scholarly journals A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 367 ◽  
Author(s):  
Sawar Khan ◽  
Ayesha Nisar ◽  
Jianqi Yuan ◽  
Xiaoping Luo ◽  
Xueqin Dou ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Haemonchus Contortus ◽  
Population Genomics ◽  
Small Ruminants ◽  
Track Record ◽  
Genome Wide ◽  
Signatures Of Selection ◽  
Parasitic Worms ◽  
Important Parasite

The most important and broad-spectrum drug used to control the parasitic worms to date is ivermectin (IVM). Resistance against IVM has emerged in parasites, and preserving its efficacy is now becoming a serious issue. The parasitic nematode Haemonchus contortus (Rudolphi, 1803) is economically an important parasite of small ruminants across the globe, which has a successful track record in IVM resistance. There are growing evidences regarding the multigenic nature of IVM resistance, and although some genes have been proposed as candidates of IVM resistance using lower magnification of genome, the genetic basis of IVM resistance still remains poorly resolved. Using the full magnification of genome, we herein applied a population genomics approach to characterize genome-wide signatures of selection among pooled worms from two susceptible and six ivermectin-resistant isolates of H. contortus, and revealed candidate genes under selection in relation to IVM resistance. These candidates also included a previously known IVM-resistance-associated candidate gene HCON_00148840, glc-3. Finally, an RNA-interference-based functional validation assay revealed the HCON_00143950 as IVM-tolerance-associated gene in H. contortus. The possible role of this gene in IVM resistance could be detoxification of xenobiotic in phase I of xenobiotic metabolism. The results of this study further enhance our understanding on the IVM resistance and continue to provide further evidence in favor of multigenic nature of IVM resistance.

scholarly journals Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

2018 ◽  
Author(s):  
Stephen R. Doyle ◽  
Christopher J. R. Illingworth ◽  
Roz Laing ◽  
David J. Bartley ◽  
Elizabeth Redman ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Haemonchus Contortus ◽  
Parasitic Nematode ◽  
Companion Animals ◽  
Small Ruminants ◽  
Genomic Diversity ◽  
Model Organisms ◽  
Partial Dominance ◽  
Genome Wide ◽  
A Genome

AbstractBackgroundInfections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved.ResultsHere, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this Q.TL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection.ConclusionsWe have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high quality reference genome in interpreting the signals of selection so identified.

scholarly journals Effect of Five Mediterranean Shrubs Extracts on Larval Exsheathment of Haemonchus contortus

2021 ◽  
Author(s):  
A. Aïssa ◽  
F. Manolaraki ◽  
H. Ben Salem ◽  
H. Hoste ◽  
K. Kraiem
Keyword(s):  
Haemonchus Contortus ◽  
Small Ruminants ◽  
Good Alternative ◽  
Gastrointestinal Nematodes ◽  
Shrub Species ◽  
Medicago Arborea ◽  
Mediterranean Shrubs ◽  
Third Stage

Background: Mediterranean shrub species cover more than 70% of the total area in Tunisia and in summer when the herbaceous species have wilted, they constitute feeding resource for livestock. The use of tanniniferous shrubs seems to be a good alternative to control gastrointestinal nematodes infections in small ruminants. This study evaluated the in vitro anthelmintic (AH) effect of Ceratonia siliqua (C. siliqua), Periploca angustifolia Labill. (P. angustifolia) and Medicago arborea (M. arborea) against Haemonchus contortus third stage larvae (L3). Methods: The larval exsheathment assay (LEA) was used to determine the proportions (%) of exsheathment of five acetonic extracts at different concentrations (1200, 600, 300, 150 μg/ml). To confirm the role of tannins in the AH effects of extracts, polyvinyl polypyrolidone (PVPP) was used as deactivating chemical tannins. Result: The highest % L3 exsheathed was recorded for M. arborea (55.01%) and the lowest value was founded for C. siliqua and P. angustifolia leaves (16.26%). Our results were concentration-dependent (P less than 0.001). The % of exsheathment increased as the time of incubation increased (P less than 0.001). P. angustifolia pods recorded the lowest EC50 value (P less than 0.05). After PVPP addition, all the acetonic extracts showed a restoration of L3 exsheathment values similar to control values (P less than 0.001).

scholarly journals A novel BR-SMAD is required for larval development in barber’s pole worm Haemonchus contortus

2021 ◽  
Vol 8 (2) ◽  
pp. 57-64
Author(s):  
Fangfang Li ◽  
Peixi Qin ◽  
Lisha Ye ◽  
Nishith Gupta ◽  
Min Hu
Keyword(s):  
Haemonchus Contortus ◽  
Developmental Stages ◽  
Small Ruminants ◽  
Bmp Signaling ◽  
Bimolecular Fluorescence Complementation ◽  
Blood Sucking ◽  
Morphogenetic Protein ◽  
Smad Proteins ◽  
Family Protein ◽  
Parasitic Worms

SMAD proteins mediate TGF-β signaling and thereby regulate the metazoan development; however, they are poorly defined in Haemonchus contortus–a common blood-sucking parasitic nematode of small ruminants. Here, we characterized an R-SMAD family protein in H. contortus termed HcSMA2, which is closely related to Caenorhabditis elegans SMA2 (CeSMA2) involved in the bone morphogenetic protein (BMP) signaling. Hcsma2 is transcribed in all developmental stages of H. contortus but highly induced in the adult male worms. The RNA interference with Hcsma2 retarded the transition of infective L3 into L4 larvae. Besides, the bimolecular fluorescence complementation revealed the interaction of HcSMA2 with a TGF-β-activated-R-SMAD (HcDAF8). Together these results show a BMP-like receptor-regulated SMAD in H. contortus that is required for larval differentiation and underscore an adaptive functional repurposing of BMP-signaling in parasitic worms.

scholarly journals Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

2020 ◽  
Vol 26 (5) ◽  
pp. 490-500
Author(s):  
A. O. Konradi
Keyword(s):  
Candidate Genes ◽  
High Performance ◽  
New Technologies ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Modern Approach ◽  
Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

scholarly journals Replication of Genome Wide Association Identified Candidate Genes Confirm the Role of Common and Rare Variants inPAX7andVAX1in the Etiology of Nonsyndromic CL(P)

2013 ◽  
Vol 161 (5) ◽  
pp. 965-972 ◽  
Author(s):  
Azeez Butali ◽  
Satoshi Suzuki ◽  
Margaret E. Cooper ◽  
Adela M. Mansilla ◽  
Karen Cuenco ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Rare Variants ◽  
Genome Wide Association ◽  
Genome Wide

scholarly journals Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

2014 ◽  
Vol 58 (12) ◽  
pp. 7475-7483 ◽  
Author(s):  
Andrew C. Kotze ◽  
Angela P. Ruffell ◽  
Aaron B. Ingham
Keyword(s):  
Haemonchus Contortus ◽  
Synergistic Effects ◽  
Cytochromes P450 ◽  
Resistance Mechanism ◽  
Fold Increase ◽  
Protective Role ◽  
Detoxification Enzymes ◽  
Content Type ◽  
Parasitic Worms

ABSTRACTWe used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos withHaemonchus contortuslarvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH)S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC50) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates thatH. contortuslarvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field.

scholarly journals Candidate genes of the development of antipsychotic-induced parkinsonism in patients with schizophrenia

2021 ◽  
Vol 57 (4) ◽  
pp. 15-35
Author(s):  
E. E. Vaiman ◽  
N. A. Shnayder ◽  
N. G. Neznanov ◽  
R. F. Nasyrova
Keyword(s):  
Candidate Genes ◽  
Neurological Complication ◽  
Leading Role ◽  
Genetic Predictors ◽  
Genome Wide ◽  
Genes Encoding ◽  
Schizophrenic Patients ◽  
Unique Decision ◽  
Genetically Determined

Antipsychotic-induced parkinsonism is an undesirable reaction from the extrapyramidal system that occurs against the background of taking antipsychotics (AP), more often in patients with schizophrenia. Antipsychotic-induced parkinsonism belongs to the group of secondary parkinsonism. Its prevalence in the world is about 36%. It is assumed that this undesirable AP reaction is genetically determined. In recent years, numerous associative genetic studies of predisposition to the development of antipsychotic-induced parkinsonism have been conducted. However, the research results are contradictory.Purpose. Review of the results of studies of genetic predictors of antipsychotic-induced parkinsonism in patients with schizophrenia.Materials and methods. We searched for full-text publications in Russian and English in the RSCI, PubMed, Web of Science, Springer databases using keywords and combined searches for words over the past decade.Results. The review considers candidate genes encoding proteins/enzymes involved in the pharmacodynamics and pharmacokinetics of AP. We analyzed 23 genome-wide studies examining 108 genetic variations, including SNV/polymorphisms of 26 candidate genes involved in the development of AIP in schizophrenic patients. Among such a set of obtained results, only 22 positive associations were revealed: rs1799732 (141CIns/Del), rs1800497 (C/T), rs6275 (C/T) DRD2; rs167771 (G/A) DRD3; VNTR*9R DAT1; rs4680 (G/A) СOMT; rs6311 (C/T) 5HTR2A; rs6318 (C/G), rs3813929 (С/Т), haplotype-997G, -759C, -697C и 68G HTR2C; rs2179652 (C/T), rs2746073 (T/A), rs4606 (C/G), rs1152746 (A/G), rs1819741 (С/Т), rs1933695 (G/A), haplotype rs1933695-G, rs2179652-C, rs4606-C, rs1819741-T и rs1152746-G, haplotype rs1933695-G, rs2179652-T, rs4606-G, rs1819741-C и rs1152746-A RGS2; haplotype TCCTC ADORA2A; rs4795390 (C/G) PPP1R1B; rs6265 (G/A) BDNF; rs12678719 (C/G) ZFPM2; rs938112 (C/A) LSMAP; rs2987902 (A/T) ABL1; HLA-B44; rs16947 (A/G), rs1135824 (A/G), rs3892097 (A/G), rs28371733 (A/G), rs5030867 (A/C), rs5030865 (A/C), rs1065852 (C/T), rs5030863 (C/G), rs5030862 (A/G), rs28371706 (C/T), rs28371725 (A/G), rs1080983 (A/G) CYP2D6. However, at the present time it should be recognized that there is no final or unique decision about the leading role of any particular SNV/polymorphism in the development of AIP.Conclusion. Disclosure of genetic predictors of AP-induced parkinsonism development may provide a key to the development of a strategy for personalized prevention and treatment of the neurological complication of AP-therapy of schizophrenia in real clinical practice.

scholarly journals Molecular population genomics: a short history

2010 ◽  
Vol 92 (5-6) ◽  
pp. 397-411 ◽  
Author(s):  
BRIAN CHARLESWORTH
Keyword(s):  
Population Genomics ◽  
Natural Populations ◽  
Molecular Approaches ◽  
Multiple Loci ◽  
Genome Wide ◽  
Wide Variability ◽  
Enzyme Mapping ◽  
The Subject ◽  
Dna Resequencing

SummaryPopulation genomics is the study of the amount and causes of genome-wide variability in natural populations, a topic that has been under discussion since Darwin. This paper first briefly reviews the early development of molecular approaches to the subject: the pioneering unbiased surveys of genetic variability at multiple loci by means of gel electrophoresis and restriction enzyme mapping. The results of surveys of levels of genome-wide variability using DNA resequencing studies are then discussed. Studies of the extent to which variability for different classes of variants (non-synonymous, synonymous and non-coding) are affected by natural selection, or other directional forces such as biased gene conversion, are also described. Finally, the effects of deleterious mutations on population fitness and the possible role of Hill–Robertson interference in shaping patterns of sequence variability are discussed.

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