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

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.

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

Genes ◽

10.3390/genes11040367 ◽

2020 ◽

Vol 11 (4) ◽

pp. 367 ◽

Cited By ~ 4

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.

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The Genetic Architecture of Ovariole Number in Drosophila melanogaster: Genes with Major, Quantitative, and Pleiotropic Effects

G3 Genes|Genome|Genetics ◽

10.1534/g3.117.042390 ◽

2017 ◽

Vol 7 (7) ◽

pp. 2391-2403 ◽

Cited By ~ 11

Author(s):

Amanda S Lobell ◽

Rachel R Kaspari ◽

Yazmin L Serrano Negron ◽

Susan T Harbison

Keyword(s):

Candidate Genes ◽

Genome Wide Association Study ◽

Natural Populations ◽

Direct Role ◽

Genome Wide ◽

A Genome ◽

Fitness Trait ◽

Sleep Parameters ◽

Activity Behavior ◽

Ovariole Number

Abstract Ovariole number has a direct role in the number of eggs produced by an insect, suggesting that it is a key morphological fitness trait. Many studies have documented the variability of ovariole number and its relationship to other fitness and life-history traits in natural populations of Drosophila. However, the genes contributing to this variability are largely unknown. Here, we conducted a genome-wide association study of ovariole number in a natural population of flies. Using mutations and RNAi-mediated knockdown, we confirmed the effects of 24 candidate genes on ovariole number, including a novel gene, anneboleyn (formerly CG32000), that impacts both ovariole morphology and numbers of offspring produced. We also identified pleiotropic genes between ovariole number traits and sleep and activity behavior. While few polymorphisms overlapped between sleep parameters and ovariole number, 39 candidate genes were nevertheless in common. We verified the effects of seven genes on both ovariole number and sleep: bin3, blot, CG42389, kirre, slim, VAChT, and zfh1. Linkage disequilibrium among the polymorphisms in these common genes was low, suggesting that these polymorphisms may evolve independently.

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Genome-Wide Association Analysis of Growth Curve Parameters in Chinese Simmental Beef Cattle

Animals ◽

10.3390/ani11010192 ◽

2021 ◽

Vol 11 (1) ◽

pp. 192

Author(s):

Xinghai Duan ◽

Bingxing An ◽

Lili Du ◽

Tianpeng Chang ◽

Mang Liang ◽

...

Keyword(s):

Beef Cattle ◽

Candidate Genes ◽

Growth Curve ◽

Growth And Development ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Coefficient Of Determination ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Genome

The objective of the present study was to perform a genome-wide association study (GWAS) for growth curve parameters using nonlinear models that fit original weight–age records. In this study, data from 808 Chinese Simmental beef cattle that were weighed at 0, 6, 12, and 18 months of age were used to fit the growth curve. The Gompertz model showed the highest coefficient of determination (R2 = 0.954). The parameters’ mature body weight (A), time-scale parameter (b), and maturity rate (K) were treated as phenotypes for single-trait GWAS and multi-trait GWAS. In total, 9, 49, and 7 significant SNPs associated with A, b, and K were identified by single-trait GWAS; 22 significant single nucleotide polymorphisms (SNPs) were identified by multi-trait GWAS. Among them, we observed several candidate genes, including PLIN3, KCNS3, TMCO1, PRKAG3, ANGPTL2, IGF-1, SHISA9, and STK3, which were previously reported to associate with growth and development. Further research for these candidate genes may be useful for exploring the full genetic architecture underlying growth and development traits in livestock.

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Genome-Wide Association Study Reveals the Genetic Basis of Cold Tolerance in Rice at the Seedling Stage

Agriculture ◽

10.3390/agriculture11040318 ◽

2021 ◽

Vol 11 (4) ◽

pp. 318

Author(s):

Tae-Ho Ham ◽

Yebin Kwon ◽

Yoonjung Lee ◽

Jisu Choi ◽

Joohyun Lee

Keyword(s):

Association Study ◽

Candidate Genes ◽

Cold Tolerance ◽

Genome Wide Association Study ◽

Seedling Stage ◽

Genome Wide Association ◽

Matrix Analysis ◽

Rice Seedlings ◽

Genome Wide ◽

A Genome

We conducted a genome-wide association study (GWAS) of cold tolerance in a collection of 127 rice accessions, including 57 Korean landraces at the seedling stage. Cold tolerance of rice seedlings was evaluated in a growth chamber under controlled conditions and scored on a 0–9 scale, based on their low-temperature response and subsequent recovery. GWAS, together with principal component analysis (PCA) and kinship matrix analysis, revealed four quantitative trait loci (QTLs) on chromosomes 1, 4, and 5 that explained 16.5% to 18.5% of the variance in cold tolerance. The genomic region underlying the QTL on chromosome four overlapped with a previously reported QTL associated with cold tolerance in rice seedlings. Similarly, one of the QTLs identified on chromosome five overlapped with a previously reported QTL associated with seedling vigor. Subsequent bioinformatic and haplotype analyses revealed three candidate genes affecting cold tolerance within the linkage disequilibrium (LD) block of these QTLs: Os01g0357800, encoding a pentatricopeptide repeat (PPR) domain-containing protein; Os05g0171300, encoding a plastidial ADP-glucose transporter; and Os05g0400200, encoding a retrotransposon protein, Ty1-copia subclass. The detected QTLs and further evaluation of these candidate genes in the future will provide strategies for developing cold-tolerant rice in breeding programs.

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Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

Journal of Personalized Medicine ◽

10.3390/jpm11010059 ◽

2021 ◽

Vol 11 (1) ◽

pp. 59

Author(s):

Kirsten Voorhies ◽

Joanne E. Sordillo ◽

Michael McGeachie ◽

Elizabeth Ampleford ◽

Alberta L. Wang ◽

...

Keyword(s):

Candidate Genes ◽

P Value ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Single Nucleotide ◽

Significance Level ◽

Bronchodilator Response ◽

Genome Wide ◽

A Genome ◽

Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

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Genome-wide association analysis reveals genetic variations and candidate genes associated with salt tolerance related traits in Gossypium hirsutum

BMC Genomics ◽

10.1186/s12864-020-07321-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Peng Xu ◽

Qi Guo ◽

Shan Meng ◽

Xianggui Zhang ◽

Zhenzhen Xu ◽

...

Keyword(s):

Salt Stress ◽

Salt Tolerance ◽

Candidate Genes ◽

Genetic Variations ◽

Genome Wide Association ◽

Cotton Production ◽

Fresh Matter ◽

Salt Stress Response ◽

Genome Wide ◽

A Genome

Abstract Background Cotton is more resistant to salt and drought stresses as compared to other field crops, which makes itself as a pioneer industrial crop in saline-alkali lands. However, abiotic stresses still negatively affect its growth and development significantly. It is therefore important to breed salt tolerance varieties which can help accelerate the improvement of cotton production. The development of molecular markers linked to causal genes has provided an effective and efficient approach for improving salt tolerance. Results In this study, a genome-wide association study (GWAS) of salt tolerance related traits at seedling stage was performed based on 2 years of phenotype identification for 217 representative upland cotton cultivars by genotyping-by-sequencing (GBS) platform. A total of 51,060 single nucleotide polymorphisms (SNPs) unevenly distributed among 26 chromosomes were screened across the cotton cultivars, and 25 associations with 27 SNPs scattered over 12 chromosomes were detected significantly (−log10p > 4) associated with three salt tolerance related traits in 2016 and 2017. Among these, the associations on chromosome A13 and D08 for relative plant height (RPH), A07 for relative shoot fresh matter weight (RSFW), A08 and A13 for relative shoot dry matter weight (RSDW) were expressed in both environments, indicating that they were likely to be stable quantitative trait loci (QTLs). A total of 12 salt-induced candidate genes were identified differentially expressed by the combination of GWAS and transcriptome analysis. Three promising genes were selected for preliminary function verification of salt tolerance. The increase of GH_A13G0171-silenced plants in salt related traits under salt stress indicated its negative function in regulating the salt stress response. Conclusions These results provided important genetic variations and candidate genes for accelerating the improvement of salt tolerance in cotton.

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Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2009.09.007 ◽

2010 ◽

Vol 125 (2) ◽

pp. 321-327.e13 ◽

Cited By ~ 60

Author(s):

Hao Wu ◽

Isabelle Romieu ◽

Min Shi ◽

Dana B. Hancock ◽

Huiling Li ◽

...

Keyword(s):

Association Study ◽

Candidate Genes ◽

Childhood Asthma ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Genome-wide association analysis of resistance to Pseudoperonospora cubensis in citron watermelon

Plant Disease ◽

10.1094/pdis-08-21-1611-re ◽

2021 ◽

Author(s):

Dennis Katuuramu ◽

Sandra Branham ◽

Amnon Levi ◽

Patrick Wechter

Keyword(s):

Candidate Genes ◽

Genome Wide Association Study ◽

Citrullus Lanatus ◽

Phenotypic Variability ◽

Germplasm Collection ◽

Snp Markers ◽

Genome Wide Association ◽

Pseudoperonospora Cubensis ◽

Genome Wide ◽

A Genome

Cultivated sweet watermelon (Citrullus lanatus) is an important vegetable crop for millions of people around the world. There are limited sources of resistance to economically important diseases within C. lanatus, whereas Citrullus amarus has a reservoir of traits that can be exploited to improve C. lanatus for resistance to biotic and abiotic stresses. Cucurbit downy mildew (CDM), caused by Pseudoperonospora cubensis, is an emerging threat to watermelon production. We screened 122 C. amarus accessions for resistance to CDM over two tests (environments). The accessions were genotyped by whole-genome resequencing to generate 2,126,759 single nucleotide polymorphic (SNP) markers. A genome-wide association study was deployed to uncover marker-trait associations and identify candidate genes underlying resistance to CDM. Our results indicate the presence of wide phenotypic variability (1.1 - 57.8%) for leaf area infection, representing a 50.7-fold variation for CDM resistance across the C. amarus germplasm collection. Broad-sense heritability estimate was 0.55, implying the presence of moderate genetic effects for resistance to CDM. The peak SNP markers associated with resistance to P. cubensis were located on chromosomes Ca03, Ca05, Ca07, and Ca11. The significant SNP markers accounted for up to 30% of the phenotypic variation and were associated with promising candidate genes encoding disease resistance proteins, leucine-rich repeat receptor-like protein kinase, and WRKY transcription factor. This information will be useful in understanding the genetic architecture of the P. cubensis-Citrullus spp. patho-system as well as development of resources for genomics-assisted breeding for resistance to CDM in watermelon.

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A Genome-Wide Association Study Reveals Candidate Genes Related to Salt Tolerance in Rice (Oryza sativa) at the Germination Stage

International Journal of Molecular Sciences ◽

10.3390/ijms19103145 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3145 ◽

Cited By ~ 8

Author(s):

Jie Yu ◽

Weiguo Zhao ◽

Wei Tong ◽

Qiang He ◽

Min-Young Yoon ◽

...

Keyword(s):

Salt Tolerance ◽

Association Study ◽

Candidate Genes ◽

Genome Wide Association Study ◽

Rice Genome ◽

Genome Wide Association ◽

Phenotypic Correlation ◽

Genome Wide ◽

A Genome ◽

Germination Stage

Salt toxicity is the major factor limiting crop productivity in saline soils. In this paper, 295 accessions including a heuristic core set (137 accessions) and 158 bred varieties were re-sequenced and ~1.65 million SNPs/indels were used to perform a genome-wide association study (GWAS) of salt-tolerance-related phenotypes in rice during the germination stage. A total of 12 associated peaks distributed on seven chromosomes using a compressed mixed linear model were detected. Determined by linkage disequilibrium (LD) blocks analysis, we finally obtained a total of 79 candidate genes. By detecting the highly associated variations located inside the genic region that overlapped with the results of LD block analysis, we characterized 17 genes that may contribute to salt tolerance during the seed germination stage. At the same time, we conducted a haplotype analysis of the genes with functional variations together with phenotypic correlation and orthologous sequence analyses. Among these genes, OsMADS31, which is a MADS-box family transcription factor, had a down-regulated expression under the salt condition and it was predicted to be involved in the salt tolerance at the rice germination stage. Our study revealed some novel candidate genes and their substantial natural variations in the rice genome at the germination stage. The GWAS in rice at the germination stage would provide important resources for molecular breeding and functional analysis of the salt tolerance during rice germination.

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Genome-wide association analysis reveals genetic variations and candidate genes associated with salt tolerance related traits in Gossypium hirsutum

10.21203/rs.3.rs-66236/v3 ◽

2020 ◽

Author(s):

Peng Xu ◽

Qi Guo ◽

Shan Meng ◽

Xianggui Zhang ◽

Zhenzhen Xu ◽

...

Keyword(s):

Salt Stress ◽

Salt Tolerance ◽

Candidate Genes ◽

Genetic Variations ◽

Genome Wide Association ◽

Cotton Production ◽

Fresh Matter ◽

Salt Stress Response ◽

Genome Wide ◽

A Genome

Abstract Background: Cotton is more resistant to salt and drought stresses as compared to other field crops, which makes itself as a pioneer industrial crop in saline-alkali lands. However, abiotic stresses still negatively affect its growth and development significantly. It is therefore important to breed salt tolerance varieties which can help accelerate the improvement of cotton production. The development of molecular markers linked to causal genes has provided an effective and efficient approach for improving salt tolerance. Results: In this study, a genome-wide association study (GWAS) of salt tolerance related traits at seedling stage was performed based on two years of phenotype identification for 217 representative upland cotton cultivars by genotyping-by-sequencing (GBS) platform. A total of 51,060 single nucleotide polymorphisms (SNPs) unevenly distributed among 26 chromosomes were screened across the cotton cultivars, and 25 associations with 27 SNPs scattered over 12 chromosomes were detected significantly (-log10p>4) associated with three salt tolerance related traits in 2016 and 2017. Among these, the associations on chromosome A13 and D08 for relative plant height (RPH), A07 for relative shoot fresh matter weight (RSFW), A08 and A13 for relative shoot dry matter weight (RSDW) were expressed in both environments, indicating that they were likely to be stable quantitative trait loci (QTLs). A total of 12 salt-induced candidate genes were identified differentially expressed by the combination of GWAS and transcriptome analysis. Three promising genes were selected for preliminary function verification of salt tolerance. The increase of GH_A13G0171-silenced plants in salt related traits under salt stress indicated its negative function in regulating the salt stress response. Conclusions: These results provided important genetic variations and candidate genes for accelerating the improvement of salt tolerance in cotton.

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