scholarly journals Population selection and sequencing of C. elegans wild isolates identifies a region on chromosome III affecting starvation resistance

2019 ◽  
Author(s):  
Amy K. Webster ◽  
Anthony Hung ◽  
Brad T. Moore ◽  
Ryan Guzman ◽  
James M. Jordan ◽  
...  
Keyword(s):  
Quantitative Traits ◽  
Natural Variation ◽  
Genome Wide Association Studies ◽  
Isogenic Line ◽  
Starvation Resistance ◽  
C Elegans ◽  
Population Selection ◽  
Wild Strains ◽  
Chromosome Iii ◽  
Over Time

ABSTRACTTo understand the genetic basis of complex traits, it is important to be able to efficiently phenotype many genetically distinct individuals. In the nematode Caenorhabditis elegans, individuals have been isolated from diverse populations around the globe and whole-genome sequenced. As a result, hundreds of wild strains with known genome sequences can be used for genome-wide association studies (GWAS). However, phenotypic analysis of these strains can be laborious, particularly for quantitative traits requiring multiple measurements per strain. Starvation resistance is likely a fitness-proximal trait for nematodes, and it is related to metabolic disease risk in humans. However, natural variation in C. elegans starvation resistance has not been characterized, and precise measurement of the trait is time-intensive. Here, we developed a population selection and sequencing-based approach to phenotype starvation resistance in a pool of 96 wild strains. We used restriction site-associated DNA sequencing (RAD-seq) to infer the frequency of each strain among survivors in a mixed culture over time during starvation. We used manual starvation survival assays to validate the trait data, confirming that strains that increased in frequency over time are starvation-resistant relative to strains that decreased in frequency. These results document natural variation in starvation resistance. Further, we found that variation in starvation resistance is significantly associated with variation at a region on chromosome III. Using a near-isogenic line (NIL), we showed the importance of this genomic interval for starvation resistance. This study demonstrates the feasibility of using population selection and sequencing in an animal model for phenotypic analyses of quantitative traits, reveals natural variation of starvation resistance in C. elegans, and identifies a genomic region that contributes to such variation.

scholarly journals Population Selection and Sequencing of Caenorhabditis elegans Wild Isolates Identifies a Region on Chromosome III Affecting Starvation Resistance

2019 ◽  
Vol 9 (10) ◽  
pp. 3477-3488 ◽  
Author(s):  
Amy K. Webster ◽  
Anthony Hung ◽  
Brad T. Moore ◽  
Ryan Guzman ◽  
James M. Jordan ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Quantitative Traits ◽  
Natural Variation ◽  
Starvation Resistance ◽  
Phenotypic Analysis ◽  
C Elegans ◽  
Population Selection ◽  
Wild Strains ◽  
Chromosome Iii ◽  
Over Time

To understand the genetic basis of complex traits, it is important to be able to efficiently phenotype many genetically distinct individuals. In the nematode Caenorhabditis elegans, individuals have been isolated from diverse populations around the globe and whole-genome sequenced. As a result, hundreds of wild strains with known genome sequences can be used for genome-wide association studies (GWAS). However, phenotypic analysis of these strains can be laborious, particularly for quantitative traits requiring multiple measurements per strain. Starvation resistance is likely a fitness-proximal trait for nematodes, and it is related to metabolic disease risk in humans. However, natural variation in C. elegans starvation resistance has not been systematically characterized, and precise measurement of the trait is time-intensive. Here, we developed a population-selection-and-sequencing-based approach to phenotype starvation resistance in a pool of 96 wild strains. We used restriction site-associated DNA sequencing (RAD-seq) to infer the frequency of each strain among survivors in a mixed culture over time during starvation. We used manual starvation survival assays to validate the trait data, confirming that strains that increased in frequency over time are starvation-resistant relative to strains that decreased in frequency. Further, we found that variation in starvation resistance is significantly associated with variation at a region on chromosome III. Using a near-isogenic line (NIL), we showed the importance of this genomic interval for starvation resistance. This study demonstrates the feasibility of using population selection and sequencing in an animal model for phenotypic analysis of quantitative traits, documents natural variation of starvation resistance in C. elegans, and identifies a genomic region that contributes to such variation.

scholarly journals Natural Variation in the npr-1 Gene Modifies Ethanol Responses of Wild Strains of C. elegans

Neuron ◽  
2004 ◽  
Vol 42 (5) ◽  
pp. 731-743 ◽  
Author(s):  
Andrew G Davies ◽  
Jill C Bettinger ◽  
Tod R Thiele ◽  
Meredith E Judy ◽  
Steven L McIntire
Keyword(s):  
Natural Variation ◽  
C Elegans ◽  
Wild Strains

scholarly journals Caenorhabditis elegans as a platform for molecular quantitative genetics and the systems biology of natural variation

2010 ◽  
Vol 92 (5-6) ◽  
pp. 331-348 ◽  
Author(s):  
BRYN E. GAERTNER ◽  
PATRICK C. PHILLIPS
Keyword(s):  
Systems Biology ◽  
Caenorhabditis Elegans ◽  
Quantitative Traits ◽  
Natural Variation ◽  
Evolutionary Genetics ◽  
Model Systems ◽  
C Elegans ◽  
Complex Phenotypes ◽  
Powerful Means ◽  
Evolutionary Context

SummaryOver the past 30 years, the characteristics that have made the nematode Caenorhabditis elegans one of the premier animal model systems have also allowed it to emerge as a powerful model system for determining the genetic basis of quantitative traits, particularly for the identification of naturally segregating and/or lab-adapted alleles with large phenotypic effects. To better understand the genetic underpinnings of natural variation in other complex phenotypes, C. elegans is uniquely poised in the emerging field of quantitative systems biology because of the extensive knowledge of cellular and neural bases to such traits. However, perturbations in standing genetic variation and patterns of linkage disequilibrium among loci are likely to limit our ability to tie understanding of molecular function to a broader evolutionary context. Coupling the experimental strengths of the C. elegans system with the ecological advantages of closely related nematodes should provide a powerful means of understanding both the molecular and evolutionary genetics of quantitative traits.

scholarly journals Natural variation in the irld gene family affects insulin/IGF signaling and starvation resistance

2021 ◽  
Author(s):  
Amy K Webster ◽  
Rojin Chitrakar ◽  
Maya Powell ◽  
Jingxian Chen ◽  
Kinsey Fisher ◽  
...  
Keyword(s):  
Nervous System ◽  
Gene Family ◽  
Natural Variation ◽  
Genetic Basis ◽  
Egf Receptor ◽  
Complex Trait ◽  
Starvation Resistance ◽  
C Elegans ◽  
Sensory Nervous System ◽  
Igf Signaling

Starvation resistance is a fundamental, disease-relevant trait, but the genetic basis of its natural variation is unknown. We developed a synthetic population-sequencing approach to measure starvation resistance for many wild C. elegans strains simultaneously. We identified three quantitative trait loci with variants in 16 insulin/EGF receptor-like domain (irld) family members. We show that four irld genes affect starvation resistance by regulating insulin/IGF signaling. We propose that IRLD proteins bind insulin-like peptides to modify signaling in the sensory nervous system thereby affecting organismal physiology. This work demonstrates efficacy of using population sequencing to dissect a complex trait, identifies irld genes that regulate insulin/IGF signaling, and shows that an expanded gene family modifies a deeply conserved signaling pathway to affect a fitness-proximal trait.

scholarly journals Quantitative Trait Loci Controlling Light and Hormone Response in Two Accessions ofArabidopsis thaliana

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 683-696 ◽  
Author(s):  
Justin O Borevitz ◽  
Julin N Maloof ◽  
Jason Lutes ◽  
Tsegaye Dabi ◽  
Joanna L Redfern ◽  
...  
Keyword(s):  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Natural Variation ◽  
Red Light ◽  
Light Response ◽  
Environment Interaction ◽  
Isogenic Line ◽  
Hormone Response ◽  
New Genes ◽  
Trait Loci

AbstractWe have mapped quantitative trait loci (QTL) responsible for natural variation in light and hormone response between the Cape Verde Islands (Cvi) and Landsberg erecta (Ler) accessions of Arabidopsis thaliana using recombinant inbred lines (RILs). Hypocotyl length was measured in four light environments: white, blue, red, and far-red light and in the dark. In addition, white light plus gibberellin (GA) and dark plus the brassinosteroid biosynthesis inhibitor brassinazole (BRZ) were used to detect hormone effects. Twelve QTL were identified that map to loci not previously known to affect light response, as well as loci where candidate genes have been identified from known mutations. Some QTL act in all environments while others show genotype-by-environment interaction. A global threshold was established to identify a significant epistatic interaction between two loci that have few main effects of their own. LIGHT1, a major QTL, has been confirmed in a near isogenic line (NIL) and maps to a new locus with effects in all light environments. The erecta mutation can explain the effect of the HYP2 QTL in the blue, BRZ, and dark environments, but not in far-red. LIGHT2, also confirmed in an NIL, has effects in white and red light and shows interaction with GA. The phenotype and map position of LIGHT2 suggest the photoreceptor PHYB as a candidate gene. Natural variation in light and hormone response thus defines both new genes and known genes that control light response in wild accessions.

scholarly journals Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

2016 ◽  
Vol 283 (1835) ◽  
pp. 20160569 ◽  
Author(s):  
M. E. Goddard ◽  
K. E. Kemper ◽  
I. M. MacLeod ◽  
A. J. Chamberlain ◽  
B. J. Hayes
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Quantitative Traits ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Crop Breeding ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Phenotype Identification

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

Abstract 288: Novel Mechanisms of Non-coding Genomic Regulation Identified in Cardiac Disease-in-a-dish Models

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Aditya Kumar ◽  
Stephanie Thomas ◽  
Kirsten Wong ◽  
Kevin Tenerelli ◽  
Valentina Lo Sardo ◽  
...  
Keyword(s):  
Heart Attack ◽  
Connexin 43 ◽  
Disease Risk ◽  
Association Studies ◽  
Correlation Coefficients ◽  
Induced Pluripotent Stem Cell ◽  
Genome Wide Association Studies ◽  
Isogenic Line ◽  
Nucleotide Polymorphisms ◽  
Increased Risk

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at gene loci that affect cardiovascular function, and while mechanisms in protein-coding loci are obvious, those in non-coding loci are difficult to determine. 9p21 is a recently identified locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction. Associations have implicated SNPs in altering smooth muscle and endothelial cell properties but have not identified adverse effects in cardiomyocytes (CMs) despite enhanced disease risk. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs and either CAD positive or negative, we assessed CM function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. “heart attack-in-a-dish” stiffening from 11 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype and disease beat synchronously on soft matrices, R/R CMs cultured on dynamically stiffened hydrogels exhibited asynchronous contractions and had significantly lower correlation coefficients versus N/N CMs in the same conditions. Dynamic stiffening reduced connexin 43 expression and gap junction assembly in R/R CMs but not N/N CMs. To eliminate patient-to-patient variability, we created an isogenic line by deleting the 9p21 gene locus from a R/R patient using TALEN-mediated gene editing, i.e. R/R KO. Deletion of the 9p21 locus restored synchronous contractility and organized connexin 43 junctions. As a non-coding locus, 9p21 appears to repress connexin transcription, leading to the phenotypes we observe, but only when the niche is stiffened as in disease. These data are the first to demonstrate that disease-specific niche remodeling, e.g. a “heart attack-in-a-dish” model, can differentially affect CM function depending on SNPs within a non-coding locus.

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