scholarly journals Parallel adaptation to higher temperatures in divergent clades of the nematodePristionchus pacificus

2016 ◽  
Author(s):  
Mark Leaver ◽  
Merve Kayhan ◽  
Angela McGaughran ◽  
Christian Roedelsperger ◽  
Anthony A. Hyman ◽  
...  
Keyword(s):  
Heat Tolerance ◽  
De Novo ◽  
Association Studies ◽  
Temperature Tolerance ◽  
Temperature Adaptation ◽  
Effect Of Temperature ◽  
Genome Wide Association Studies ◽  
Cellular Mechanisms ◽  
Ancestral Polymorphism ◽  
Evolutionary Mechanisms

AbstractStudying the effect of temperature on fertility is particularly important in the light of ongoing climate change. We need to know if organisms can adapt to higher temperatures and, if so, what are the evolutionary mechanisms behind such adaptation. Such studies have been hampered by the lack different populations of sufficient sizes with which to relate the phenotype of temperature tolerance to the underlying genotypes. Here, we examined temperature adaptation in populations of the nematodePristionchus pacificus, in which individual strains are able to successfully reproduce at 30°C. Analysis of the frequency of heat tolerant strains in different temperature zones on La Réunion supports that this trait is subject to natural selection. Reconstruction of ancestral states along the phylogeny of highly differentiatedP. pacificusclades suggests that heat tolerance evolved multiple times independently. This is further supported by genome wide association studies showing that heat tolerance is a polygenic trait and that different loci are used by individualP. pacificusclades to develop heat tolerance. More precisely, analysis of allele frequencies indicated that most genetic markers that are associated with heat tolerance are only polymorphic in individual clades. While in someP. pacificusclades, parallel evolution of heat tolerance can be explained by ancestral polymorphism or by gene flow across clades, we observe at least one clearly distinct and independent scenario where heat tolerance emerged byde novomutation. Thus, temperature tolerance evolved at least two times independently in the evolutionary history of this species. Our data suggest that studies of wild populations ofP. pacificuswill reveal distinct cellular mechanisms driving temperature adaptation.

scholarly journals Genotypic and Phenotypic Characterization of Lettuce Bacterial Pathogen Xanthomonas hortorum pv. vitians Populations Collected in Quebec, Canada

Agronomy ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2386
Author(s):  
Pierre-Olivier Hébert ◽  
Martin Laforest ◽  
Dong Xu ◽  
Marie Ciotola ◽  
Mélanie Cadieux ◽  
...  
Keyword(s):  
Leaf Spot ◽  
Genome Wide Association Study ◽  
De Novo ◽  
Association Studies ◽  
Genome Wide Association ◽  
Phenotypic Characterization ◽  
Genome Wide Association Studies ◽  
Bacterial Leaf Spot ◽  
Eastern Canada ◽  
Genome Wide

Bacterial leaf spot of lettuce, caused by Xanthomonas hortorum pv. vitians, is an economically important disease worldwide. For instance, it caused around 4 million CAD in losses in only a few months during the winter of 1992 in Florida. Because only one pesticide is registered to control this disease in Canada, the development of lettuce cultivars tolerant to bacterial leaf spot remains the most promising approach to reduce the incidence and severity of the disease in lettuce fields. The lack of information about the genetic diversity of the pathogen, however, impairs breeding programs, especially when disease resistance is tested on newly developed lettuce germplasm lines. To evaluate the diversity of X. hortorum pv. vitians, a multilocus sequence analysis was performed on 694 isolates collected in Eastern Canada through the summers of 2014 to 2017 and two isolates in 1996 and 2007. All isolates tested were clustered into five phylogroups. Six pathotypes were identified following pathogenicity tests conducted in greenhouses, but when phylogroups were compared with pathotypes, no correlation could be drawn. However, in vitro production of xanthan and xanthomonadins was investigated, and isolates with higher production of xanthomonadins were generally causing less severe symptoms on the tolerant cultivar Little Gem. Whole-genome sequencing was undertaken for 95 isolates belonging to the pathotypes identified, and de novo assembly made with reads unmapped to the reference strain’s genome sequence resulted in 694 contigs ranging from 128 to 120,795 bp. Variant calling was performed prior to genome-wide association studies computed with single-nucleotide polymorphisms (SNPs), copy-number variants and gaps. Polymorphisms with significant p-values were only found on the cultivar Little Gem. Our results allowed molecular identification of isolates likely to cause bacterial leaf spot of lettuce, using two SNPs identified through genome-wide association study.

scholarly journals Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

2019 ◽  
Author(s):  
Kunling Huang ◽  
Yuchang Wu ◽  
Junha Shin ◽  
Ye Zheng ◽  
Alireza Fotuhi Siahpirani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Transmission Disequilibrium ◽  
Fold Enrichment ◽  
Common Genetic Variants ◽  
Regulated Gene Expression

AbstractRecent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p=2.1e-7), a transcription factor (TF) mainly expressed in developmental brain. TF targets regulated by POU3F2 showed a 2.1-fold enrichment for known ASD genes (p=4.6e-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p=7.1e-5). These results provide a clear example of the connection between ASD genes affected by very rare mutations and an unlinked key regulator affected by common genetic variations.

scholarly journals Truncating mutation in TANC2 in a Chinese boy associated with Lennox-Gastaut syndrome: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Tian ◽  
Zhen Shi ◽  
Chi Hou ◽  
Wenjuan Li ◽  
Xiuying Wang ◽  
...  
Keyword(s):  
Antiepileptic Drugs ◽  
Nonsense Mutation ◽  
Synapse Formation ◽  
De Novo ◽  
Association Studies ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Scaffolding Protein ◽  
Genome Wide Association Studies ◽  
Truncating Mutation

Abstract Background Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that can be caused by brain malformations or genetic mutations. Recently, genome-wide association studies have led to the identification of novel mutations associated with LGS. The TANC2 gene, encodes a synaptic scaffolding protein that interacts with other proteins at the postsynaptic density to regulate dendritic spines and excitatory synapse formation. The TANC2 gene mutations were reported in neurodevelopmental disorders and epilepsy but not in LGS ever. Case presentation Here we describe the case of a boy with LGS who presented with multiple seizure patterns, such as myoclonic, atonic, atypical absence, generalized tonic-clonic, focal seizures, and notable cognitive and motor regression. The seizures were refractory to many antiepileptic drugs. He got seizure-free with ketogenic diet combined with antiepileptic drugs. A de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene was identified by the whole-exome sequencing and confirmed by Sanger sequencing. Conclusion We described the first Chinese case with LGS associated to a de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene, which would expand the clinical spectrum related to TANC2 mutations and contribute to better understanding of genotype-phenotype relationship to guide precision medicine.

scholarly journals The complex genomic basis of rapid convergent adaptation to pesticides across continents in a fungal plant pathogen

2020 ◽  
Author(s):  
Fanny E. Hartmann ◽  
Tiziana Vonlanthen ◽  
Nikhil Kumar Singh ◽  
Megan McDonald ◽  
Andrew Milgate ◽  
...  
Keyword(s):  
Selective Sweep ◽  
De Novo ◽  
Association Studies ◽  
Strong Support ◽  
Phenotypic Trait ◽  
Phenotypic Traits ◽  
Genome Wide Association Studies ◽  
Zymoseptoria Tritici ◽  
Standing Variation ◽  
Genome Wide

AbstractConvergent evolution leads to identical phenotypic traits in different species or populations. Convergence can be driven by standing variation allowing selection to favor identical alleles in parallel or the same mutations can arise independently. However, the molecular basis of such convergent adaptation remains often poorly resolved. Pesticide resistance in agricultural ecosystems is a hallmark of convergence in phenotypic traits. Here, we analyze the major fungal pathogen Zymoseptoria tritici causing serious losses on wheat and with parallel fungicide resistance emergence across continents. We sampled three population pairs each from a different continent spanning periods early and late in the application of fungicides. To identify causal loci for resistance, we combined knowledge from molecular genetics work and performed genome-wide association studies (GWAS) on a global set of isolates. We discovered yet unknown factors in azole resistance including membrane stability functions. We found strong support for the ‘hotspot’ model of resistance evolution with parallel changes in a small set of loci but additional loci showed more population-specific allele frequency changes. Genome-wide scans of selection showed that half of all known resistance loci were overlapping a selective sweep region. Hence, the application of fungicides was one of the major selective agents acting on the pathogen over the past decades. Furthermore, loci identified through GWAS showed the highest overlap with selective sweep regions underlining the importance to map phenotypic trait variation in evolving populations. Our population genomic analyses showed that both de novo mutations and gene flow likely contributed to the parallel emergence of resistance.

De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

2021 ◽  
Vol 118 (47) ◽  
pp. e2112032118
Author(s):  
Anne-Perrine Foray ◽  
Sophie Candon ◽  
Sara Hildebrand ◽  
Cindy Marquet ◽  
Fabrice Valette ◽  
...  
Keyword(s):  
Rare Variants ◽  
De Novo ◽  
Association Studies ◽  
Nod Mice ◽  
Individual Risk ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Significant Difference

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

scholarly journals Two Synthetic 18-Way Outcrossed Populations of Diploid Budding Yeast with Utility for Complex Trait Dissection

Genetics ◽  
2020 ◽  
Vol 215 (2) ◽  
pp. 323-342 ◽  
Author(s):  
Robert A. Linder ◽  
Arundhati Majumder ◽  
Mahul Chakraborty ◽  
Anthony Long
Keyword(s):  
Complex Traits ◽  
De Novo ◽  
Budding Yeast ◽  
Association Studies ◽  
Haplotype Frequency ◽  
Error Rates ◽  
Genome Wide Association Studies ◽  
Link Type ◽  
Standing Variation ◽  
Median Error

Advanced-generation multiparent populations (MPPs) are a valuable tool for dissecting complex traits, having more power than genome-wide association studies to detect rare variants and higher resolution than F2 linkage mapping. To extend the advantages of MPPs in budding yeast, we describe the creation and characterization of two outbred MPPs derived from 18 genetically diverse founding strains. We carried out de novo assemblies of the genomes of the 18 founder strains, such that virtually all variation segregating between these strains is known, and represented those assemblies as Santa Cruz Genome Browser tracks. We discovered complex patterns of structural variation segregating among the founders, including a large deletion within the vacuolar ATPase VMA1, several different deletions within the osmosensor MSB2, a series of deletions and insertions at PRM7 and the adjacent BSC1, as well as copy number variation at the dehydrogenase ALD2. Resequenced haploid recombinant clones from the two MPPs have a median unrecombined block size of 66 kb, demonstrating that the population is highly recombined. We pool-sequenced the two MPPs to 3270× and 2226× coverage and demonstrated that we can accurately estimate local haplotype frequencies using pooled data. We further downsampled the pool-sequenced data to ∼20–40× and showed that local haplotype frequency estimates remained accurate, with median error rates 0.8 and 0.6% at 20× and 40×, respectively. Haplotypes frequencies are estimated much more accurately than SNP frequencies obtained directly from the same data. Deep sequencing of the two populations revealed that 10 or more founders are present at a detectable frequency for > 98% of the genome, validating the utility of this resource for the exploration of the role of standing variation in the architecture of complex traits.

scholarly journals Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

2017 ◽  
Vol 114 (9) ◽  
pp. 2301-2306 ◽  
Author(s):  
Arushi Varshney ◽  
Laura J. Scott ◽  
Ryan P. Welch ◽  
Michael R. Erdos ◽  
Peter S. Chines ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
De Novo ◽  
Association Studies ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Genome Wide Association Studies ◽  
Factor X ◽  
Risk Alleles

Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition.

scholarly journals Common alleles of CMT2 and NRPE1 are major determinants of de novo DNA methylation variation in Arabidopsis thaliana

2019 ◽  
Author(s):  
Eriko Sasaki ◽  
Taiji Kawakatsu ◽  
Joseph Ecker ◽  
Magnus Nordborg
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Cytosine Methylation ◽  
De Novo ◽  
Association Studies ◽  
Published Data ◽  
Epigenetic Mark ◽  
Stabilizing Selection ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractDNA cytosine methylation is an epigenetic mark associated with silencing of transposable elements (TEs) and heterochromatin formation. In plants, it occurs in three sequence contexts: CG, CHG, and CHH (where H is A, T, or C). The latter does not allow direct inheritance of methylation during DNA replication due to lack of symmetry, and methylation must therefore be re-established every cell generation. Genome-wide association studies (GWAS) have previously shown that CMT2 and NRPE1 are major determinants of genome-wide patterns of TE CHH-methylation. Here we instead focus on CHH-methylation of individual TEs and TE-families, allowing us to identify the pathways involved in CHH-methylation simply from natural variation and confirm the associations by comparing them with mutant phenotypes. Methylation at TEs targeted by the RNA-directed DNA methylation (RdDM) pathway is unaffected by CMT2 variation, but is strongly affected by variation at NRPE1, which is largely responsible for the longitudinal cline in this phenotype. In contrast, CMT2-targeted TEs are affected by both loci, which jointly explain 7.3% of the phenotypic variation (13.2% of total genetic effects). There is no longitudinal pattern for this phenotype, however, because the geographic patterns appear to compensate for each other in a pattern suggestive of stabilizing selection.Author SummaryDNA methylation is a major component of transposon silencing, and essential for genomic integrity. Recent studies revealed large-scale geographic variation as well as the existence of major trans-acting polymorphisms that partly explained this variation. In this study, we re-analyze previously published data (The 1001 Epigenomes), focusing on de novo DNA methylation patterns of individual TEs and TE families rather than on genome-wide averages (as was done in previous studies). GWAS of the patterns reveals the underlying regulatory networks, and allowed us to comprehensively characterize trans-regulation of de novo DNA methylation and its role in the striking geographic pattern for this phenotype.

scholarly journals Modelling the Functional Genomics of Parkinson’s in Caenorhabditis elegans: LRRK2 and Beyond

2021 ◽  
Author(s):  
Rachael J Chandler ◽  
Susanna Cogo ◽  
Patrick A Lewis ◽  
Eva Kevei
Keyword(s):  
Caenorhabditis Elegans ◽  
Current Knowledge ◽  
Association Studies ◽  
Mendelian Disease ◽  
Genome Wide Association Studies ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Functional Models

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

Abstract 20: Tribbles1 (Trib1) is a Novel Regulator of in vivo Hepatic Fatty Acid Lipogenesis in the Mouse.

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Robert C Bauer ◽  
Jian Cui ◽  
Anthony P Kent ◽  
Daniel J Rader
Keyword(s):  
Fatty Acid ◽  
Transcriptional Control ◽  
De Novo ◽  
Association Studies ◽  
Liver Weight ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Pcr Analysis ◽  
Genome Wide Association Studies

Tribbles1 (TRIB1) was recently identified in genome-wide association studies as being strongly linked to plasma levels of VLDL, HDL, LDL, and TG as well as coronary artery disease in humans. Previous experiments in mice using AAV-mediated hepatic overexpression of Trib1 confirmed this association, as mice overexpressing Trib1 exhibited reductions of 45% and 57% in plasma total cholesterol (TC) and TG, respectively ( Burkhardt et al, 2010 ). Here we report a Trib1 liver-specific knockout mouse (Trib1_LSKO) created through AAV-mediated delivery of Cre recombinase into adult mice with a floxed version of Trib1. Four weeks after infection, Trib1_LSKO mice exhibited 21% and 70% increases in TC and TG, respectively ( p =0.01 and 0.02), as compared to floxed Trib1 littermates infected with null virus (Controls). Trib1_LSKO animals also exhibited a 25% increase in liver weight ( p <0.01), and histological analysis revealed steatotic livers in LSKO mice. Real-time PCR analysis revealed >2-fold increases in the hepatic transcription of genes involved in fatty acid synthesis in Trib1_LSKO mice as compared to Controls. Examination of hepatic lipids revealed a 78% increase in hepatic TG content ( p <0.001) of Trib1_LSKO mouse livers, while no significant change in hepatic cholesterol was observed. When de novo lipogenesis was measured using [3H]-acetate, Trib1_LSKO animals exhibited significantly increased production of TG (3.6-fold, p <0.001), fatty acids (2.2-fold, p =0.02), diacylglycerol (1.8-fold, p <0.01), and phospholipids (2-fold, p =0.05). Microarray analysis of Trib1_LSKO livers compared to Controls revealed greater than 1,600 genes that were significantly altered between the two groups (fold change>1.5, FDR<10%). Pathway analysis suggested that the altered gene set was enriched for genes downstream of C/EBP and C/EBP. Western blot analysis of liver extracts showed increases in both C/EBP and C/EBP levels in Trib1_LSKO mice compared to Controls. In conclusion, Trib1 is a novel regulator of de novo lipogenesis in mice, presumably through the regulation of lipogenic gene transcription. This transcriptional control may be regulated by increased levels of C/EBP and/or C/EBP, or an as yet undetermined target of Trib1.

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