed a high level of genetic diversity with the highest level found in breeds admixed with zebu cattle, which were clearly differentiated from all other breeds. Within-breed kinships revealed seven highly inbred Creole breeds for which measures are needed to avoid further genetic erosion. However, if contribution to heterozygosity was the only criterion considered, some of these breeds had the lowest priority for conservation decisions. The Weitzman approach prioritized highly differentiated breeds, such as Guabala, Romosinuano, Cr. Patagonico, Siboney and Caracu, while kinship-based methods prioritized mainly zebu-related breeds. With the combined approaches, breed ranking depended on the weights given to the within- and between-breed components of diversity. Overall, the Creole groups of breeds were generally assigned a higher priority for conservation than the European groups of breeds. Conservation priorities differed significantly according to the weight given to within- and between-breed genetic diversity. Thus, when establishing conservation programs, it is necessary to also take into account other features. Creole cattle and local isolated breeds retain a high level of genetic diversity. The development of sustainable breeding and crossbreeding programs for Creole breeds, and the added value resulting from their products should be taken into consideration to ensure their long-term survival.
    Full-text · Article · Sep 2013 · Genetics Selection Evolution
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    ABSTRACT: To assist cattle producers transition from microsatellite (MS) to single nucleotide polymorphism (SNP) genotyping for parental verification we previously devised an effective and inexpensive method to impute MS alleles from SNP haplotypes. While the reported method was verified with only a limited data set (N = 479) from Brown Swiss, Guernsey, Holstein, and Jersey cattle, some of the MS-SNP haplotype associations were concordant across these phylogenetically diverse breeds. This implied that some haplotypes predate modern breed formation and remain in strong linkage disequilibrium. To expand the utility of MS allele imputation across breeds, MS and SNP data from more than 8000 animals representing 39 breeds (Bos taurus and B. indicus) were used to predict 9410 SNP haplotypes, incorporating an average of 73 SNPs per haplotype, for which alleles from 12 MS markers could be accurately be imputed. Approximately 25% of the MS-SNP haplotypes were present in multiple breeds (N = 2 to 36 breeds). These shared haplotypes allowed for MS imputation in breeds that were not represented in the reference population with only a small increase in Mendelian inheritance inconsistancies. Our reported reference haplotypes can be used for any cattle breed and the reported methods can be applied to any species to aid the transition from MS to SNP genetic markers. While ~91% of the animals with imputed alleles for 12 MS markers had ≤1 Mendelian inheritance conflicts with their parents' reported MS genotypes, this figure was 96% for our reference animals, indicating potential errors in the reported MS genotypes. The workflow we suggest autocorrects for genotyping errors and rare haplotypes, by MS genotyping animals whose imputed MS alleles fail parentage verification, and then incorporating those animals into the reference dataset.
    Full-text · Article · Sep 2013 · Frontiers in Genetics
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    ABSTRACT: Variants in the EDNRB, KIT, MITF, PAX3 and TRPM1 genes are known to cause white spotting phenotypes in horses, which can range from the common white markings up to completely white horses. In this study, we investigated these candidate genes in 169 horses with white spotting phenotypes not explained by the previously described variants. We identified a novel missense variant, PAX3:p.Pro32Arg, in Appaloosa horses with a splashed white phenotype in addition to their leopard complex spotting patterns. We also found three novel variants in the KIT gene. The splice site variant c.1346+1G>A occurred in a Swiss Warmblood horse with a pronounced depigmentation phenotype. The missense variant p.Tyr441Cys was present in several part-bred Arabians with sabino-like depigmentation phenotypes. Finally, we provide evidence suggesting that the common and widely distributed KIT:p.Arg682His variant has a very subtle white-increasing effect, which is much less pronounced than the effect of the other described KIT variants. We termed the new KIT variants W18-W20 to provide a simple and unambiguous nomenclature for future genetic testing applications.
    Full-text · Article · May 2013 · Animal Genetics
  • M. C. T. Penedo · Terje Raudsepp
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    ABSTRACT: This chapter contains sections titled: Introduction Genetic Tests for Individual Identification and Parentage Analysis Genetic Tests for Genetic Diseases Genetic Tests for Phenotypic Traits Future Developments in Molecular Genetic Testing Karyotyping Services Available for the Horse Molecular Genetic Testing and Equine Cytogenetic Resources References
    No preview · Chapter · Feb 2013
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    Full-text · Dataset · Feb 2013
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    ABSTRACT: Horses were domesticated from the Eurasian steppes 5,000-6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. F(ST) calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection.
    Full-text · Article · Jan 2013 · PLoS ONE
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    ABSTRACT: Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.
    Full-text · Article · Jan 2013 · PLoS Genetics
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    Full-text · Dataset · Jan 2013

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