The Molecular Genetic Basis of Herbivory between Butterflies and their Host-Plants

AbstractInteractions between herbivorous insects and their host-plants are a central component of terrestrial food webs and a critical topic in agriculture, where a substantial fraction of potential crop yield is lost annually to pests. Important insights into plant-insect interactions have come from research on specific plant defenses and insect detoxification mechanisms. Yet, much remains unknown about the molecular mechanisms that mediate plant-insect interactions. Here we use multiple genome-wide approaches to map the molecular basis of herbivory from both plant and insect perspectives, focusing on butterflies and their larval host-plants. Parallel genome-wide association studies in the Cabbage White butterfly, Pieris rapae, and its host-plant, Arabidopsis thaliana, pinpointed a small number of butterfly and plant genes that influenced herbivory. These genes, along with much of the genome, were regulated in a dynamic way over the time course of the feeding interaction. Comparative analyses, including diverse butterfly/plant systems, showed a variety of genome-wide responses to herbivory, yet a core set of highly conserved genes in butterflies as well as their host-plants. These results greatly expand our understanding of the genomic causes and evolutionary consequences of ecological interactions across two of Nature’s most diverse taxa, butterflies and flowering plants.

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Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era

Neurosurgical FOCUS ◽

10.3171/2019.4.focus19204 ◽

2019 ◽

Vol 47 (1) ◽

pp. E10 ◽

Cited By ~ 6

Author(s):

Nardin Samuel ◽

Ivan Radovanovic

Keyword(s):

Intracranial Aneurysm ◽

Genetic Basis ◽

Molecular Mechanisms ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Association Studies ◽

Genome Wide Association Studies ◽

Genetic Aberrations ◽

Aneurysm Formation ◽

Genome Wide ◽

Risk Of Rupture

OBJECTIVEDespite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture.METHODSA literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis.RESULTSA total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response.CONCLUSIONSComprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

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Challenges and progress in interpretation of non-coding genetic variants associated with human disease

Experimental Biology and Medicine ◽

10.1177/1535370217713750 ◽

2017 ◽

Vol 242 (13) ◽

pp. 1325-1334 ◽

Cited By ~ 19

Author(s):

Yizhou Zhu ◽

Cagdas Tazearslan ◽

Yousin Suh

Keyword(s):

Molecular Mechanisms ◽

Target Genes ◽

Disease Risk ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Functional Interpretation ◽

Genome Wide ◽

Coding Variants

Genome-wide association studies have shown that the far majority of disease-associated variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes contribute to disease risk. To identify truly causal non-coding variants and their affected target genes remains challenging but is a critical step to translate the genetic associations to molecular mechanisms and ultimately clinical applications. Here we review genomic/epigenomic resources and in silico tools that can be used to identify causal non-coding variants and experimental strategies to validate their functionalities. Impact statement Most signals from genome-wide association studies (GWASs) map to the non-coding genome, and functional interpretation of these associations remained challenging. We reviewed recent progress in methodologies of studying the non-coding genome and argued that no single approach allows one to effectively identify the causal regulatory variants from GWAS results. By illustrating the advantages and limitations of each method, our review potentially provided a guideline for taking a combinatorial approach to accurately predict, prioritize, and eventually experimentally validate the causal variants.

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Multivariate genome-wide association studies on the tissue compartments of human brain identify novel loci underpinning brain development and neuropsychiatric outcomes.

10.1101/2021.06.24.449723 ◽

2021 ◽

Author(s):

Chun Chieh Fan ◽

Robert Loughnan ◽

Diliana Pechva ◽

Chi-Hua Chen ◽

Donald Hagler ◽

...

Keyword(s):

Human Brain ◽

Molecular Mechanisms ◽

Association Studies ◽

Risk Tolerance ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Imaging Features ◽

Genome Wide ◽

Neuropsychiatric Diseases ◽

Tissue Compartments

It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. The genome-wide signals are strongly overlapped with neuropsychiatric diseases, cognitive functions, risk tolerance, and immune responses. Our results implicate the shared molecular mechanisms between tissue microstructures of brain and neuropsychiatric outcomes with astrocyte involvement in the early developmental stage.

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Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

10.1101/743864 ◽

2019 ◽

Cited By ~ 2

Author(s):

James Boocock ◽

Megan Leask ◽

Yukinori Okada ◽

Hirotaka Matsuo ◽

Yusuke Kawamura ◽

...

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Association Studies ◽

Organic Anion ◽

Serum Urate ◽

Regulatory Function ◽

Eqtl Analysis ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Causal Genes

AbstractSerum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.Author SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

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A novel quantile regression approach for eQTL discovery

10.1101/070052 ◽

2016 ◽

Author(s):

Xiaoyu Song ◽

Gen Li ◽

Iuliana Ionita-Laza ◽

Ying Wei

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Linear Regression ◽

Genetic Variants ◽

Molecular Mechanisms ◽

Association Studies ◽

Expression Level ◽

Special Focus ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractOver the past decade, there has been a remarkable improvement in our understanding of the role of genetic variation in complex human diseases, especially via genome-wide association studies. However, the underlying molecular mechanisms are still poorly characterized, impending the development of therapeutic interventions. Identifying genetic variants that influence the expression level of a gene, i.e. expression quantitative trait loci (eQTLs), can help us understand how genetic variants influence traits at the molecular level. While most eQTL studies focus on identifying mean effects on gene expression using linear regression, evidence suggests that genetic variation can impact the entire distribution of the expression level. Indeed, several studies have already investigated higher order associations with a special focus on detecting heteroskedasticity. In this paper, we develop a Quantile Rank-score Based Test (QRBT) to identify eQTLs that are associated with the conditional quantile functions of gene expression. We have applied the proposed QRBT to the Genotype-Tissue Expression project, an international tissue bank for studying the relationship between genetic variation and gene expression in human tissues, and found that the proposed QRBT complements the existing methods, and identifies new eQTLs with heterogeneous effects genome-wideacross different quantile levels. Notably, we show that the eQTLs identified by QRBT but missed by linear regression are more likely to be tissue specific, and also associated with greater enrichment in genome-wide significant SNPs from the GWAS catalog. An R package implementing QRBT is available on our website.

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Genomic architecture of biomass heterosis inArabidopsis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705423114 ◽

2017 ◽

Vol 114 (30) ◽

pp. 8101-8106 ◽

Cited By ~ 26

Author(s):

Mei Yang ◽

Xuncheng Wang ◽

Diqiu Ren ◽

Hao Huang ◽

Miqi Xu ◽

...

Keyword(s):

Candidate Genes ◽

Molecular Mechanisms ◽

Association Studies ◽

Expression Patterns ◽

Natural Populations ◽

Genome Wide Association Studies ◽

Genomic Architecture ◽

Genome Wide ◽

Stimulus Responsive ◽

Abiotic Stimuli

Heterosis is most frequently manifested by the substantially increased vigorous growth of hybrids compared with their parents. Investigating genomic variations in natural populations is essential to understand the initial molecular mechanisms underlying heterosis in plants. Here, we characterized the genomic architecture associated with biomass heterosis in 200Arabidopsishybrids. The genome-wide heterozygosity of hybrids makes a limited contribution to biomass heterosis, and no locus shows an obvious overdominance effect in hybrids. However, the accumulation of significant genetic loci identified in genome-wide association studies (GWAS) in hybrids strongly correlates with better-parent heterosis (BPH). Candidate genes for biomass BPH fall into diverse biological functions, including cellular, metabolic, and developmental processes and stimulus-responsive pathways. Important heterosis candidates includeWUSCHEL,ARGOS, and some genes that encode key factors involved in cell cycle regulation. Interestingly, transcriptomic analyses in representativeArabidopsishybrid combinations reveal that heterosis candidate genes are functionally enriched in stimulus-responsive pathways, including responses to biotic and abiotic stimuli and immune responses. In addition, stimulus-responsive genes are repressed to low-parent levels in hybrids with high BPH, whereas middle-parent expression patterns are exhibited in hybrids with no BPH. Our study reveals a genomic architecture for understanding the molecular mechanisms of biomass heterosis inArabidopsis, in which the accumulation of the superior alleles of genes involved in metabolic and cellular processes improve the development and growth of hybrids, whereas the overall repressed expression of stimulus-responsive genes prioritizes growth over responding to environmental stimuli in hybrids under normal conditions.

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Inflammation-Related Risk Loci in Genome-Wide Association Studies of Coronary Artery Disease

Cells ◽

10.3390/cells10020440 ◽

2021 ◽

Vol 10 (2) ◽

pp. 440

Author(s):

Carina Mauersberger ◽

Heribert Schunkert ◽

Hendrik B. Sager

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Molecular Mechanisms ◽

Association Studies ◽

Genome Wide Association ◽

Considerable Proportion ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Related Risk ◽

Artery Disease

Although the importance of inflammation in atherosclerosis is now well established, the exact molecular processes linking inflammation to the development and course of the disease are not sufficiently understood. In this context, modern genetics—as applied by genome-wide association studies (GWAS)—can serve as a comprehensive and unbiased tool for the screening of potentially involved pathways. Indeed, a considerable proportion of loci discovered by GWAS is assumed to affect inflammatory processes. Despite many well-replicated association findings, however, translating genomic hits to specific molecular mechanisms remains challenging. This review provides an overview of the currently most relevant inflammation-related GWAS findings in coronary artery disease and explores their potential clinical perspectives.

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Sex Differences in the Genetics of Sarcoidosis Across European and African Ancestry Populations

10.21203/rs.3.rs-382787/v1 ◽

2021 ◽

Author(s):

Ying Xiong ◽

Susanna Kullberg ◽

Lori Garman ◽

Nathan Pezant ◽

David Ellinghaus ◽

...

Keyword(s):

Sex Differences ◽

Molecular Mechanisms ◽

Association Studies ◽

The United States ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome ◽

Löfgren’S Syndrome

Abstract Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two sarcoidosis clinical phenotypes: Löfgren's syndrome (LS) and non- Löfgren's syndrome (non-LS).Methods: A meta-analysis of genome-wide association studies was conducted in Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by replication look-up in the UK Biobank (n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in males and females in each cohort, respectively. The association test was based on logistic regression using the additive model in LS and non-LS independently. Additionally, gene-based analysis, expression quantitative trait loci (eQTL) assessments, and enrichment analysis were performed to discover functionally relevant mechanisms related to biological sex. Results: In LS sarcoidosis, we identified various sex-dependent genetic variations (798 SNPs in males and 703 SNPs in females). Genetic findings in sex groups were explicitly located in the extended major histocompatibility complex. In non-LS, we detected 16 SNPs in males and 38 in females, primarily localized to the MHC class II region. Additionally, the ANXA11 gene, a well-documented locus in sarcoidosis, was associated exclusively with non-LS males. Gene-based, eQTL assessment and enrichment analyses revealed distinct sex-dependent genomic loci and gene expression variation in the sex groups. Conclusions: Our findings provide new evidence of the existence of sex-dependent genetic variations underlying sarcoidosis genetic architecture. These findings suggest a sex bias in molecular mechanisms of sarcoidosis.

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Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

10.1101/2020.09.22.20198937 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anubha Mahajan ◽

Cassandra N Spracklen ◽

Weihua Zhang ◽

Maggie CY Ng ◽

Lauren E Petty ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fine Mapping ◽

Molecular Mechanisms ◽

Association Studies ◽

Population Diversity ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Diverse Populations ◽

Genome Wide

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

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TREM2 Limits Progression of Deficits and Spreading of Tau Pathology in Mice

10.21203/rs.3.rs-741896/v1 ◽

2021 ◽

Author(s):

Astrid F. Feiten ◽

Carol Au ◽

Annika van Hummel ◽

Julia van der Hoven ◽

Yuanyuan Deng ◽

...

Keyword(s):

Molecular Mechanisms ◽

Association Studies ◽

Amyloid Β ◽

Distinct Pattern ◽

Genome Wide Association Studies ◽

Tau Pathology ◽

Functional Deficits ◽

Genome Wide ◽

Deficient Mice

Abstract Background. Amyloid-β (Aβ) and tau form pathogenic lesions in Alzheimer’s disease (AD) brains. As ΑD clinically progresses, tau pathology propagates in a very distinct pattern between connected brain areas. The molecular mechanisms underlying this tau pathology spread remain largely unknown. Genome-wide association studies have identified polymorphisms in triggering receptor expressed on myeloid cells 2 ( TREM2 ) as genetic risk factors for AD and regulators of Aβ pathology-dependent tau propagation. Whether TREM2 contributes to neuron-to-neuron spreading of pathological tau remains unknown.Methods. Here, we crossed Trem2- deficient mice with P301S tau transgenic TAU58 mice and subjected the mice to behavioral testing and assessed neuropathology. Microglial activation states were determined using cytometry by of flight (CyTOF) and quantitative PCR. Tau spreading was assessed in vivo using tracing of focal tau expression.Results. Trem2 depletion significantly aggravated tau-induced early-onset motor and behavioural deficits. Neuropathologically, Trem2 reduction increased the number of hyperphosphorylated tau lesions in young TAU58 brains and reduced disease-associated microglia. Direct assessment of inter-neuronal spread of tau in vivo revealed significantly enhanced propagation of tau in the absence of Trem2 , suggesting that microglial TREM2 limits the progression of tau pathology in disease.Conclusion. Taken together, our data suggests that reduced TREM2 function accelerates the onset and progression of functional deficits and tau neuropathology in tau transgenic mice, which is - at least in part - due to increased tau spreading. Therefore, reduced TREM2 function may contribute to early AD by augmenting tau toxicity and its inter-neuronal propagation.

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