146 results on '"Kidd JM"'
Search Results
52. Comparative efficacy of human-simulated epithelial lining fluid exposures of tedizolid, linezolid and vancomycin in neutropenic and immunocompetent murine models of staphylococcal pneumonia.
- Author
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Kidd JM, Abdelraouf K, and Nicolau DP
- Subjects
- Animals, Colony Count, Microbial, Disease Models, Animal, Female, Lung microbiology, Mice, Inbred BALB C, Neutropenia complications, Protein Synthesis Inhibitors, Treatment Outcome, Anti-Bacterial Agents therapeutic use, Linezolid therapeutic use, Oxazolidinones therapeutic use, Pneumonia, Staphylococcal drug therapy, Tetrazoles therapeutic use, Vancomycin therapeutic use
- Abstract
Objectives: Few antibiotics are approved to treat Staphylococcus aureus pneumonia. Tedizolid is an oxazolidinone with potent in vitro activity against S. aureus and is currently under investigation for hospital-acquired and ventilator-associated bacterial pneumonia. Limited data exist on the comparative efficacy of tedizolid versus current first-line treatments vancomycin and linezolid in the compromised host. Our objective was to compare the efficacy of human-simulated epithelial lining fluid (ELF) exposures of tedizolid, linezolid and vancomycin against S. aureus in neutropenic and immunocompetent murine pneumonia models., Methods: Eight S. aureus isolates (four MRSA and four MSSA) were studied. Neutropenic and immunocompetent mice were inoculated intranasally with bacterial suspensions of 107 and 109 cfu/mL, respectively, then treated for up to 72 h with model-specific regimens of tedizolid, linezolid and vancomycin simulating human ELF exposures after clinical doses. Mice were sacrificed at 24, 48 or 72 h and changes in log10 cfu/lungs were compared with 0 h controls., Results: Mean bacterial burdens at 0 h were 5.81 and 8.17 log10 cfu/lungs for neutropenic and immunocompetent mice, respectively, and increased at 24 h in the absence of antibiotic treatment to 7.97 and 9.00 log10 cfu/lungs, respectively. In neutropenic and immunocompetent mice, tedizolid was associated with bacterial density changes of -2.69 ± 0.62 and -3.57 ± 0.88 log10 cfu/lungs at 72 h, respectively. In both models, tedizolid treatment produced greater bacterial reductions than vancomycin and was not statistically significantly different from linezolid., Conclusions: Human-simulated ELF exposures of tedizolid demonstrated sustained efficacy in compromised and competent models of pneumonia. Validation of these findings in patients is warranted., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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53. Origin and recent expansion of an endogenous gammaretroviral lineage in domestic and wild canids.
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Halo JV, Pendleton AL, Jarosz AS, Gifford RJ, Day ML, and Kidd JM
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- Animals, Computational Biology, High-Throughput Nucleotide Sequencing, Proviruses classification, Proviruses genetics, Retroviridae Infections virology, Canidae, Endogenous Retroviruses classification, Endogenous Retroviruses genetics, Evolution, Molecular, Retroviridae Infections veterinary
- Abstract
Background: Vertebrate genomes contain a record of retroviruses that invaded the germlines of ancestral hosts and are passed to offspring as endogenous retroviruses (ERVs). ERVs can impact host function since they contain the necessary sequences for expression within the host. Dogs are an important system for the study of disease and evolution, yet no substantiated reports of infectious retroviruses in dogs exist. Here, we utilized Illumina whole genome sequence data to assess the origin and evolution of a recently active gammaretroviral lineage in domestic and wild canids., Results: We identified numerous recently integrated loci of a canid-specific ERV-Fc sublineage within Canis, including 58 insertions that were absent from the reference assembly. Insertions were found throughout the dog genome including within and near gene models. By comparison of orthologous occupied sites, we characterized element prevalence across 332 genomes including all nine extant canid species, revealing evolutionary patterns of ERV-Fc segregation among species as well as subpopulations., Conclusions: Sequence analysis revealed common disruptive mutations, suggesting a predominant form of ERV-Fc spread by trans complementation of defective proviruses. ERV-Fc activity included multiple circulating variants that infected canid ancestors from the last 20 million to within 1.6 million years, with recent bursts of germline invasion in the sublineage leading to wolves and dogs.
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- 2019
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54. Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.
- Author
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Stein GE, Smith CL, Scharmen A, Kidd JM, Cooper C, Kuti J, Mitra S, Nicolau DP, and Havlichek DH
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- Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents administration & dosage, Azabicyclo Compounds administration & dosage, Ceftazidime administration & dosage, Drug Combinations, Enterobacteriaceae drug effects, Enterobacteriaceae physiology, Enterobacteriaceae Infections drug therapy, Female, Humans, Male, Microbial Sensitivity Tests, Microbial Viability drug effects, Middle Aged, Monte Carlo Method, Prospective Studies, Serum chemistry, Time Factors, beta-Lactamase Inhibitors administration & dosage, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Azabicyclo Compounds pharmacokinetics, Azabicyclo Compounds pharmacology, Ceftazidime pharmacokinetics, Ceftazidime pharmacology, Critical Illness, beta-Lactamase Inhibitors pharmacokinetics, beta-Lactamase Inhibitors pharmacology
- Abstract
Background: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients., Patients and Methods: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA., Results: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log
10 CFU/mL reduction) activity against each of the study isolates., Conclusion: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.- Published
- 2019
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55. Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration.
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Sivakumaran TA, Igo RP Jr, Kidd JM, Itsara A, Kopplin LJ, Chen W, Hagstrom SA, Peachey NS, Francis PJ, Klein ML, Chew EY, Ramprasad VL, Tay WT, Mitchell P, Seielstad M, Stambolian DE, Edwards AO, Lee KE, Leontiev DV, Jun G, Wang Y, Tian L, Qiu F, Henning AK, LaFramboise T, Sen P, Aarthi M, George R, Raman R, Das MK, Vijaya L, Kumaramanickavel G, Wong TY, Swaroop A, Abecasis GR, Klein R, Klein BEK, Nickerson DA, Eichler EE, and Iyengar SK
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0025598.].
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- 2018
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56. Optimizing Antibiotic Administration for Pneumonia.
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Motos A, Kidd JM, and Nicolau DP
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- Anti-Bacterial Agents pharmacology, Humans, Pneumonia pathology, Anti-Bacterial Agents therapeutic use, Pneumonia drug therapy
- Abstract
Pneumonia, including community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, and ventilator-acquired bacterial pneumonia, carries unacceptably high morbidity and mortality. Despite advances in antimicrobial therapy, emergence of multidrug resistance and high rates of treatment failure have made optimization of antibiotic efficacy a priority. This review focuses on pharmacokinetic and pharmacodynamic approaches to antibacterial optimization within the lung environment and in the setting of critical illness. Strategies for including these approaches in drug development programs as well as clinical practice are described and reviewed., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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57. Corrigendum to Physical Compatibility of Meropenem and Vaborbactam with Select Intravenous Drugs During Simulated Y-site Administration [Clinical Therapeutics 40 (2018) 261-269].
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Kidd JM, Avery LM, Asempa TE, Nicolau DP, and Kuti JL
- Published
- 2018
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58. Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model.
- Author
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Kidd JM, Abdelraouf K, Asempa TE, Humphries RM, and Nicolau DP
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- Animals, Drug Resistance, Bacterial, Enterococcus faecalis pathogenicity, Enterococcus faecium pathogenicity, Gram-Positive Bacterial Infections microbiology, Humans, Mice, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents therapeutic use, Daptomycin pharmacokinetics, Daptomycin therapeutic use, Enterococcus faecalis drug effects, Enterococcus faecium drug effects, Gram-Positive Bacterial Infections drug therapy, Thigh microbiology
- Abstract
The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log
10 -CFU reduction of Enterococcus faecalis and Enterococcus faecium We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios ( f AUC0-24 /MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the f AUC0-24 /MIC required to achieve bacteriostasis and a 1-log10 -CFU reduction. For E. faecium , a 1-log10 -CFU reduction required an f AUC0-24 /MIC of 12.9 ( R2 = 0.71). For E. faecalis , a 1-log10 -CFU reduction was not achieved, while the f AUC0-24 /MIC required for stasis was 7.2 ( R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10 -CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10 -CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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59. Physical compatibility of plazomicin with select i.v. drugs during simulated Y-site administration.
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Asempa TE, Avery LM, Kidd JM, Kuti JL, and Nicolau DP
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- Drug Compounding, Drug Incompatibility, Glucose chemistry, Humans, Nephelometry and Turbidimetry, Sisomicin chemistry, Sodium Chloride chemistry, Anti-Bacterial Agents chemistry, Infusions, Intravenous, Sisomicin analogs & derivatives
- Abstract
Purpose: The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported., Methods: Plazomicin injection solution (500 mg/10 mL) was diluted in 0.9% sodium chloride or 5% dextrose for injection to a final volume of 50 mL (final plazomicin concentration, 24 mg/mL), consistent with a 15-mg/kg dose administered to an 80-kg patient (i.e., 1,200 mg). All other i.v. drugs were reconstituted according to manufacturers' recommendations and diluted with 0.9% sodium chloride or 5% dextrose for injection to the upper range of concentrations used clinically. Y-site conditions were simulated by mixing 5 mL of plazomicin solution with 5 mL of tested drug solutions in a 1:1 ratio. Solutions were assessed for visual (via color and Tyndall beam testing), turbidity (using a laboratory-grade turbidimeter), and pH changes over a 60-minute observation period. Incompatibility was defined a priori as precipitation, color change, a positive Tyndall test, or a turbidity change of ≥0.5 nephelometric turbidity units at any time during the 60-minute observation period., Results: Plazomicin was physically compatible with 79 of the 92 drugs tested. Determinations of physical incompatibility with plazomicin were made for 13 drugs: albumin, amiodarone, amphotericin B deoxycholate, anidulafungin, calcium chloride, daptomycin, esomeprazole, heparin, levofloxacin, methylprednisolone, micafungin, phenytoin, and propofol, CONCLUSION: Plazomicin at a concentration of 24 mg/mL was physically compatible with 85% of the drugs tested, including 31 of 36 antimicrobial agents., Competing Interests: DisclosuresThe study was funded by Achaogen Inc. Dr. Nicolau has received funding from Achaogen Inc. for other studies; he has declared no other potential conflicts of interest. The other authors have declared no potential conflicts of interest., (Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)
- Published
- 2018
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60. Developing and interpreting aqueous functional assays for comparative property-activity relationships of different nanoparticles.
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Kidd JM, Hanigan D, Truong L, Hristovski K, Tanguay R, and Westerhoff P
- Abstract
It is difficult to relate intrinsic nanomaterial properties to their functional behavior in the environment. Unlike frameworks for dissolved organic chemicals, there are few frameworks comparing multiple and inter-related properties of engineered nanomaterials (ENMs) to their fate, exposure, and hazard in environmental systems. We developed and evaluated reproducibility and inter-correlation of 12 physical, chemical, and biological functional assays in water for eight different engineered nanomaterials (ENMs) and interpreted results using activity-profiling radar plots. The functional assays were highly reproducible when run in triplicate (average coefficient of variation [CV]=6.6%). Radar plots showed that each nanomaterial exhibited unique activity profiles. Reactivity assays showed dissolution or aggregation potential for some ENMs. Surprisingly, multi-walled carbon nanotubes (MWCNTs) exhibited movement in a magnetic field. We found high inter-correlations between cloud point extraction (CPE) and distribution to sewage sludge (R
2 =0.99), dissolution at pH8 and pH4.9 (R2 =0.98), and dissolution at pH8 and zebrafish mortality at 24hpf (R2 =0.94). Additionally, most ENMs tend to distribute out of water and into other phases (i.e., soil surfaces, surfactant micelles, and sewage sludge). The activity-profiling radar plots provide a framework and estimations of likely ENM disposition in the environment., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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61. Comparison of village dog and wolf genomes highlights the role of the neural crest in dog domestication.
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Pendleton AL, Shen F, Taravella AM, Emery S, Veeramah KR, Boyko AR, and Kidd JM
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- Animals, DNA Copy Number Variations, Genetic Variation, Genome, Haplotypes genetics, Phenotype, Selection, Genetic, Dogs genetics, Domestication, Neural Crest physiology, Wolves genetics
- Abstract
Background: Domesticated from gray wolves between 10 and 40 kya in Eurasia, dogs display a vast array of phenotypes that differ from their ancestors, yet mirror other domesticated animal species, a phenomenon known as the domestication syndrome. Here, we use signatures persisting in dog genomes to identify genes and pathways possibly altered by the selective pressures of domestication., Results: Whole-genome SNP analyses of 43 globally distributed village dogs and 10 wolves differentiated signatures resulting from domestication rather than breed formation. We identified 246 candidate domestication regions containing 10.8 Mb of genome sequence and 429 genes. The regions share haplotypes with ancient dogs, suggesting that the detected signals are not the result of recent selection. Gene enrichments highlight numerous genes linked to neural crest and central nervous system development as well as neurological function. Read depth analysis suggests that copy number variation played a minor role in dog domestication., Conclusions: Our results identify genes that act early in embryogenesis and can confer phenotypes distinguishing domesticated dogs from wolves, such as tameness, smaller jaws, floppy ears, and diminished craniofacial development as the targets of selection during domestication. These differences reflect the phenotypes of the domestication syndrome, which can be explained by alterations in the migration or activity of neural crest cells during development. We propose that initial selection during early dog domestication was for behavior, a trait influenced by genes which act in the neural crest, which secondarily gave rise to the phenotypes of modern dogs.
- Published
- 2018
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62. Analysis of the canid Y-chromosome phylogeny using short-read sequencing data reveals the presence of distinct haplogroups among Neolithic European dogs.
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Oetjens MT, Martin A, Veeramah KR, and Kidd JM
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- Animals, Coyotes classification, DNA, Mitochondrial genetics, Dogs classification, Genetic Variation, Genome, Male, Wolves classification, Coyotes genetics, Dogs genetics, Evolution, Molecular, Haplotypes, Phylogeny, Sequence Analysis, DNA methods, Wolves genetics, Y Chromosome
- Abstract
Background: Most genetic analyses of ancient and modern dogs have focused on variation in the autosomes or on the mitochondria. Mitochondrial DNA is more easily obtained from ancient samples than nuclear DNA and mitochondrial analyses have revealed important insights into the evolutionary history of canids. Utilizing a recently published dog Y-chromosome reference, we analyzed Y-chromosome sequence across a diverse collection of canids and determined the Y haplogroup of three ancient European dogs., Results: We identified 1121 biallelic Y-chromosome SNVs using whole-genome sequences from 118 canids and defined variants diagnostic to distinct dog Y haplogroups. Similar to that of the mitochondria and previous more limited studies of Y diversity, we observe several deep splits in the Y-chromosome tree which may be the result of retained Y-chromosome diversity which predates dog domestication or post-domestication admixture with wolves. We find that Y-chromosomes from three ancient European dogs (4700-7000 years old) belong to distinct clades., Conclusions: We estimate that the time to the most recent comment ancestor of dog Y haplogroups is 68-151 thousand years ago. Analysis of three Y-chromosomes from the Neolithic confirms long stranding population structure among European dogs.
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- 2018
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63. Spliced integrated retrotransposed element (SpIRE) formation in the human genome.
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Larson PA, Moldovan JB, Jasti N, Kidd JM, Beck CR, and Moran JV
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- HeLa Cells, Humans, Polymorphism, Genetic, Promoter Regions, Genetic, RNA Splicing, RNA, Messenger metabolism, Evolution, Molecular, Genome, Human, Long Interspersed Nucleotide Elements genetics, Retroelements genetics
- Abstract
Human Long interspersed element-1 (L1) retrotransposons contain an internal RNA polymerase II promoter within their 5' untranslated region (UTR) and encode two proteins, (ORF1p and ORF2p) required for their mobilization (i.e., retrotransposition). The evolutionary success of L1 relies on the continuous retrotransposition of full-length L1 mRNAs. Previous studies identified functional splice donor (SD), splice acceptor (SA), and polyadenylation sequences in L1 mRNA and provided evidence that a small number of spliced L1 mRNAs retrotransposed in the human genome. Here, we demonstrate that the retrotransposition of intra-5'UTR or 5'UTR/ORF1 spliced L1 mRNAs leads to the generation of spliced integrated retrotransposed elements (SpIREs). We identified a new intra-5'UTR SpIRE that is ten times more abundant than previously identified SpIREs. Functional analyses demonstrated that both intra-5'UTR and 5'UTR/ORF1 SpIREs lack Cis-acting transcription factor binding sites and exhibit reduced promoter activity. The 5'UTR/ORF1 SpIREs also produce nonfunctional ORF1p variants. Finally, we demonstrate that sequence changes within the L1 5'UTR over evolutionary time, which permitted L1 to evade the repressive effects of a host protein, can lead to the generation of new L1 splicing events, which, upon retrotransposition, generates a new SpIRE subfamily. We conclude that splicing inhibits L1 retrotransposition, SpIREs generally represent evolutionary "dead-ends" in the L1 retrotransposition process, mutations within the L1 5'UTR alter L1 splicing dynamics, and that retrotransposition of the resultant spliced transcripts can generate interindividual genomic variation.
- Published
- 2018
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64. Novel pharmacotherapy for the treatment of hospital-acquired and ventilator-associated pneumonia caused by resistant gram-negative bacteria.
- Author
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Kidd JM, Kuti JL, and Nicolau DP
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- Administration, Inhalation, Amikacin pharmacology, Amikacin therapeutic use, Ceftazidime pharmacology, Ceftazidime therapeutic use, Cephalosporins pharmacology, Cephalosporins therapeutic use, Clinical Trials as Topic, Drug Resistance, Multiple, Bacterial drug effects, Gram-Negative Bacteria drug effects, Gram-Negative Bacteria isolation & purification, Humans, Pneumonia, Ventilator-Associated microbiology, Sisomicin analogs & derivatives, Sisomicin pharmacology, Sisomicin therapeutic use, Anti-Bacterial Agents therapeutic use, Pneumonia, Ventilator-Associated drug therapy
- Abstract
Introduction: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP., Areas Covered: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed., Expert Opinion: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated.
- Published
- 2018
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65. Physical Compatibility of Meropenem and Vaborbactam With Select Intravenous Drugs During Simulated Y-site Administration.
- Author
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Kidd JM, Avery LM, Asempa TE, Nicolau DP, and Kuti JL
- Subjects
- Anti-Bacterial Agents administration & dosage, Boronic Acids administration & dosage, Drug Incompatibility, Humans, Infusions, Intravenous, Meropenem administration & dosage, Anti-Bacterial Agents chemistry, Boronic Acids chemistry, Meropenem chemistry
- Abstract
Purpose: Meropenem/vaborbactam is a novel intravenous antibiotic combining the carbapenem, meropenem, with a novel β-lactamase inhibitor, vaborbactam. Meropenem/vaborbactam is administered as a 3-hour infusion given every 8 hours, thereby potentially restricting an intravenous line for 9 h/d. Intravenous medications may be given concurrently via Y-site when compatibility data are available. Herein, physical compatibility was determined for the identification which medications can be coadministered with meropenem/vaborbactam via Y-site., Methods: Y-site administration was simulated in vitro by admixing 5 mL of meropenem 8 mg/mL and vaborbactam 8 mg/mL with an equal volume of 88 other diluted intravenous medications, including 34 antimicrobials. All other medications were diluted with 0.9% sodium chloride to the upper range of concentrations considered standard for intravenous infusion. Visual inspection, turbidity measurement, and pH measurement were performed prior to admixture, directly after admixture, and at time points up to 3 hours after admixture., Findings: Of the 88 medications tested, meropenem/vaborbactam was compatible with 73 (83%), including many antibiotics such as aminoglycosides (amikacin, gentamicin, and tobramycin), colistin, fosfomycin, linezolid, tedizolid, tigecycline, and vancomycin. Physical incompatibility was observed with albumin, amiodarone, anidulafungin, calcium chloride, caspofungin, ceftaroline, ciprofloxacin, daptomycin, diphenhydramine, dobutamine, isavuconazole, midazolam, nicardipine, ondansetron, and phenytoin., Implications: The majority of intravenous medications tested were found to be physically compatible with meropenem/vaborbactam. These data will help pharmacists and nurses to improve line access in patients receiving meropenem/vaborbactam., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)
- Published
- 2018
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66. Production and economic responses to intensification of pasture-based dairy production systems.
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Macdonald KA, Penno JW, Lancaster JAS, Bryant AM, Kidd JM, and Roche JR
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- Animals, Female, Milk, Poaceae, Seasons, Silage, Animal Feed, Animal Nutritional Physiological Phenomena, Cattle physiology, Dairying methods, Lactation physiology
- Abstract
Production from pasture-based dairy farms can be increased through using N fertilizer to increase pasture grown, increasing stocking rate, importing feeds from off farm (i.e., supplementary feeds, such as cereal silages, grains, or co-product feeds), or through a combination of these strategies. Increased production can improve profitability, provided the marginal cost of the additional milk produced is less than the milk price received. A multiyear production system experiment was established to investigate the biological and economic responses to intensification on pasture-based dairy farms; 7 experimental farmlets were established and managed independently for 3 yr. Paddocks and cows were randomly allocated to farmlet, such that 3 farmlets had stocking rates of 3.35 cows/ha (LSR) and 4 farmlets had stocking rates of 4.41 cows/ha (HSR). Of the LSR farmlets, 1 treatment received no N fertilizer, whereas the other 2 received either 200 or 400 kg of N/ha per year (200N and 400N, respectively). No feed was imported from off-farm for the LSR farmlets. Of the 4 HSR farmlets, 3 treatments received 200N and the fourth treatment received 400N; cows on 2 of the HSR-200N farmlet treatments also received 1.3 or 1.1 t of DM/cow per year of either cracked corn grain or corn silage, respectively. Data were analyzed for consistency of farmlet response over years using mixed models, with year and farmlet as fixed effects and the interaction of farmlet with year as a random effect. The biological data and financial data extracted from a national economic database were used to model the statement of financial performance for the farmlets and determine the economic implications of increasing milk production/cow and per ha (i.e., farm intensification). Applying 200N or 400N increased pasture grown per hectare and milk production per cow and per hectare, whereas increasing stocking rate did not affect pasture grown or milk production per hectare, but reduced milk production per cow. Importing feed in the HSR farmlets increased milk production per cow and per hectare. Marginal milk production responses to additional feed (i.e., either pasture or imported supplementary feed) were between 0.8 and 1.2 kg of milk/kg of DM offered (73 to 97 g of fat and protein/kg of feed DM) and marginal response differences between feeds were explained by metabolizable energy content differences (0.08 kg of milk/MJ of metabolizable energy offered). The marginal milk production response to additional feed was quadratic, with the greatest milk production generated from the initial investment in feed; 119, 99, and 55 g of fat and protein were produced per kilogram of feed DM by reducing the annual feed deficit from 1.6 to 1.0, 1.0 to 0.5, and 0.5 to 0 t of DM, respectively. Economic modeling indicated that the marginal cost of milk produced from pasture resulting from applied N fertilizer was less than the milk price; therefore, strategic use of N fertilizer to increase pasture grown increased farm operating profit per hectare. In comparison, operating profit declined with purchased feed, despite high marginal milk production responses. The results have implications for the strategic direction of grazing dairy farms, particularly in export-oriented industries, where the prices of milk and feed inputs are subject to the considerable volatility of commodity markets., (The Authors. Published by the Federation of Animal Science Societies and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).)
- Published
- 2017
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67. Ancient European dog genomes reveal continuity since the Early Neolithic.
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Botigué LR, Song S, Scheu A, Gopalan S, Pendleton AL, Oetjens M, Taravella AM, Seregély T, Zeeb-Lanz A, Arbogast RM, Bobo D, Daly K, Unterländer M, Burger J, Kidd JM, and Veeramah KR
- Subjects
- Animals, Domestication, Genetic Variation, Phylogeography, Biological Evolution, DNA, Mitochondrial genetics, Dogs genetics, Genome
- Abstract
Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000-40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic.
- Published
- 2017
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68. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.
- Author
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McConnell MJ, Moran JV, Abyzov A, Akbarian S, Bae T, Cortes-Ciriano I, Erwin JA, Fasching L, Flasch DA, Freed D, Ganz J, Jaffe AE, Kwan KY, Kwon M, Lodato MA, Mills RE, Paquola ACM, Rodin RE, Rosenbluh C, Sestan N, Sherman MA, Shin JH, Song S, Straub RE, Thorpe J, Weinberger DR, Urban AE, Zhou B, Gage FH, Lehner T, Senthil G, Walsh CA, Chess A, Courchesne E, Gleeson JG, Kidd JM, Park PJ, Pevsner J, and Vaccarino FM
- Subjects
- Brain metabolism, Cell Division genetics, DNA Damage, DNA Mutational Analysis methods, DNA Repair genetics, DNA Replication, Genome, Human, Germ Cells metabolism, Humans, Nerve Net growth & development, Nerve Net metabolism, Neural Stem Cells metabolism, Neurons metabolism, Brain abnormalities, Mental Disorders genetics, Mosaicism, Nervous System Diseases genetics, Neural Stem Cells physiology, Neurons physiology
- Abstract
Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders., (Copyright © 2017, American Association for the Advancement of Science.)
- Published
- 2017
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69. Modeling Human Population Separation History Using Physically Phased Genomes.
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Song S, Sliwerska E, Emery S, and Kidd JM
- Subjects
- Bayes Theorem, Black People genetics, Genotype, Haplotypes, Humans, Male, Polymorphism, Single Nucleotide, Genetics, Population methods, Genome, Human, Models, Genetic
- Abstract
Phased haplotype sequences are a key component in many population genetic analyses since variation in haplotypes reflects the action of recombination, selection, and changes in population size. In humans, haplotypes are typically estimated from unphased sequence or genotyping data using statistical models applied to large reference panels. To assess the importance of correct haplotype phase on population history inference, we performed fosmid pool sequencing and resolved phased haplotypes of five individuals from diverse African populations (including Yoruba, Esan, Gambia, Maasai, and Mende). We physically phased 98% of heterozygous SNPs into haplotype-resolved blocks, obtaining a block N50 of 1 Mbp. We combined these data with additional phased genomes from San, Mbuti, Gujarati, and Centre de'Etude du Polymorphism Humain European populations and analyzed population size and separation history using the pairwise sequentially Markovian coalescent and multiple sequentially Markovian coalescent models. We find that statistically phased haplotypes yield a more recent split-time estimation compared with experimentally phased haplotypes. To better interpret patterns of cross-population coalescence, we implemented an approximate Bayesian computation approach to estimate population split times and migration rates by fitting the distribution of coalescent times inferred between two haplotypes, one from each population, to a standard isolation-with-migration model. We inferred that the separation between hunter-gatherer populations and other populations happened ∼120-140 KYA, with gene flow continuing until 30-40 KYA; separation between west-African and out-of-African populations happened ∼70-80 KYA; while the separation between Maasai and out-of-African populations happened ∼50 KYA., (Copyright © 2017 by the Genetics Society of America.)
- Published
- 2017
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70. Renal Survival in Patients with Collapsing Compared with Not Otherwise Specified FSGS.
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Laurin LP, Gasim AM, Derebail VK, McGregor JG, Kidd JM, Hogan SL, Poulton CJ, Detwiler RK, Jennette JC, Falk RJ, and Nachman PH
- Subjects
- Adolescent, Adult, Aged, Biopsy, Calcineurin Inhibitors therapeutic use, Disease Progression, Female, Follow-Up Studies, Glomerular Filtration Rate, Glomerulosclerosis, Focal Segmental complications, Glomerulosclerosis, Focal Segmental physiopathology, Glucocorticoids therapeutic use, Humans, Kidney Failure, Chronic etiology, Kidney Transplantation, Male, Middle Aged, Proteinuria urine, Remission Induction, Renal Dialysis, Retrospective Studies, Serum Albumin metabolism, Survival Analysis, Time Factors, Young Adult, Glomerulosclerosis, Focal Segmental drug therapy, Glomerulosclerosis, Focal Segmental pathology, Immunosuppressive Agents therapeutic use, Kidney pathology, Kidney Failure, Chronic therapy
- Abstract
Background and Objectives: Idiopathic collapsing FSGS has historically been associated with poor renal outcomes. Minimal clinical data exist on the efficacy of immunosuppressive therapy. Our study sought to provide a comprehensive description of renal survival in patients with collapsing and not otherwise specified FSGS after controlling for factors affecting renal prognosis., Design, Setting, Participants, & Measurements: We performed a retrospective analysis of an inception cohort study of patients diagnosed between 1989 and 2012. All potential patients with collapsing FSGS fulfilling the inclusion criteria were identified and compared with patients with not otherwise specified FSGS (approximately 1:2 ratio) on the basis of biopsy report and record availability. Time to ESRD was analyzed using Cox proportional hazards models., Results: In total, 187 patients were studied (61 collapsing and 126 not otherwise specified), with a mean follow-up of 96 months. At baseline, patients with collapsing FSGS had higher median proteinuria (12.2 [5.6-14.8] versus 4.4 [2.3-8.1] g/d, respectively; P <0.001), lower median albuminemia (2.4 [1.9-3.0] versus 2.9 [1.8-3.7] g/dl, respectively; P =0.12), and lower median eGFR (48 [26-73] versus 60 [42-92] ml/min per 1.73 m
2 , respectively; P =0.01) than patients with not otherwise specified FSGS. The proportion of patients with remission of proteinuria was similar in patients with collapsing FSGS and patients with not otherwise specified FSGS (65.7% [23 of 35] versus 63.2% [72 of 114], respectively; P =0.84). The overall renal outcome (ESRD defined as eGFR<15 ml/min per 1.73 m2 , dialysis, or transplantation) of patients with collapsing FSGS was not poorer than that of patients with not otherwise specified FSGS in multivariate analyses after adjusting for baseline characteristics and immunotherapy (hazard ratio, 1.78; 95% confidence interval, 0.92 to 3.45)., Conclusions: Compared with not otherwise specified FSGS, idiopathic collapsing FSGS presented with more severe nephrotic syndrome and lower eGFR but had a similar renal survival after controlling for exposure to immunosuppressive treatment. These results highlight the importance of early diagnosis and institution of immunosuppressive therapy in patients with collapsing FSGS., (Copyright © 2016 by the American Society of Nephrology.)- Published
- 2016
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71. Y-Chromosome Structural Diversity in the Bonobo and Chimpanzee Lineages.
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Oetjens MT, Shen F, Emery SB, Zou Z, and Kidd JM
- Subjects
- Animals, Azoospermia genetics, Evolution, Molecular, Gene Amplification, Male, Selection, Genetic, Testis metabolism, Genomic Structural Variation, Pan paniscus genetics, Pan troglodytes genetics, Y Chromosome genetics
- Abstract
The male-specific regions of primate Y-chromosomes (MSY) are enriched for multi-copy genes highly expressed in the testis. These genes are located in large repetitive sequences arranged as palindromes, inverted-, and tandem repeats termed amplicons. In humans, these genes have critical roles in male fertility and are essential for the production of sperm. The structure of human and chimpanzee amplicon sequences show remarkable difference relative to the remainder of the genome, a difference that may be the result of intense selective pressure on male fertility. Four subspecies of common chimpanzees have undergone extended periods of isolation and appear to be in the early process of subspeciation. A recent study found amplicons enriched for testis-expressed genes on the primate X-chromosome the target of hard selective sweeps, and male-fertility genes on the Y-chromosome may also be the targets of selection. However, little is understood about Y-chromosome amplicon diversity within and across chimpanzee populations. Here, we analyze nine common chimpanzee (representing three subspecies: Pan troglodytes schweinfurthii, Pan troglodytes ellioti, and Pan troglodytes verus) and two bonobo (Pan paniscus) male whole-genome sequences to assess Y ampliconic copy-number diversity across the Pan genus. We observe that the copy number of Y chromosome amplicons is variable among chimpanzees and bonobos, and identify several lineage-specific patterns, including variable copy number of azoospermia candidates RBMY and DAZ We detect recurrent switchpoints of copy-number change along the ampliconic tracts across chimpanzee populations, which may be the result of localized genome instability or selective forces., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2016
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72. Resolving complex structural genomic rearrangements using a randomized approach.
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Zhao X, Emery SB, Myers B, Kidd JM, and Mills RE
- Subjects
- Algorithms, Chromosome Breakpoints, Computer Simulation, Humans, Reproducibility of Results, Software, Web Browser, Computational Biology methods, Gene Rearrangement, Genome, Human, Genomics methods, Translocation, Genetic
- Abstract
Complex chromosomal rearrangements are structural genomic alterations involving multiple instances of deletions, duplications, inversions, or translocations that co-occur either on the same chromosome or represent different overlapping events on homologous chromosomes. We present SVelter, an algorithm that identifies regions of the genome suspected to harbor a complex event and then resolves the structure by iteratively rearranging the local genome structure, in a randomized fashion, with each structure scored against characteristics of the observed sequencing data. SVelter is able to accurately reconstruct complex chromosomal rearrangements when compared to well-characterized genomes that have been deeply sequenced with both short and long reads.
- Published
- 2016
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73. Discovery of unfixed endogenous retrovirus insertions in diverse human populations.
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Wildschutte JH, Williams ZH, Montesion M, Subramanian RP, Kidd JM, and Coffin JM
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- Female, Humans, Male, Alleles, Endogenous Retroviruses genetics, Genetic Loci, Mutagenesis, Insertional, Polymorphism, Genetic, Terminal Repeat Sequences
- Abstract
Endogenous retroviruses (ERVs) have contributed to more than 8% of the human genome. The majority of these elements lack function due to accumulated mutations or internal recombination resulting in a solitary (solo) LTR, although members of one group of human ERVs (HERVs), HERV-K, were recently active with members that remain nearly intact, a subset of which is present as insertionally polymorphic loci that include approximately full-length (2-LTR) and solo-LTR alleles in addition to the unoccupied site. Several 2-LTR insertions have intact reading frames in some or all genes that are expressed as functional proteins. These properties reflect the activity of HERV-K and suggest the existence of additional unique loci within humans. We sought to determine the extent to which other polymorphic insertions are present in humans, using sequenced genomes from the 1000 Genomes Project and a subset of the Human Genome Diversity Project panel. We report analysis of a total of 36 nonreference polymorphic HERV-K proviruses, including 19 newly reported loci, with insertion frequencies ranging from <0.0005 to >0.75 that varied by population. Targeted screening of individual loci identified three new unfixed 2-LTR proviruses within our set, including an intact provirus present at Xq21.33 in some individuals, with the potential for retained infectivity.
- Published
- 2016
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74. The Time Scale of Recombination Rate Evolution in Great Apes.
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Stevison LS, Woerner AE, Kidd JM, Kelley JL, Veeramah KR, McManus KF, Bustamante CD, Hammer MF, and Wall JD
- Subjects
- Animals, Chromosome Mapping, Chromosomes genetics, Genetic Variation, Gorilla gorilla genetics, Humans, Pan troglodytes genetics, Papio genetics, Species Specificity, Evolution, Molecular, Hominidae genetics, Linkage Disequilibrium genetics, Recombination, Genetic
- Abstract
We present three linkage-disequilibrium (LD)-based recombination maps generated using whole-genome sequence data from 10 Nigerian chimpanzees, 13 bonobos, and 15 western gorillas, collected as part of the Great Ape Genome Project (Prado-Martinez J, et al. 2013. Great ape genetic diversity and population history. Nature 499:471-475). We also identified species-specific recombination hotspots in each group using a modified LDhot framework, which greatly improves statistical power to detect hotspots at varying strengths. We show that fewer hotspots are shared among chimpanzee subspecies than within human populations, further narrowing the time scale of complete hotspot turnover. Further, using species-specific PRDM9 sequences to predict potential binding sites (PBS), we show higher predicted PRDM9 binding in recombination hotspots as compared to matched cold spot regions in multiple great ape species, including at least one chimpanzee subspecies. We found that correlations between broad-scale recombination rates decline more rapidly than nucleotide divergence between species. We also compared the skew of recombination rates at centromeres and telomeres between species and show a skew from chromosome means extending as far as 10-15 Mb from chromosome ends. Further, we examined broad-scale recombination rate changes near a translocation in gorillas and found minimal differences as compared to other great ape species perhaps because the coordinates relative to the chromosome ends were unaffected. Finally, on the basis of multiple linear regression analysis, we found that various correlates of recombination rate persist throughout the African great apes including repeats, diversity, and divergence. Our study is the first to analyze within- and between-species genome-wide recombination rate variation in several close relatives., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
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75. Ipilimumab-associated minimal-change disease.
- Author
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Kidd JM and Gizaw AB
- Subjects
- Humans, Antineoplastic Agents adverse effects, Kidney Diseases chemically induced
- Published
- 2016
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76. Distance from sub-Saharan Africa predicts mutational load in diverse human genomes.
- Author
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Henn BM, Botigué LR, Peischl S, Dupanloup I, Lipatov M, Maples BK, Martin AR, Musharoff S, Cann H, Snyder MP, Excoffier L, Kidd JM, and Bustamante CD
- Subjects
- Africa South of the Sahara, Alleles, Animals, Asian People genetics, Black People genetics, Computer Simulation, Conserved Sequence, Evolution, Molecular, Founder Effect, Gene Flow, Genetic Diseases, Inborn genetics, Genetic Drift, Genotype, Homing Behavior, Humans, Indians, Central American genetics, Models, Genetic, Selection, Genetic, Ethnicity genetics, Genome, Human, Human Migration, Mutation
- Abstract
The Out-of-Africa (OOA) dispersal ∼ 50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.
- Published
- 2016
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77. Discovery and characterization of Alu repeat sequences via precise local read assembly.
- Author
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Wildschutte JH, Baron A, Diroff NM, and Kidd JM
- Subjects
- Chromosome Breakpoints, Genome, Human, Genotyping Techniques, Humans, Sequence Analysis, DNA, Alu Elements, Genomics methods
- Abstract
Alu insertions have contributed to >11% of the human genome and ∼30-35 Alu subfamilies remain actively mobile, yet the characterization of polymorphic Alu insertions from short-read data remains a challenge. We build on existing computational methods to combine Alu detection and de novo assembly of WGS data as a means to reconstruct the full sequence of insertion events from Illumina paired end reads. Comparison with published calls obtained using PacBio long-reads indicates a false discovery rate below 5%, at the cost of reduced sensitivity due to the colocation of reference and non-reference repeats. We generate a highly accurate call set of 1614 completely assembled Alu variants from 53 samples from the Human Genome Diversity Project (HGDP) panel. We utilize the reconstructed alternative insertion haplotypes to genotype 1010 fully assembled insertions, obtaining >99% agreement with genotypes obtained by PCR. In our assembled sequences, we find evidence of premature insertion mechanisms and observe 5' truncation in 16% of AluYa5 and AluYb8 insertions. The sites of truncation coincide with stem-loop structures and SRP9/14 binding sites in the Alu RNA, implicating L1 ORF2p pausing in the generation of 5' truncations. Additionally, we identified variable AluJ and AluS elements that likely arose due to non-retrotransposition mechanisms., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2015
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78. An integrated map of structural variation in 2,504 human genomes.
- Author
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Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, Zhang Y, Ye K, Jun G, Fritz MH, Konkel MK, Malhotra A, Stütz AM, Shi X, Casale FP, Chen J, Hormozdiari F, Dayama G, Chen K, Malig M, Chaisson MJP, Walter K, Meiers S, Kashin S, Garrison E, Auton A, Lam HYK, Mu XJ, Alkan C, Antaki D, Bae T, Cerveira E, Chines P, Chong Z, Clarke L, Dal E, Ding L, Emery S, Fan X, Gujral M, Kahveci F, Kidd JM, Kong Y, Lameijer EW, McCarthy S, Flicek P, Gibbs RA, Marth G, Mason CE, Menelaou A, Muzny DM, Nelson BJ, Noor A, Parrish NF, Pendleton M, Quitadamo A, Raeder B, Schadt EE, Romanovitch M, Schlattl A, Sebra R, Shabalin AA, Untergasser A, Walker JA, Wang M, Yu F, Zhang C, Zhang J, Zheng-Bradley X, Zhou W, Zichner T, Sebat J, Batzer MA, McCarroll SA, Mills RE, Gerstein MB, Bashir A, Stegle O, Devine SE, Lee C, Eichler EE, and Korbel JO
- Subjects
- Amino Acid Sequence, Genetic Predisposition to Disease, Genetics, Medical, Genetics, Population, Genome-Wide Association Study, Genomics, Genotype, Haplotypes genetics, Homozygote, Humans, Molecular Sequence Data, Mutation Rate, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Sequence Analysis, DNA, Sequence Deletion genetics, Genetic Variation genetics, Genome, Human genetics, Physical Chromosome Mapping
- Abstract
Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
- Published
- 2015
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79. All that leaks is not blood.
- Author
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Gizaw A and Kidd JM
- Subjects
- Color, Humans, Hypotension diagnosis, Hypotension etiology, Male, Middle Aged, Dialysis Solutions chemistry, Hydroxocobalamin adverse effects, Hypotension drug therapy, Liver Transplantation adverse effects, Renal Dialysis
- Published
- 2015
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80. The development of a prototype measure of the co-production of health in routine consultations for people with long-term conditions.
- Author
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Realpe AX, Wallace LM, Adams AE, and Kidd JM
- Abstract
Objectives: (i) To develop a prototype measure of co-production of health (CPH) in consultations for people with long-term conditions (LTCs); and (ii) to undertake initial validation of it, using a measure of patient-centred care, as defined by the Roter interaction analysis system (RIAS)., Methods: Mixed methods were applied. A qualitative study gathered 11 experts' views on what comprised CPH behaviours. These were operationalised and a prototype measure applied to a convenience sample of 50 video-recorded consultations involving clinicians trained in self-management support and patients with LTCs at health services in six UK locations., Results: Twenty-two CPH behaviours were identified. High frequencies of CPH behaviours in consultations were associated with greater patient-centeredness, less clinician verbal dominance, and more patient communication control in comparison to consultations where CPH behaviours were less frequent., Conclusion: Although the CPH tool is promising, further testing is required in order to improve reliability and validity., Practical Implications: In the future, the measure could be used to test interventions to promote patient participation in decision making about self-management., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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81. Adverse events and infectious burden, microbes and temporal outline from immunosuppressive therapy in antineutrophil cytoplasmic antibody-associated vasculitis with native renal function.
- Author
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McGregor JG, Negrete-Lopez R, Poulton CJ, Kidd JM, Katsanos SL, Goetz L, Hu Y, Nachman PH, Falk RJ, and Hogan SL
- Subjects
- Adult, Aged, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Antibodies, Antineutrophil Cytoplasmic immunology, Drug-Related Side Effects and Adverse Reactions epidemiology, Female, Humans, Incidence, Kidney drug effects, Longitudinal Studies, Male, Middle Aged, North Carolina epidemiology, Prognosis, Staphylococcal Infections chemically induced, Staphylococcal Infections epidemiology, Staphylococcal Infections mortality, Staphylococcus aureus isolation & purification, Survival Rate, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Drug-Related Side Effects and Adverse Reactions etiology, Immunosuppressive Agents adverse effects, Kidney physiology, Peroxidase immunology, Staphylococcal Infections microbiology
- Abstract
Background: Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV., Methods: Biopsy-proven AAV patients (diagnosed 1/1991-6/2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals., Results: A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Staphylococcus aureus was most frequently seen among positive cultures (41%, 78 S. aureus/192 total positive cultures), and only one Pneumocystis jiroveci pneumonia (6 weeks into treatment). All-cause death in 12 months was associated with infections (% deaths: 0 infections 3%; 1-2 infections 10%, ≥3 infections 13%, P = 0.002). Controlling for age, sex and kidney function, patients with severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0-8.7; P = 0.001)., Conclusions: More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2015
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82. Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody-associated vasculitis.
- Author
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McGregor JG, Hogan SL, Kotzen ES, Poulton CJ, Hu Y, Negrete-Lopez R, Kidd JM, Katsanos SL, Bunch DO, Nachman PH, and Falk RJ
- Subjects
- Adult, Aged, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis mortality, Antibodies, Antineutrophil Cytoplasmic immunology, Cohort Studies, Cyclophosphamide therapeutic use, Female, Humans, Male, Middle Aged, Prognosis, Recurrence, Remission Induction, Rituximab, Survival Rate, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Antibodies, Monoclonal, Murine-Derived therapeutic use, Immunosuppressive Agents therapeutic use
- Abstract
Background: Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) since 2003. Our objective was to describe outcomes and adverse events following rituximab since that time in an inception cohort., Methods: Patients with AAV (diagnosed 1991-2012) who received rituximab (n = 120) were evaluated and incidence per person-year (PPY) with 95% confidence interval was calculated for relapse and infections. Time to remission and relapse by number of rituximab infusions given per treatment course (≤2 versus >2) and by ever having been exposed to cyclophosphamide were compared using Kaplan-Meier curves. Rituximab-treated patients were characterized in comparison with AAV patients treated with cyclophosphamide but not exposed to rituximab (n = 351) using Fisher's exact or rank tests., Results: Rituximab resulted in 86% achieving remission and 41% having a subsequent relapse in a median of 19 months (range 9-29). Time to remission and relapse were similar between rituximab infusion courses (≤2 versus >2; remission P = 0.86 and relapse P = 0.78, respectively). Incidence of relapse was 0.22 PPY (0.14, 0.31) and of severe infection was 0.12 PPY (0.08, 0.24). Time to relapse was shorter in those never exposed to cyclophosphamide (n = 20): 50% by 8 months versus 50% by 24 and 30 months for those with prior or concurrent exposure to cyclophosphamide (n = 100). Compared with those who never received rituximab, rituximab-treated patients were younger (P < 0.001), more likely to have granulomatosis with polyangiitis (P = 0.001) and had more upper airway (P = 0.01) and less kidney involvement (P = 0.007)., Conclusions: Rituximab is beneficial when prescribed outside of a trial setting. Response to treatment and relapse is similar regardless of infusion number. Rituximab without cyclophosphamide may result in a shorter time to relapse supporting combination of these therapies., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2015
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83. Inference of gorilla demographic and selective history from whole-genome sequence data.
- Author
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McManus KF, Kelley JL, Song S, Veeramah KR, Woerner AE, Stevison LS, Ryder OA, Ape Genome Project G, Kidd JM, Wall JD, Bustamante CD, and Hammer MF
- Subjects
- Animals, Genetic Fitness, Genome, Human genetics, Genomics, Gorilla gorilla classification, Humans, Metagenomics, Genome genetics, Gorilla gorilla genetics, Selection, Genetic genetics
- Abstract
Although population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole-genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor approximately 261 ka, and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage approximately 68 ka. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of 1.4-fold around 970 ka and a recent 5.6-fold contraction in population size 23 ka. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2015
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- View/download PDF
84. The genomic landscape of polymorphic human nuclear mitochondrial insertions.
- Author
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Dayama G, Emery SB, Kidd JM, and Mills RE
- Subjects
- Genome, Human, Genomics methods, Humans, Molecular Sequence Data, Mutagenesis, Insertional, Phylogeny, Cell Nucleus genetics, Genome, Mitochondrial, Polymorphism, Genetic
- Abstract
The transfer of mitochondrial genetic material into the nuclear genomes of eukaryotes is a well-established phenomenon that has been previously limited to the study of static reference genomes. The recent advancement of high throughput sequencing has enabled an expanded exploration into the diversity of polymorphic nuclear mitochondrial insertions (NumtS) within human populations. We have developed an approach to discover and genotype novel Numt insertions using whole genome, paired-end sequencing data. We have applied this method to a thousand individuals in 20 populations from the 1000 Genomes Project and other datasets and identified 141 new sites of Numt insertions, extending our current knowledge of existing NumtS by almost 20%. We find that recent Numt insertions are derived from throughout the mitochondrial genome, including the D-loop, and have integration biases that differ in some respects from previous studies on older, fixed NumtS in the reference genome. We determined the complete inserted sequence for a subset of these events and have identified a number of nearly full-length mitochondrial genome insertions into nuclear chromosomes. We further define their age and origin of insertion and present an analysis of their potential impact to ongoing studies of mitochondrial heteroplasmy and disease., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2014
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85. Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture.
- Author
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Martin AR, Costa HA, Lappalainen T, Henn BM, Kidd JM, Yee MC, Grubert F, Cann HM, Snyder M, Montgomery SB, and Bustamante CD
- Subjects
- Genome, Human, HapMap Project, Human Genome Project, Human Migration, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci genetics, Gene Expression Profiling, Gene Regulatory Networks, Genetics, Population, Haplotypes genetics
- Abstract
Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP). The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and regulatory genetics across populations from the broadest points of human migration history yet sampled.
- Published
- 2014
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86. Exome capture from saliva produces high quality genomic and metagenomic data.
- Author
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Kidd JM, Sharpton TJ, Bobo D, Norman PJ, Martin AR, Carpenter ML, Sikora M, Gignoux CR, Nemat-Gorgani N, Adams A, Guadalupe M, Guo X, Feng Q, Li Y, Liu X, Parham P, Hoal EG, Feldman MW, Pollard KS, Wall JD, Bustamante CD, and Henn BM
- Subjects
- Genome, Human, Genotype, HLA Antigens genetics, High-Throughput Nucleotide Sequencing methods, Humans, Microbiota, Molecular Sequence Data, Mouth microbiology, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, KIR genetics, Exome, Genomics, Metagenomics, Saliva chemistry, Saliva microbiology
- Abstract
Background: Targeted capture of genomic regions reduces sequencing cost while generating higher coverage by allowing biomedical researchers to focus on specific loci of interest, such as exons. Targeted capture also has the potential to facilitate the generation of genomic data from DNA collected via saliva or buccal cells. DNA samples derived from these cell types tend to have a lower human DNA yield, may be degraded from age and/or have contamination from bacteria or other ambient oral microbiota. However, thousands of samples have been previously collected from these cell types, and saliva collection has the advantage that it is a non-invasive and appropriate for a wide variety of research., Results: We demonstrate successful enrichment and sequencing of 15 South African KhoeSan exomes and 2 full genomes with samples initially derived from saliva. The expanded exome dataset enables us to characterize genetic diversity free from ascertainment bias for multiple KhoeSan populations, including new exome data from six HGDP Namibian San, revealing substantial population structure across the Kalahari Desert region. Additionally, we discover and independently verify thirty-one previously unknown KIR alleles using methods we developed to accurately map and call the highly polymorphic HLA and KIR loci from exome capture data. Finally, we show that exome capture of saliva-derived DNA yields sufficient non-human sequences to characterize oral microbial communities, including detection of bacteria linked to oral disease (e.g. Prevotella melaninogenica). For comparison, two samples were sequenced using standard full genome library preparation without exome capture and we found no systematic bias of metagenomic information between exome-captured and non-captured data., Conclusions: DNA from human saliva samples, collected and extracted using standard procedures, can be used to successfully sequence high quality human exomes, and metagenomic data can be derived from non-human reads. We find that individuals from the Kalahari carry a higher oral pathogenic microbial load than samples surveyed in the Human Microbiome Project. Additionally, rare variants present in the exomes suggest strong population structure across different KhoeSan populations.
- Published
- 2014
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87. How do early emotional experiences in the operating theatre influence medical student learning in this environment?
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Bowrey DJ and Kidd JM
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- Education, Medical, Undergraduate, Female, Humans, Male, Qualitative Research, Stress, Psychological epidemiology, Stress, Psychological physiopathology, United Kingdom, Emotions, General Surgery education, Learning, Operating Rooms, Students, Medical psychology
- Abstract
Background: The emotions experienced by medical students on first exposure to the operating theatre are unknown. It is also unclear what influence these emotions have on the learning process., Purposes: To understand the emotions experienced by students when in the operating theatre for the first time and the impact of these emotions on learning., Methods: Nine 3rd-year medical students participated in semistructured interviews to explore these themes. A qualitative approach was used; interviews were transcribed and coded thematically., Results: All participants reported initial negative emotions (apprehension, anxiety, fear, shame, overwhelmed), with excitement being reported by 3. Six participants considered that their anxiety was so overwhelming that it was detrimental to their learning. Participants described a period of familiarization to the environment, after which learning was facilitated. Early learning experiences centered around adjustment to the physical environment of the operating theatre. Factors driving initial negative feelings were loss of familiarity, organizational issues, concerns about violating protocol, and a fear of syncope. Participants considered that it took a median of 1 week (range = 1 day-3 weeks) or 5 visits to the operating theatre (range = 1-10) before feeling comfortable in the new setting. Emotions experienced on subsequent visits to the operating theatre were predominantly positive (enjoyment, happiness, confident, involved, pride). Two participants reported negative feelings related to social exclusion. Being included in the team was a powerful determinant of enjoyment., Conclusions: These findings indicate that for learning in the operating theatre to be effective, addressing the negative emotions of the students might be beneficial. This could be achieved by a formal orientation program for both learners and tutors in advance of attendance in the operating theatre. For learning to be optimized, students must feel a sense of inclusion in the theatre community of practice.
- Published
- 2014
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88. Sequencing Y chromosomes resolves discrepancy in time to common ancestor of males versus females.
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Poznik GD, Henn BM, Yee MC, Sliwerska E, Euskirchen GM, Lin AA, Snyder M, Quintana-Murci L, Kidd JM, Underhill PA, and Bustamante CD
- Subjects
- Black People genetics, Evolution, Molecular, Female, Genome, Mitochondrial genetics, Haploidy, Humans, Male, Mutation, Phylogeny, Sequence Analysis, DNA, Time Factors, Chromosomes, Human, Y classification, Chromosomes, Human, Y genetics, Genetic Variation
- Abstract
The Y chromosome and the mitochondrial genome have been used to estimate when the common patrilineal and matrilineal ancestors of humans lived. We sequenced the genomes of 69 males from nine populations, including two in which we find basal branches of the Y-chromosome tree. We identify ancient phylogenetic structure within African haplogroups and resolve a long-standing ambiguity deep within the tree. Applying equivalent methodologies to the Y chromosome and the mitochondrial genome, we estimate the time to the most recent common ancestor (T(MRCA)) of the Y chromosome to be 120 to 156 thousand years and the mitochondrial genome T(MRCA) to be 99 to 148 thousand years. Our findings suggest that, contrary to previous claims, male lineages do not coalesce significantly more recently than female lineages.
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- 2013
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89. A tale of two haplotypes: the EDA2R/AR Intergenic region is the most divergent genomic segment between Africans and East Asians in the human genome.
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Casto AM, Henn BM, Kidd JM, Bustamante CD, and Feldman MW
- Subjects
- Alleles, Biological Evolution, Chromosomes, Human, X, Female, Gene Frequency, Genetics, Population, Humans, Male, Polymorphism, Single Nucleotide, Asian People genetics, Black People genetics, DNA, Intergenic genetics, Genome, Human, Haplotypes genetics, Receptors, Androgen genetics, Xedar Receptor genetics
- Abstract
Single nucleotide polymorphisms (SNPs) with large allele frequency differences between human populations are relatively rare. The longest run of SNPs with an allele frequency difference of one between the Yoruba of Nigeria and the Han Chinese is found on the long arm of the X chromosome in the intergenic region separating the EDA2R and AR genes. It has been proposed that the unusual allele frequency distributions of these SNPs are the result of a selective sweep affecting African populations that occurred after the out-of-Africa migration. To investigate the evolutionary history of the EDA2R/AR intergenic region, we characterized the haplotype structure of 52 of its highly differentiated SNPs. Using a publicly available data set of 3,000 X chromosomes from 65 human populations, we found that nearly all human X chromosomes carry one of two modal haplotypes for these 52 SNPs. The predominance of two highly divergent haplotypes at this locus was confirmed by use of a subset of individuals sequenced to high coverage. The first of these haplotypes, the α-haplotype is at high frequencies in most of the African populations surveyed and likely arose before the separation of African populations into distinct genetic entities. The second, the β-haplotype, is frequent or fixed in all non-African populations and likely arose in East Africa before the out-of-Africa migration. We also observed a small group or rare haplotypes with no clear relationship to the α- and β-haplotypes. These haplotypes occur at relatively high frequencies in African hunter-gatherer populations, such as the San and Mbuti Pygmies. Our analysis indicates that these haplotypes are part of a pool of diverse, ancestral haplotypes that have now been almost entirely replaced by the α- and β-haplotypes. We suggest that the rise of the α- and β-haplotypes was the result of the demographic forces that human populations experienced during the formation of modern African populations and the out-of-Africa migration. However, we also present evidence that this region is the target of selection in the form of positive selection on the α- and β-haplotypes and of purifying the selection against α/β recombinants., (Copyright © 2013 Wayne State University Press, Detroit, Michigan 48201-1309.)
- Published
- 2012
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90. Limited evidence for classic selective sweeps in African populations.
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Granka JM, Henn BM, Gignoux CR, Kidd JM, Bustamante CD, and Feldman MW
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- Cluster Analysis, Computer Simulation, Genetics, Population, Haplotypes, Humans, Models, Genetic, Polymorphism, Single Nucleotide, Black People genetics, Selection, Genetic
- Abstract
While hundreds of loci have been identified as reflecting strong-positive selection in human populations, connections between candidate loci and specific selective pressures often remain obscure. This study investigates broader patterns of selection in African populations, which are underrepresented despite their potential to offer key insights into human adaptation. We scan for hard selective sweeps using several haplotype and allele-frequency statistics with a data set of nearly 500,000 genome-wide single-nucleotide polymorphisms in 12 highly diverged African populations that span a range of environments and subsistence strategies. We find that positive selection does not appear to be a strong determinant of allele-frequency differentiation among these African populations. Haplotype statistics do identify putatively selected regions that are shared across African populations. However, as assessed by extensive simulations, patterns of haplotype sharing between African populations follow neutral expectations and suggest that tails of the empirical distributions contain false-positive signals. After highlighting several genomic regions where positive selection can be inferred with higher confidence, we use a novel method to identify biological functions enriched among populations' empirical tail genomic windows, such as immune response in agricultural groups. In general, however, it seems that current methods for selection scans are poorly suited to populations that, like the African populations in this study, are affected by ascertainment bias and have low levels of linkage disequilibrium, possibly old selective sweeps, and potentially reduced phasing accuracy. Additionally, population history can confound the interpretation of selection statistics, suggesting that greater care is needed in attributing broad genetic patterns to human adaptation.
- Published
- 2012
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91. Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.
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Kidd JM, Gravel S, Byrnes J, Moreno-Estrada A, Musharoff S, Bryc K, Degenhardt JD, Brisbin A, Sheth V, Chen R, McLaughlin SF, Peckham HE, Omberg L, Bormann Chung CA, Stanley S, Pearlstein K, Levandowsky E, Acevedo-Acevedo S, Auton A, Keinan A, Acuña-Alonzo V, Barquera-Lozano R, Canizales-Quinteros S, Eng C, Burchard EG, Russell A, Reynolds A, Clark AG, Reese MG, Lincoln SE, Butte AJ, De La Vega FM, and Bustamante CD
- Subjects
- Genetics, Population methods, Heterozygote, Humans, Polymorphism, Single Nucleotide, Genome, Human, Haplotypes genetics, Population genetics, Racial Groups genetics
- Abstract
Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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92. Structural diversity and African origin of the 17q21.31 inversion polymorphism.
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Steinberg KM, Antonacci F, Sudmant PH, Kidd JM, Campbell CD, Vives L, Malig M, Scheinfeldt L, Beggs W, Ibrahim M, Lema G, Nyambo TB, Omar SA, Bodo JM, Froment A, Donnelly MP, Kidd KK, Tishkoff SA, and Eichler EE
- Subjects
- Africa, Black People genetics, Evolution, Molecular, Gene Frequency, Haplotypes, Humans, In Situ Hybridization, Fluorescence, Linkage Disequilibrium, Phylogeny, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Chromosome Inversion genetics, Chromosomes, Human, Pair 17 genetics
- Abstract
The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2') lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps.
- Published
- 2012
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93. Detecting and annotating genetic variations using the HugeSeq pipeline.
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Lam HY, Pan C, Clark MJ, Lacroute P, Chen R, Haraksingh R, O'Huallachain M, Gerstein MB, Kidd JM, Bustamante CD, and Snyder M
- Subjects
- Algorithms, Genome, Human, Humans, Sequence Analysis, DNA, Databases, Genetic, Polymorphism, Single Nucleotide
- Published
- 2012
- Full Text
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94. Variation of BMP3 contributes to dog breed skull diversity.
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Schoenebeck JJ, Hutchinson SA, Byers A, Beale HC, Carrington B, Faden DL, Rimbault M, Decker B, Kidd JM, Sood R, Boyko AR, Fondon JW 3rd, Wayne RK, Bustamante CD, Ciruna B, and Ostrander EA
- Subjects
- Animals, Biological Evolution, Breeding, Chromosome Mapping, Genome-Wide Association Study, Genotype, Humans, Mutation, Missense, Pets, Phenotype, Skull anatomy & histology, Zebrafish genetics, Bone Morphogenetic Protein 3 genetics, Craniosynostoses genetics, Dogs genetics, Genetic Variation, Quantitative Trait Loci, Skull metabolism
- Abstract
Since the beginnings of domestication, the craniofacial architecture of the domestic dog has morphed and radiated to human whims. By beginning to define the genetic underpinnings of breed skull shapes, we can elucidate mechanisms of morphological diversification while presenting a framework for understanding human cephalic disorders. Using intrabreed association mapping with museum specimen measurements, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Our detailed analysis using whole-genome sequencing uncovers a missense mutation in BMP3. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Our study reveals the causal variant for a canine QTL contributing to a major morphologic trait., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2012
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95. The effectiveness of case-based learning in health professional education. A BEME systematic review: BEME Guide No. 23.
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Thistlethwaite JE, Davies D, Ekeocha S, Kidd JM, MacDougall C, Matthews P, Purkis J, and Clay D
- Subjects
- Attitude of Health Personnel, Clinical Competence, Consumer Behavior, Faculty, Health Knowledge, Attitudes, Practice, Humans, Inservice Training, Learning, Education, Professional methods, Health Personnel education, Problem-Based Learning
- Abstract
Background: Case-based learning (CBL) is a long established pedagogical method, which is defined in a number of ways depending on the discipline and type of 'case' employed. In health professional education, learning activities are commonly based on patient cases. Basic, social and clinical sciences are studied in relation to the case, are integrated with clinical presentations and conditions (including health and ill-health) and student learning is, therefore, associated with real-life situations. Although many claims are made for CBL as an effective learning and teaching method, very little evidence is quoted or generated to support these claims. We frame this review from the perspective of CBL as a type of inquiry-based learning., Aim: To explore, analyse and synthesise the evidence relating to the effectiveness of CBL as a means of achieving defined learning outcomes in health professional prequalification training programmes., Selection Criteria: We focused the review on CBL for prequalification health professional programmes including medicine, dentistry, veterinary science, nursing and midwifery, social care and the allied health professions (physiotherapy, occupational therapy, etc.). Papers were required to have outcome data on effectiveness., Search Strategies: The search covered the period from 1965 to week 4 September 2010 and the following databases: ASSIA, CINAHL, EMBASE, Education Research, Medline and Web of Knowledge (WoK). Two members of the topic review group (TRG) independently reviewed the 173 abstracts retrieved from Medline and compared findings. As there was good agreement on inclusion, one went onto review the WoK and ASSIA EndNote databases and the other the Embase, CINAHL and Education Research databases to decide on papers to submit for coding. Coding and data analysis: The TRG modified the standard best evidence medical education coding sheet to fit our research questions and assessed each paper for quality. After a preliminary reliability exercise, each full paper was read and graded by one reviewer with the papers scoring 3-5 (of 5) for strength of findings being read by a second reviewer. A summary of each completed coding form was entered into an Excel spread sheet. The type of data in the papers was not amenable to traditional meta-analysis because of the variability in interventions, information given, student numbers (and lack of) and timings. We, therefore, adopted a narrative synthesis method to compare, contrast, synthesise and interpret the data, working within a framework of inquiry-based learning., Results: The final number of coded papers for inclusion was 104. The TRG agreed that 23 papers would be classified as of higher quality and significance (22%). There was a wide diversity in the type, timing, number and length of exposure to cases and how cases were defined. Medicine was the most commonly included profession. Numbers of students taking part in CBL varied from below 50 to over 1000. The shortest interventions were two hours, and one case, whereas the longest was CBL through a whole year. Group sizes ranged from students working alone to over 30, with the majority between 2 and 15 students per group. The majority of studies involved single cohorts of students (61%), with 29% comparing multiple groups, 8% involving different year groups and 2% with historical controls. The outcomes evaluation was either carried out postintervention only (78 papers; 75%), preintervention and postintervention (23 papers; 22%) or during and postintervention (3 papers; <3%). Our analysis provided the basis for discussion of definitions of CBL, methods used and advocated, topics and learning outcomes and whether CBL is effective based on the evaluation data., Conclusion: Overwhelmingly, students enjoy CBL and think that it enhances their learning. The empirical data taken as a whole are inconclusive as to the effects on learning compared with other types of activity. Teachers enjoy CBL, partly because it engages, and is perceived to motivate, students. CBL seems to foster learning in small groups though whether this is the case delivery or the group learning effect is unclear.
- Published
- 2012
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96. Gorilla genome structural variation reveals evolutionary parallelisms with chimpanzee.
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Ventura M, Catacchio CR, Alkan C, Marques-Bonet T, Sajjadian S, Graves TA, Hormozdiari F, Navarro A, Malig M, Baker C, Lee C, Turner EH, Chen L, Kidd JM, Archidiacono N, Shendure J, Wilson RK, and Eichler EE
- Subjects
- Animals, Base Sequence, Chromosome Mapping, Chromosome Structures, Comparative Genomic Hybridization, Humans, In Situ Hybridization, Fluorescence, Karyotype, Molecular Sequence Data, Segmental Duplications, Genomic, Sequence Analysis, DNA, Evolution, Molecular, Genomic Structural Variation, Gorilla gorilla genetics, Pan troglodytes genetics
- Abstract
Structural variation has played an important role in the evolutionary restructuring of human and great ape genomes. Recent analyses have suggested that the genomes of chimpanzee and human have been particularly enriched for this form of genetic variation. Here, we set out to assess the extent of structural variation in the gorilla lineage by generating 10-fold genomic sequence coverage from a western lowland gorilla and integrating these data into a physical and cytogenetic framework of structural variation. We discovered and validated over 7665 structural changes within the gorilla lineage, including sequence resolution of inversions, deletions, duplications, and mobile element insertions. A comparison with human and other ape genomes shows that the gorilla genome has been subjected to the highest rate of segmental duplication. We show that both the gorilla and chimpanzee genomes have experienced independent yet convergent patterns of structural mutation that have not occurred in humans, including the formation of subtelomeric heterochromatic caps, the hyperexpansion of segmental duplications, and bursts of retroviral integrations. Our analysis suggests that the chimpanzee and gorilla genomes are structurally more derived than either orangutan or human genomes.
- Published
- 2011
- Full Text
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97. Hunter-gatherer genomic diversity suggests a southern African origin for modern humans.
- Author
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Henn BM, Gignoux CR, Jobin M, Granka JM, Macpherson JM, Kidd JM, Rodríguez-Botigué L, Ramachandran S, Hon L, Brisbin A, Lin AA, Underhill PA, Comas D, Kidd KK, Norman PJ, Parham P, Bustamante CD, Mountain JL, and Feldman MW
- Subjects
- Africa, Culture, Ethnicity genetics, Genome, Human, Humans, Linkage Disequilibrium, Biological Evolution, Black People genetics, Genetic Variation, Genetics, Population, Polymorphism, Single Nucleotide
- Abstract
Africa is inferred to be the continent of origin for all modern human populations, but the details of human prehistory and evolution in Africa remain largely obscure owing to the complex histories of hundreds of distinct populations. We present data for more than 580,000 SNPs for several hunter-gatherer populations: the Hadza and Sandawe of Tanzania, and the ≠Khomani Bushmen of South Africa, including speakers of the nearly extinct N|u language. We find that African hunter-gatherer populations today remain highly differentiated, encompassing major components of variation that are not found in other African populations. Hunter-gatherer populations also tend to have the lowest levels of genome-wide linkage disequilibrium among 27 African populations. We analyzed geographic patterns of linkage disequilibrium and population differentiation, as measured by F(ST), in Africa. The observed patterns are consistent with an origin of modern humans in southern Africa rather than eastern Africa, as is generally assumed. Additionally, genetic variation in African hunter-gatherer populations has been significantly affected by interaction with farmers and herders over the past 5,000 y, through both severe population bottlenecks and sex-biased migration. However, African hunter-gatherer populations continue to maintain the highest levels of genetic diversity in the world.
- Published
- 2011
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98. Population-genetic properties of differentiated human copy-number polymorphisms.
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Campbell CD, Sampas N, Tsalenko A, Sudmant PH, Kidd JM, Malig M, Vu TH, Vives L, Tsang P, Bruhn L, and Eichler EE
- Subjects
- Comparative Genomic Hybridization, Genetic Loci genetics, Genotype, Geography, Humans, Linkage Disequilibrium genetics, Mutagenesis, Insertional genetics, Polymorphism, Single Nucleotide genetics, DNA Copy Number Variations genetics, Genetics, Population
- Abstract
Copy-number variants (CNVs) can reach appreciable frequencies in the human population, and recent discoveries have shown that several of these copy-number polymorphisms (CNPs) are associated with human diseases, including lupus, psoriasis, Crohn disease, and obesity. Despite new advances, significant biases remain in terms of CNP discovery and genotyping. We developed a method based on single-channel intensity data and benchmarked against copy numbers determined from sequencing read depth to successfully obtain CNP genotypes for 1495 CNPs from 487 human DNA samples of diverse ethnic backgrounds. This microarray contained CNPs in segmental duplication-rich regions and insertions of sequences not represented in the reference genome assembly or on standard SNP microarray platforms. We observe that CNPs in segmental duplications are more likely to be population differentiated than CNPs in unique regions (p = 0.015) and that biallelic CNPs show greater stratification when compared to frequency-matched SNPs (p = 0.0026). Although biallelic CNPs show a strong correlation of copy number with flanking SNP genotypes, the majority of multicopy CNPs do not (40% with r > 0.8). We selected a subset of CNPs for further characterization in 1876 additional samples from 62 populations; this revealed striking population-differentiated structural variants in genes of clinical significance such as OCLN, a tight junction protein involved in hepatitis C viral entry. Our microarray design allows these variants to be rapidly tested for disease association and our results suggest that CNPs (especially those that cannot be imputed from SNP genotypes) might have contributed disproportionately to human diversity and selection., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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99. Mapping copy number variation by population-scale genome sequencing.
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Mills RE, Walter K, Stewart C, Handsaker RE, Chen K, Alkan C, Abyzov A, Yoon SC, Ye K, Cheetham RK, Chinwalla A, Conrad DF, Fu Y, Grubert F, Hajirasouliha I, Hormozdiari F, Iakoucheva LM, Iqbal Z, Kang S, Kidd JM, Konkel MK, Korn J, Khurana E, Kural D, Lam HY, Leng J, Li R, Li Y, Lin CY, Luo R, Mu XJ, Nemesh J, Peckham HE, Rausch T, Scally A, Shi X, Stromberg MP, Stütz AM, Urban AE, Walker JA, Wu J, Zhang Y, Zhang ZD, Batzer MA, Ding L, Marth GT, McVean G, Sebat J, Snyder M, Wang J, Ye K, Eichler EE, Gerstein MB, Hurles ME, Lee C, McCarroll SA, and Korbel JO
- Subjects
- Gene Duplication genetics, Genetic Predisposition to Disease genetics, Genotype, Humans, Mutagenesis, Insertional genetics, Reproducibility of Results, Sequence Analysis, DNA, Sequence Deletion genetics, DNA Copy Number Variations genetics, Genetics, Population, Genome, Human genetics, Genomics
- Abstract
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
- Published
- 2011
- Full Text
- View/download PDF
100. Comparative and demographic analysis of orang-utan genomes.
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Locke DP, Hillier LW, Warren WC, Worley KC, Nazareth LV, Muzny DM, Yang SP, Wang Z, Chinwalla AT, Minx P, Mitreva M, Cook L, Delehaunty KD, Fronick C, Schmidt H, Fulton LA, Fulton RS, Nelson JO, Magrini V, Pohl C, Graves TA, Markovic C, Cree A, Dinh HH, Hume J, Kovar CL, Fowler GR, Lunter G, Meader S, Heger A, Ponting CP, Marques-Bonet T, Alkan C, Chen L, Cheng Z, Kidd JM, Eichler EE, White S, Searle S, Vilella AJ, Chen Y, Flicek P, Ma J, Raney B, Suh B, Burhans R, Herrero J, Haussler D, Faria R, Fernando O, Darré F, Farré D, Gazave E, Oliva M, Navarro A, Roberto R, Capozzi O, Archidiacono N, Della Valle G, Purgato S, Rocchi M, Konkel MK, Walker JA, Ullmer B, Batzer MA, Smit AF, Hubley R, Casola C, Schrider DR, Hahn MW, Quesada V, Puente XS, Ordoñez GR, López-Otín C, Vinar T, Brejova B, Ratan A, Harris RS, Miller W, Kosiol C, Lawson HA, Taliwal V, Martins AL, Siepel A, Roychoudhury A, Ma X, Degenhardt J, Bustamante CD, Gutenkunst RN, Mailund T, Dutheil JY, Hobolth A, Schierup MH, Ryder OA, Yoshinaga Y, de Jong PJ, Weinstock GM, Rogers J, Mardis ER, Gibbs RA, and Wilson RK
- Subjects
- Animals, Centromere genetics, Cerebrosides metabolism, Chromosomes, Evolution, Molecular, Female, Gene Rearrangement genetics, Genetic Speciation, Genetics, Population, Humans, Male, Phylogeny, Population Density, Population Dynamics, Species Specificity, Genetic Variation, Genome genetics, Pongo abelii genetics, Pongo pygmaeus genetics
- Abstract
'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.
- Published
- 2011
- Full Text
- View/download PDF
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