scholarly journals A two-locus system with strong epistasis underlies rapid parasite-mediated evolution of host resistance

2020 ◽  
Author(s):  
Camille Ameline ◽  
Yann Bourgeois ◽  
Felix Vögtli ◽  
Eevi Savola ◽  
Jason Andras ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Genetic Model ◽  
Genetic Recombination ◽  
Bacterial Pathogen ◽  
Host Population ◽  
Strong Increase ◽  
Adaptive Responses ◽  
A Genome ◽  
Frequency Changes ◽  
Locus System

Abstract Parasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen, Pasteuria ramosa, in a natural host population of Daphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome wide association study (GWAS), we built a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Such epistatic effects with strong fitness consequences in host-parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.

scholarly journals A two-locus system with strong epistasis underlies rapid parasite-mediated evolution of host resistance

2020 ◽  
Author(s):  
Camille Ameline ◽  
Yann Bourgeois ◽  
Felix Vögtli ◽  
Eevi Savola ◽  
Jason Andras ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Genetic Model ◽  
Genetic Recombination ◽  
Bacterial Pathogen ◽  
Host Population ◽  
Strong Increase ◽  
Adaptive Responses ◽  
A Genome ◽  
Frequency Changes ◽  
Locus System

AbstractParasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen, Pasteuria ramosa, in a natural host population of Daphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome wide association study (GWAS), we obtained a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Applying the model to the dynamics of the field population revealed moderate changes in allele frequencies at the two resistance loci relative to the profound changes observed at the phenotypic level. This apparent discrepancy is explained by strong epistasis and dominance at the two resistance loci, which reduces the effect of selection on alleles at both loci. Such epistatic effects with strong fitness consequences in host-parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.

A Genetic Model To Predict Response to Glatiramer Acetate Developed from a Genome Wide Association Study (GWAS) (IN3-2.003)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. IN3-2.003-IN3-2.003
Author(s):  
F. Macciardi ◽  
J. Cohen ◽  
M. Comabella Lopez ◽  
G. Comi ◽  
G. Cutter ◽  
...  
Keyword(s):  
Association Study ◽  
Glatiramer Acetate ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals GWAS of Post-Orthodontic Aggressive External Apical Root Resorption Identified Multiple Putative Loci at X-Y Chromosomes

2020 ◽  
Vol 10 (4) ◽  
pp. 169
Author(s):  
Paula Iber-Díaz ◽  
Raquel Senen-Carramolino ◽  
Alejandro Iglesias-Linares ◽  
Pablo Fernández-Navarro ◽  
Carlos Flores-Mir ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Root Resorption ◽  
Genetic Model ◽  
Nucleotide Polymorphisms ◽  
Apical Root Resorption ◽  
A Genome ◽  
Increased Risk ◽  
External Apical Root Resorption

Personalized dental medicine requires from precise and customized genomic diagnostic. To conduct an association analysis over multiple putative loci and genes located at chromosomes 2, 4, 8, 12, 18, X, and Y, potentially implicated in an extreme type of external apical root resorption secondary to orthodontic forces (aEARR). A genome-wide association study of aEARR was conducted with 480 patients [ratio~1:3 case/control]. Genomic DNA was extracted and analyzed using the high-throughput Axiom platform with the GeneTitan® MC Instrument. Up to 14,377 single nucleotide polymorphisms (SNPs) were selected at candidate regions and clinical/diagnostic data were recorded. A descriptive analysis of the data along with a backward conditional binary logistic regression was used to calculate odds ratios, with 95% confidence intervals [p < 0.05]. To select the best SNP candidates, a logistic regression model was fitted assuming a log-additive genetic model using R software [p < 0.0001]. In this sample the top lead genetic variants associated with aEARR were two novel putative genes located in the X chromosome, specifically, STAG 2 gene, rs151184635 and RP1-30E17.2 gene, rs55839915. These variants were found to be associated with an increased risk of aEARR, particularly restricted to men [OR: 6.09; 95%CI: 2.6–14.23 and OR: 6.86; 95%CI: 2.65–17.81, respectively]. Marginal associations were found at previously studied variants such as SSP1: rs11730582 [OR: 0.54; 95%CI: 0.34–0.86; p = 0.008], P2RX7: rs1718119 [OR: 0.6; 95%CI: 0.36–1.01; p = 0.047], and TNFRSF11A: rs8086340 [OR: 0.6; 95%CI: 0.38–0.95; p = 0.024]), found solely in females. Multiple putative genetic variants located at chromosomes X and Y are potentially implicated in an extreme phenotype of aEARR. A gender-linked association was noted.

scholarly journals Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus)

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Georgina Samaha ◽  
Claire M. Wade ◽  
Julia Beatty ◽  
Leslie A. Lyons ◽  
Linda M. Fleeman ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
Sequence Data ◽  
Pancreatic Beta Cell ◽  
Whole Genome Sequence ◽  
Cell Dysfunction ◽  
Genome Wide ◽  
A Genome ◽  
Pathologic Features

Abstract Diabetes mellitus, a common endocrinopathy affecting domestic cats, shares many clinical and pathologic features with type 2 diabetes in humans. In Australia and Europe, diabetes mellitus is almost four times more common among Burmese cats than in other breeds. As a genetically isolated population, the diabetic Australian Burmese cat provides a spontaneous genetic model for studying diabetes mellitus in humans. Studying complex diseases in pedigreed breeds facilitates tighter control of confounding factors including population stratification, allelic frequencies and environmental heterogeneity. We used the feline SNV array and whole genome sequence data to undertake a genome wide-association study and runs of homozygosity analysis, of a case–control cohort of Australian and European Burmese cats. Our results identified diabetes-associated haplotypes across chromosomes A3, B1 and E1 and selective sweeps across the Burmese breed on chromosomes B1, B3, D1 and D4. The locus on chromosome B1, common to both analyses, revealed coding and splice region variants in candidate genes, ANK1, EPHX2 and LOX2, implicated in diabetes mellitus and lipid dysregulation. Mapping this condition in Burmese cats has revealed a polygenic spectrum, implicating loci linked to pancreatic beta cell dysfunction, lipid dysregulation and insulin resistance in the pathogenesis of diabetes mellitus in the Burmese cat.

Abstract 051: Genome-wide Association Study Identifies 12 Loci for Habitual Consumption of Bitter and Sweet Beverages

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Victor W Zhong ◽  
Sandra Sanchez-Roige ◽  
Peter Kraft ◽  
Rob M Van Dam ◽  
Daniel I Chasman ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
Taste Perception ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Multiple Snps ◽  
Genome Wide ◽  
A Genome

Introduction: Widely consumed beverages (e.g., soft drinks, coffee, tea) are critical sources of energy, added sugar and phytochemicals and are associated with obesity and chronic disease. Taste perception and preferences are highly heritable and strong determinants of food and beverage choice. We aimed to identify novel loci underlying habitual bitter and sweet beverage intake. Methods: We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage intake in participants of European ancestry in the UK Biobank. Diet was assessed via multiple 24-h diet recalls (n=84703, subset) or questionnaire (n=335909, all). Bitter beverage intake was the sum of coffee, tea and grapefruit juice. Sweet beverage intake was the sum of artificially and sugar sweetened beverages and other fruit juice. Multivariable linear regression under an additive genetic model was applied. GW-significant (P < 5х10 -8 ) SNPs were followed-up for replication in independent studies of European ancestry. Results: Multiple SNPs spanning 11 loci were associated with bitter beverage intake (P <5х10 -8 , Table 1), and at least 5 of them reflected the caffeine content of coffee and tea. Multiple SNPs in the obesity candidate gene FTO were associated with sweet beverage intake (P <5х10 -8 ). The effect size per allele ranged from 0.02 to 0.2 cup per day. Loci in/near AHR, CYP1A2, and FTO were associated with both bitter and sweet beverage intake but in opposite directions. Replication efforts are ongoing. So far, associations at all loci, except 1q25.2 and 2q36.2, were replicated (P range: 0.04 to 1.8x10 -8 ) in independent studies (n=17322) which provided 80% power for replicating 8 of these 12 loci at P=0.05. Conclusions: Loci linked to caffeine metabolism and obesity predisposition rather than taste are major determinants of beverage intake. These and other identified loci have been linked to chronic disease and risk factors, suggesting causal or pleiotropic effects. Our findings have potential public health and methodological implications.

Abstract P358: Discovery Loci and Generalization of Platelet Count Associations in the Hispanic Community Health Study: Study of Latinos (HCHS/SoL)

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Chani J Hodonsky ◽  
Ursula Schick ◽  
Jean Morrison ◽  
Cathy Laurie ◽  
John H Eckfeldt ◽  
...  
Keyword(s):  
Platelet Count ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Structural Integrity ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
The United States ◽  
Actin Binding ◽  
Health Study ◽  
A Genome

Background: The biology of platelets_anuclear megakaryocyte fragments required for clotting_is well defined, with abnormalities resulting in clotting disorders ranging from asymptomatic to severe. Although platelet count (PLT) is highly heritable (h 2 =0.57 in NHANES), genetic regulation of this trait remains incompletely characterized. In particular, Hispanic Latinos are a diverse population in which the genetic variability of PLT has not been analyzed. We aimed to 1) identify novel loci associated with PLT in participants of HCHS/SoL; and 2) determine if previously identified PLT loci generalize to the Hispanic Latino population. Methods: We performed a genome-wide association study of PLT in 12,491 participants of HCHS/SoL, which includes individuals with Dominican, Puerto Rican, Mexican, Cuban, South American, and Central American ancestral origins residing in the United States. Participants were genotyped on the Illumina SoL Omni2.5M array and imputed to the 1000 Genomes Phase I Reference panel. We implemented linear mixed-model regression assuming an additive genetic model, adjusting for sex, age, study center, ancestry and sample weights, and including random effects for individual relatedness, household, and block group. Results: Ten independent loci were significantly (α = 5x10 -8 ) associated with PLT in HCHS/SoL and 13 of 57 previously identified platelet-count GWAS loci generalized to HCHS/SoL (+/-500kb, α = 8.78x10 -4 ). Discovery loci included a significant association near GABBR1 (rs3131857, MAF = 40%, β = -0.16) and a suggestive association near ETV7 (rs9470264, MAF = 20%, β = -0.19). Furthermore, a noncoding variant in ACTN1 was associated with increased PLT (rs117672662, MAF = 6%, β = 0.61); ACTN1 codes for alpha-actinin, a multi-isoform actin-binding protein involved in cytoskeleton organization and platelet/megakaryocyte structural integrity. Missense mutations in ACTN1 were recently implicated in congenital thrombocytopenia; exome sequencing also associated this locus with PLT, which supports a potential functional role in PLT for this gene. Conditional regression analyses to assess secondary association signals are in progress. Conclusions: Genetic associations in two discovery loci ( ETV7 and GABBR1 ) underscore the benefit of using diverse populations in GWAS. Expanding the number of loci associated with platelet count will help elucidate disease mechanisms and develop approaches to treat platelet disorders in populations of all ancestries.

scholarly journals Genetic slippage after sex maintains diversity for parasite resistance in a natural host population

2021 ◽  
Author(s):  
Camille Ameline ◽  
Felix Voegtli ◽  
Jason Andras ◽  
Eric Dexter ◽  
Jan Engelstaedter ◽  
...  
Keyword(s):  
Genetic Model ◽  
Large Population ◽  
Bacterial Pathogen ◽  
Host Population ◽  
Natural Host ◽  
Parasite Resistance ◽  
Resting Stages ◽  
Resistance Evolution ◽  
Multiple Loci ◽  
Cyclical Pattern

Although parasite-mediated selection is thought to be a major driver of host evolution, its influence on genetic variation for parasite resistance is not yet well understood. We monitored a large population of the planktonic crustacean Daphnia magna over eight years, as it underwent yearly epidemics of the bacterial pathogen Pasteuria ramosa. We observed a cyclical pattern of resistance evolution: resistant phenotypes increased in frequency throughout the epidemics, but susceptibility was restored each spring when hosts hatched from sexual resting stages, a phenomenon described as genetic slippage in response to sex. Collecting and hatching D. magna resting stages across multiple seasons showed that largely resistant host populations can produce susceptible offspring through recombination. Resting stages produced throughout the planktonic season accurately represent the hatching population cohort of the following spring. A genetic model of resistance developed for this host-parasite system, based on multiple loci and strong epistasis, is in partial agreement with these findings. Our results reveal that, despite strong selection for resistance in a natural host population, genetic slippage after sexual reproduction has the potential to maintain genetic diversity of host resistance.

Abstract 15465: Precision Medicine Approach to Resistant Hypertension: Genetic Markers of Resistant Hypertension Through a Genome-wide Association Study (GWAS) in the Secondary Prevention of Subcortical Strokes (SPS3)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Nihal El Rouby ◽  
Caitrin W McDonough ◽  
Yan Gong ◽  
Leslie A McClure ◽  
Braxton D Mitchell ◽  
...  
Keyword(s):  
Resistant Hypertension ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
Antihypertensive Drugs ◽  
Meta Analysis ◽  
Multiple Logistic Regression Analysis ◽  
Strong Linkage Disequilibrium ◽  
Functional Variants ◽  
A Genome ◽  
Increased Risk

Introduction: Resistant hypertension (RHTN), a blood pressure (BP) ≥140/90 mm Hg despite ≥ 3 antihypertensive drugs or BP < 140/90 mm Hg using ≥ 4 drugs, is associated with increased incidence of adverse cardiovascular outcomes, especially stroke. Hypothesis and objective: We hypothesize common variants exist in the genes regulating BP response and may lead to RHTN in some patients. Methods: A discovery cohort of hypertensive participants were included as cases (as defined above) or controls (N=719; 263 whites, 322 Hispanics, and 134 African Americans) from SPS3-GENES. They were genotyped on the Illumina Omni 5 Exome chip. Multiple logistic regression analysis was conducted separately in each race using an additive genetic model, adjusting for predictors for RHTN, principle components for ancestry and BP target treatment arms. Results from the 3 racial groups were combined using meta-analysis with inverse-variance weighting, with the hypothesis that functional variants are consistent across races. The associations of seven SNPs that met the suggestive level of association (p <1 x10-5) in the SPS3 meta-analysis were tested for replication in 1,194 participants (657 whites, and 537 Hispanics) from the INternational VErapamil-SR trandolapril STudy GENEtic Substudy (INVEST-GENES). Bonferroni adjusted p was set at 0.007 to correct for multiple comparisons. Combined meta-analysis between INVEST and SPS3 was conducted for replicated SNPs or SNPs that had consistent association in the two cohorts with a nominal significance. Results: A missense SNP (rs3766160; Asp114Asn) in CELA2B was associated with increased risk of RHTN in SPS3 (Combined OR=1.8, p=6x10-6)). The same SNP replicated in INVEST (Combined OR=1.3, p=0.004; INVEST/SPS3 meta-p=4.5x10-7). An intronic SNP rs3789592 in strong linkage disequilibrium (r2=0.98) with a missense SNP (rs1049434; Asp490Glu) in SLC16A1 was associated with RHTN in SPS3 (Combined OR=2.0, p=7.6x10-7) and had a consistent association in INVEST (Combined OR=1.2, p=0.048; INVEST/SPS3 meta-p=7.6x10-7). Conclusion: Genetic loci in CELA2B, SLC16A1 were identified and confirmed for association in two cohorts. These associations, if further validated may help identify those patients at risk for RHTN.

scholarly journals Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures

2018 ◽  
Author(s):  
Jie Zheng ◽  
Winfried Maerz ◽  
Ingrid Gergei ◽  
Marcus Kleber ◽  
Christiane Drechsler ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Neck ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Adaptive Responses ◽  
Mineral Density ◽  
A Genome

ABSTRACTIn bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6×10−49), and GALNT1 (β=0.11 per G allele, P=4.4×10−11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= −0.12, 95%CI= −0.20 to −0.05) and eBMD (β= −0.12, 95%CI= −0.14 to −0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.

A Genetic Model To Predict Response to Glatiramer Acetate Developed from a Genome Wide Association Study (GWAS) (S20.003)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. S20.003-S20.003
Author(s):  
F. Macciardi ◽  
J. Cohen ◽  
M. Comabella Lopez ◽  
G. Comi ◽  
G. Cutter ◽  
...  
Keyword(s):  
Association Study ◽  
Glatiramer Acetate ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome
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