scholarly journals Evaluating the power and limitations of genome-wide association mapping in C. elegans

2021 ◽  
Author(s):  
Samuel J. Widmayer ◽  
Kathryn S. Evans ◽  
Stefan Zdraljevic ◽  
Erik C. Andersen
Keyword(s):  
Quantitative Trait ◽  
Complex Traits ◽  
Genetic Basis ◽  
Natural Populations ◽  
Evolutionary Genetics ◽  
Genome Wide Association ◽  
C Elegans ◽  
Quantitative Genetic ◽  
Genome Wide ◽  
Simulation Based

A central goal of evolutionary genetics in Caenorhabditis elegans is to understand the genetic basis of traits that contribute to adaptation and fitness. Genome-wide association (GWA) mappings scan the genome for individual genetic variants that are significantly correlated with phenotypic variation in a population, or quantitative trait loci (QTL). GWA mappings are a popular choice for quantitative genetic analyses because the QTL that are discovered segregate in natural populations. Despite numerous successful mapping experiments, the empirical performance of GWA mappings has not, to date, been formally evaluated for this species. We developed an open-source GWA mapping pipeline called NemaScan and used a simulation-based approach to provide benchmarks of mapping performance among wild C. elegans strains. Simulated trait heritability and complexity determined the spectrum of QTL detected by GWA mappings. Power to detect smaller-effect QTL increased with the number of strains sampled from the C. elegans Natural Diversity Resource (CeNDR). Population structure was a major driver of variation in GWA mapping performance, with populations shaped by recent selection exhibiting significantly lower false discovery rates than populations composed of more divergent strains. We also recapitulated previous GWA mappings of experimentally validated quantitative trait variants. Our simulation-based evaluation of GWA performance provides the community with critical context for pursuing quantitative genetic studies using CeNDR to elucidate the genetic basis of complex traits in C. elegans natural populations.

scholarly journals GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

2020 ◽  
Author(s):  
Nasa Sinnott-Armstrong ◽  
Sahin Naqvi ◽  
Manuel Rivas ◽  
Jonathan K Pritchard
Keyword(s):  
Complex Traits ◽  
Genetic Basis ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Uk Biobank ◽  
The Core ◽  
Genome Wide ◽  
Core Genes

SummaryGenome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. However, for most traits it remains difficult to interpret what genes and biological processes are impacted by the top hits. Here, as a contrast, we describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—that are biologically simpler than most diseases, and for which we know a great deal in advance about the core genes and pathways. Unlike most GWAS of complex traits, for all three traits we find that most top hits are readily interpretable. We observe huge enrichment of significant signals near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of variation in each trait, including insights into differences in testosterone regulation between females and males. Meanwhile, in other respects the results are reminiscent of GWAS for more-complex traits. In particular, even these molecular traits are highly polygenic, with most of the variance coming not from core genes, but from thousands to tens of thousands of variants spread across most of the genome. Given that diseases are often impacted by many distinct biological processes, including these three, our results help to illustrate why so many variants can affect risk for any given disease.

scholarly journals Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

2016 ◽  
Vol 25 (10) ◽  
pp. 2113-2129 ◽  
Author(s):  
Steven Offenbacher ◽  
Kimon Divaris ◽  
Silvana P. Barros ◽  
Kevin L. Moss ◽  
Julie T. Marchesan ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Association Study ◽  
Complex Traits ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide

scholarly journals Polygenicity and epistasis underlie fitness-proximal traits in the Caenorhabditis elegans multiparental experimental evolution (CeMEE) panel

2017 ◽  
Author(s):  
Luke M. Noble ◽  
Ivo Chelo ◽  
Thiago Guzella ◽  
Bruno Afonso ◽  
David D. Riccardi ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Experimental Evolution ◽  
Complex Traits ◽  
Genetic Basis ◽  
Natural Populations ◽  
Phenotypic Variance ◽  
Nucleotide Polymorphisms ◽  
C Elegans ◽  
Mapping Panel ◽  
Trait Locus

ABSTRACTUnderstanding the genetic basis of complex traits remains a major challenge in biology. Polygenicity, phenotypic plasticity and epistasis contribute to phenotypic variance in ways that are rarely clear. This uncertainty is problematic for estimating heritability, for predicting individual phenotypes from genomic data, and for parameterizing models of phenotypic evolution. Here we report a recombinant inbred line (RIL) quantitative trait locus (QTL) mapping panel for the hermaphroditic nematode Caenorhabditis elegans, the C. elegans multiparental experimental evolution (CeMEE) panel. The CeMEE panel, comprising 507 RILs, was created by hybridization of 16 wild isolates, experimental evolution at moderate population sizes and predominant outcrossing for 140-190 generations, and inbreeding by selfing for 13-16 generations. The panel contains 22% of single nucleotide polymorphisms known to segregate in natural populations, and complements existing mapping resources for C. elegans by providing high nucleotide diversity across >95% of the genome. We apply it to study the genetic basis of two fitness components, fertility and hermaphrodite body size at time of reproduction, with high broad sense heritability in the CeMEE. While simulations show we should detect common alleles with additive effects as small as 5%, at gene-level resolution, the genetic architectures of these traits does not feature such alleles. We instead find that a significant fraction of trait variance, particularly for fertility, can be explained by sign epistasis with weak main effects. In congruence, phenotype prediction, while generally poor (r2 < 10%), requires modeling epistasis for optimal accuracy, with most variance attributed to the highly recombinant, rapidly evolving chromosome arms.

scholarly journals Genome-Wide Association for Itraconazole Sensitivity in Non-Resistant Clinical Isolates of Aspergillus fumigatus

2020 ◽  
Author(s):  
Shu Zhao ◽  
Wenbo Ge ◽  
Akira Watanabe ◽  
Jarrod R. Fortwendel ◽  
John G. Gibbons
Keyword(s):  
Aspergillus Fumigatus ◽  
Complex Traits ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Clinical Isolates ◽  
Genome Wide Association ◽  
Azole Resistance ◽  
Genome Wide ◽  
Population Structure Analysis ◽  
Recent Emergence

AbstractAspergillus fumigatus is a potentially lethal opportunistic pathogen that infects over ∼200,000 people and causes ∼100,000 deaths per year globally. Treating A. fumigatus infections is particularly challenging because of the recent emergence of azole-resistance. The majority of studies focusing on the molecular mechanisms underlying azole resistance have examined azole-resistant isolates. However, isolates that are susceptible to azoles also display variation in their sensitivity, presenting a unique opportunity to identify genes contributing to azole sensitivity. Here, we used genome-wide association (GWA) analysis to identify loci involved in azole sensitivity by analyzing the association between 68,853 SNPs and itraconazole (ITCZ) minimum inhibitory concentration (MIC) in 76 clinical isolates of A. fumigatus from Japan. Population structure analysis suggests the presence of four distinct populations, with ITCZ MICs distributed relatively evenly across populations. We independently conducted GWA when treating ITCZ MIC as a quantitative trait and a binary trait and identified two SNPs with strong associations that were identified in both analyses. These SNPs fell within the coding regions of Afu2g02220 and Afu2g02140. We functionally validated Afu2g02220 by knocking it out using a CRISPR/Cas-9 approach, because orthologs of this gene are involved in sterol modification and ITCZ targets the ergosterol pathway. Knockout strains displayed no difference in growth compared to the parent strain in minimal media, yet a minor but consistent inhibition of growth in the presence of 0.15 ug/ml ITCZ. Our results suggest that GWA paired with efficient gene deletion is a powerful and unbiased strategy for identifying the genetic basis of complex traits in A. fumigatus.ImportanceAspergillus fumigatus is a pathogenic mold that can infect and kill individuals with compromised immune systems. The azole class of drugs provide antifungal activity against A. fumigatus infections and have become an essential treatment strategy. Unfortunately, A. fumigatus azole resistance has recently emerged and rapidly risen in frequency making treatment more challenging. Our understanding of the molecular basis of azole sensitivity has been shaped mainly through candidate gene studies. Unbiased approaches are necessary to understand the full repertoire of genes and genetic variants underlying azole resistance and sensitivity. Here, we provide the first application of genome-wide association analysis in A. fumigatus in the identification of a gene (Afu2g02220) that contributes to itraconazole susceptibility. Our approach, which combines association mapping and CRISPR/Cas-9 for functional validation of candidate genes, has broad application for investigating the genetic basis of complex traits in fungal systems.

scholarly journals Thinking About the Evolution of Complex Traits in the Era of Genome-Wide Association Studies

2019 ◽  
Vol 20 (1) ◽  
pp. 461-493 ◽  
Author(s):  
Guy Sella ◽  
Nicholas H. Barton
Keyword(s):  
Complex Traits ◽  
Genetic Basis ◽  
Association Studies ◽  
Practical Importance ◽  
Complex Trait ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Heritable Variation ◽  
Genome Wide ◽  
Polygenic Adaptation

Many traits of interest are highly heritable and genetically complex, meaning that much of the variation they exhibit arises from differences at numerous loci in the genome. Complex traits and their evolution have been studied for more than a century, but only in the last decade have genome-wide association studies (GWASs) in humans begun to reveal their genetic basis. Here, we bring these threads of research together to ask how findings from GWASs can further our understanding of the processes that give rise to heritable variation in complex traits and of the genetic basis of complex trait evolution in response to changing selection pressures (i.e., of polygenic adaptation). Conversely, we ask how evolutionary thinking helps us to interpret findings from GWASs and informs related efforts of practical importance.

scholarly journals The genetic basis of cooperation and conflict in natural populations of a model symbiont

2021 ◽  
Author(s):  
Rebecca T Batstone ◽  
Liana T Burghardt ◽  
Katy D Heath
Keyword(s):  
Nucleotide Diversity ◽  
Genetic Basis ◽  
Balancing Selection ◽  
Association Studies ◽  
Natural Populations ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Ensifer Meliloti ◽  
Single Versus

Although mutualisms are defined as net beneficial interactions among species, whether fitness conflict or alignment drive the evolution of these interactions is unclear. Examining the relationships between host and symbiont fitness proxies at both the organismal and genomic levels can provide new insights. Here, we utilized data from several genome-wide association studies (GWAS) that involved 191 strains of the N-fixing rhizobium symbiont, Ensifer meliloti, collected from natural populations being paired in single or mixed inoculation with two genotypes of the host Medicago truncatula to determine how different proxies of microbial fitness were related to one another, and examine signatures of fitness conflict and alignment between host and symbiont at both the whole-organism and genomic levels. We found little evidence for fitness conflict; instead, loci tended to have concordant effects on both host and symbiont fitness and showed heightened nucleotide diversity and signatures of balancing selection compared to the rest of the genome. We additionally found that single versus competitive measures of rhizobium fitness are distinct, and that the latter should be used given that they better reflect the ecological conditions rhizobia experience in nature. Our results suggest that although conflict appears to be largely resolved in natural populations of rhizobia, mutualistic coevolution between legumes and rhizobia can nonetheless maintain genetic diversity, potentially explaining why variation in symbiotic traits persists in nature.

scholarly journals Identification of Quantitative Trait Loci for Related Traits of Stalk Lodging Resistance Using Genome-wide Association Studies in Maize (Zea mays L.)

2021 ◽  
Author(s):  
Lifen Wu ◽  
Yunxiao Zheng ◽  
Fuchao Jiao ◽  
Ming Wang ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Zea Mays ◽  
Quantitative Trait Loci ◽  
Association Mapping ◽  
Quantitative Trait ◽  
Genetic Basis ◽  
Genome Wide Association ◽  
Lodging Resistance ◽  
Mapping Panel ◽  
Genome Wide ◽  
Stalk Lodging

Abstract Background: Stalk lodging is one of the main factors affecting maize (Zea mays L.) yield and limiting mechanized harvesting. Developing maize varieties with high stalk lodging resistance requires exploring the genetic basis of lodging resistance-associated agronomic traits. Stalk strength is an important indicator to evaluate maize lodging and can be evaluated by measuring stalk rind penetrometer resistance (RPR) and stalk buckling strength (SBS). And morphological traits of the stalk for the third internodes length (TIL), fourth internode length (FIL), third internode diameter (TID), and the fourth internode diameter (FID) traits are associated with stalk lodging resistance.Results: In this study, 248 genome-wide association study (GWAS) panel with 83,057 single nucleotide polymorphisms (SNPs) were used to detect the quantitative trait loci (QTLs) for six stalk lodging resistance-related traits. The heritability of all traits ranged from 0.59 to 0.72 in the association mapping panel. A total of 85 significant SNPs were identified for the association mapping panel using best linear unbiased prediction (BLUP) values of all traits. Additionally, five candidate genes were associated with stalk strength traits, which were either directly or indirectly associated with cell wall components. Conclusions: These findings contribute to our understanding of the genetic basis of maize stalk lodging and provide valuable theoretical guidance for lodging resistance in maize breeding in the future.

scholarly journals Comprehensive Genome-Wide Association Analysis Reveals the Genetic Basis of Root System Architecture in Soybean

2020 ◽  
Vol 11 ◽  
Author(s):  
Waldiodio Seck ◽  
Davoud Torkamaneh ◽  
François Belzile
Keyword(s):  
Root System ◽  
System Architecture ◽  
Phenotypic Variation ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Primary Root ◽  
Root System Architecture ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

Increasing the understanding genetic basis of the variability in root system architecture (RSA) is essential to improve resource-use efficiency in agriculture systems and to develop climate-resilient crop cultivars. Roots being underground, their direct observation and detailed characterization are challenging. Here, were characterized twelve RSA-related traits in a panel of 137 early maturing soybean lines (Canadian soybean core collection) using rhizoboxes and two-dimensional imaging. Significant phenotypic variation (P &lt; 0.001) was observed among these lines for different RSA-related traits. This panel was genotyped with 2.18 million genome-wide single-nucleotide polymorphisms (SNPs) using a combination of genotyping-by-sequencing and whole-genome sequencing. A total of 10 quantitative trait locus (QTL) regions were detected for root total length and primary root diameter through a comprehensive genome-wide association study. These QTL regions explained from 15 to 25% of the phenotypic variation and contained two putative candidate genes with homology to genes previously reported to play a role in RSA in other species. These genes can serve to accelerate future efforts aimed to dissect genetic architecture of RSA and breed more resilient varieties.

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