Strain-Specific Liver Metabolite Profiles in Medaka

The relationship between genetic variation and phenotypic traits is often poorly understood since specific genotypes do not always easily translate into associated phenotypes, especially for complex disorders. The genetic background has been shown to affect metabolic pathways and thus contribute to variations in the metabolome. Here, we tested the suitability of NMR metabolomics for comparative analysis of fish lines as a first step towards phenotype-genotype association studies. The Japanese rice fish, medaka (Oryzias latipes), is a widely used genetic vertebrate model with several isogenic inbred laboratory strains. We used liver extracts of medaka iCab and HO5 strains as a paradigm to test the feasibility of distinguishing the metabolome of two different inbred strains. Fifteen metabolites could be detected in uni- and multivariate analyses that showed strain-specific levels. Differences could be assigned to specific metabolic pathways. Our results show that NMR spectroscopy is a suitable method to detect variance of the metabolome caused by subtle genetic differences. Thus, it has the potential to address genotype–phenotype associations in medaka, providing an additional level of phenotypic analysis.

Download Full-text

Genomic Analysis, Progress and Future Perspectives in Dairy Cattle Selection: A Review

Animals ◽

10.3390/ani11030599 ◽

2021 ◽

Vol 11 (3) ◽

pp. 599

Author(s):

Miguel A. Gutierrez-Reinoso ◽

Pedro M. Aponte ◽

Manuel Garcia-Herreros

Keyword(s):

Dairy Cattle ◽

Production Efficiency ◽

Association Studies ◽

Phenotypic Traits ◽

Progeny Testing ◽

Genome Wide Association Studies ◽

Genetic Progress ◽

Breeding Programs ◽

Increased Risk ◽

Selection Of

Genomics comprises a set of current and valuable technologies implemented as selection tools in dairy cattle commercial breeding programs. The intensive progeny testing for production and reproductive traits based on genomic breeding values (GEBVs) has been crucial to increasing dairy cattle productivity. The knowledge of key genes and haplotypes, including their regulation mechanisms, as markers for productivity traits, may improve the strategies on the present and future for dairy cattle selection. Genome-wide association studies (GWAS) such as quantitative trait loci (QTL), single nucleotide polymorphisms (SNPs), or single-step genomic best linear unbiased prediction (ssGBLUP) methods have already been included in global dairy programs for the estimation of marker-assisted selection-derived effects. The increase in genetic progress based on genomic predicting accuracy has also contributed to the understanding of genetic effects in dairy cattle offspring. However, the crossing within inbred-lines critically increased homozygosis with accumulated negative effects of inbreeding like a decline in reproductive performance. Thus, inaccurate-biased estimations based on empirical-conventional models of dairy production systems face an increased risk of providing suboptimal results derived from errors in the selection of candidates of high genetic merit-based just on low-heritability phenotypic traits. This extends the generation intervals and increases costs due to the significant reduction of genetic gains. The remarkable progress of genomic prediction increases the accurate selection of superior candidates. The scope of the present review is to summarize and discuss the advances and challenges of genomic tools for dairy cattle selection for optimizing breeding programs and controlling negative inbreeding depression effects on productivity and consequently, achieving economic-effective advances in food production efficiency. Particular attention is given to the potential genomic selection-derived results to facilitate precision management on modern dairy farms, including an overview of novel genome editing methodologies as perspectives toward the future.

Download Full-text

Abstract 233: Isoproterenol-induced Cardiac Hypertrophy And Failure In Mice: Gene Network Modeling

Circulation Research ◽

10.1161/res.113.suppl_1.a233 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Christoph D Rau ◽

Jessica Wang ◽

Shuxun Ren ◽

Zhihua Wang ◽

Hongmei Ruan ◽

...

Keyword(s):

Heart Failure ◽

Association Studies ◽

Inbred Strains ◽

Genome Wide Association Studies ◽

Strong Correlations ◽

Hotspot Analysis ◽

Linear Relationships ◽

Genome Wide ◽

Echocardiographic Parameters ◽

Hybrid Mouse Diversity Panel

Heart failure is highly heterogeneous and as a result, relatively few insights into the pathways and drivers of heart failure have been identified using system-wide methods such as genome-wide association studies (GWAS). We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) for high resolution GWAS and systems genetics in mice. Eight week old female mice from 93 unique inbred strains of the HMDP were given 20 μg/g/day of isoproterenol through an abdominally implanted Alzet micropump. Three weeks post-implantation, all mice were sacrificed, along with age-matched controls. The mice exhibited widely varying degrees of hypertrophy and heart functioning. A portion of the left ventricle was processed and arrayed on an Illumina Mouse Ref 8.0 platform. We used Maximal Information Component Analysis, a novel method of network construction which allows for non-linear relationships between genes as well as non-binary partitioning of genes into sub-networks to subdivide the expression data into a series of modules. In order to identify modules which may contribute to Isoproterenol-induced hypertrophy and failure, we examined the correlation of each module to clinically relevant cardiac traits traits such as organ weights and echocardiographic parameters. We identified several modules with strong correlations to multiple heart failure-related clinical traits, including one module of 41 genes which contained several genes of interest, including Lgals3, a diagnostic marker for heart failure. Utilizing eQTL hotspot analysis, we have identified a locus which is involved in the regulation of this module. A gene within this locus, Magi2, regulates the turnover of the β-adrenergic receptor and represents a likely candidate for the response to isoproterenol.

Download Full-text

HAPPI GWAS: Holistic Analysis with Pre and Post Integration GWAS

10.1101/2020.04.07.998690 ◽

2020 ◽

Cited By ~ 2

Author(s):

Marianne L. Slaten ◽

Yen On Chan ◽

Vivek Shrestha ◽

Alexander E. Lipka ◽

Ruthie Angelovici

Keyword(s):

Association Studies ◽

Phenotypic Traits ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Gwas Analysis ◽

Genome Wide ◽

Large Populations ◽

Unbiased Estimates ◽

Best Linear Unbiased ◽

Automated Pipeline

AbstractMotivationAdvanced publicly available sequencing data from large populations have enabled in-formative genome-wide association studies (GWAS) that associate SNPs with phenotypic traits of interest. Many publicly available tools able to perform GWAS have been developed in response to increased demand. However, these tools lack a comprehensive pipeline that includes both pre-GWAS analysis such as outlier removal, data transformation, and calculation of Best Linear Unbiased Predictions (BLUPs) or Best Linear Unbiased Estimates (BLUEs). In addition, post-GWAS analysis such as haploblock analysis and candidate gene identification are lacking.ResultsHere, we present HAPPI GWAS, an open-source GWAS tool able to perform pre-GWAS, GWAS, and post-GWAS analysis in an automated pipeline using the command-line interface.AvailabilityHAPPI GWAS is written in R for any Unix-like operating systems and is available on GitHub (https://github.com/Angelovici-Lab/HAPPI.GWAS.git)[email protected]

Download Full-text

The Histone Deacetylases HosA and HdaA Affect the Phenotype and Transcriptomic and Metabolic Profiles of Aspergillus niger

Toxins ◽

10.3390/toxins11090520 ◽

2019 ◽

Vol 11 (9) ◽

pp. 520 ◽

Cited By ~ 2

Author(s):

Xuejie Li ◽

Lijie Pan ◽

Bin Wang ◽

Li Pan

Keyword(s):

Metabolic Pathways ◽

Histone Deacetylases ◽

Chromatin Accessibility ◽

Growth Stress ◽

Pigment Production ◽

Histone Acetyltransferases ◽

Metabolic Profiles ◽

Phenotypic Analysis ◽

Histone Modifying Enzymes ◽

New Strategies

Histone acetylation is an important modification for the regulation of chromatin accessibility and is controlled by two kinds of histone-modifying enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). In filamentous fungi, there is increasing evidence that HATs and HDACs are critical factors related to mycelial growth, stress response, pathogenicity and production of secondary metabolites (SMs). In this study, seven A. niger histone deacetylase-deficient strains were constructed to investigate their effects on the strain growth phenotype as well as the transcriptomic and metabolic profiles of secondary metabolic pathways. Phenotypic analysis showed that deletion of hosA in A. niger FGSC A1279 leads to a significant reduction in growth, pigment production, sporulation and stress resistance, and deletion of hdaA leads to an increase in pigment production in liquid CD medium. According to the metabolomic analysis, the production of the well-known secondary metabolite fumonisin was reduced in both the hosA and hdaA mutants, and the production of kojic acid was reduced in the hdaA mutant and slightly increased in the hosA mutant. Results suggested that the histone deacetylases HosA and HdaA play a role in development and SM biosynthesis in A. niger FGSC A1279. Histone deacetylases offer new strategies for regulation of SM synthesis.

Download Full-text

Coexpression network and phenotypic analysis identify metabolic pathways associated with the effect of warming on grain yield components in wheat

PLoS ONE ◽

10.1371/journal.pone.0199434 ◽

2018 ◽

Vol 13 (6) ◽

pp. e0199434 ◽

Cited By ~ 5

Author(s):

Christine Girousse ◽

Jane Roche ◽

Claire Guerin ◽

Jacques Le Gouis ◽

Sandrine Balzegue ◽

...

Keyword(s):

Grain Yield ◽

Metabolic Pathways ◽

Yield Components ◽

Coexpression Network ◽

Phenotypic Analysis ◽

Grain Yield Components

Download Full-text

The New Frontier of Functional Genomics: From Chromatin Architecture and Noncoding RNAs to Therapeutic Targets

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555220926158 ◽

2020 ◽

Vol 25 (6) ◽

pp. 568-580

Author(s):

Natali Papanicolaou ◽

Alessandro Bonetti

Keyword(s):

Gene Expression ◽

Association Studies ◽

Noncoding Rnas ◽

Regulatory Elements ◽

Long Noncoding Rnas ◽

Human Diseases ◽

Genome Wide Association Studies ◽

Complex Disorders ◽

Chromatin Architecture ◽

Common Diseases

Common diseases are complex, multifactorial disorders whose pathogenesis is influenced by the interplay of genetic predisposition and environmental factors. Genome-wide association studies have interrogated genetic polymorphisms across genomes of individuals to test associations between genotype and susceptibility to specific disorders, providing insights into the genetic architecture of several complex disorders. However, genetic variants associated with the susceptibility to common diseases are often located in noncoding regions of the genome, such as tissue-specific enhancers or long noncoding RNAs, suggesting that regulatory elements might play a relevant role in human diseases. Enhancers are cis-regulatory genomic sequences that act in concert with promoters to regulate gene expression in a precise spatiotemporal manner. They can be located at a considerable distance from their cognate target promoters, increasing the difficulty of their identification. Genomes are organized in domains of chromatin folding, namely topologically associating domains (TADs). Identification of enhancer–promoter interactions within TADs has revealed principles of cell-type specificity across several organisms and tissues. The vast majority of mammalian genomes are pervasively transcribed, accounting for a previously unappreciated complexity of the noncoding RNA fraction. Particularly, long noncoding RNAs have emerged as key players for the establishment of chromatin architecture and regulation of gene expression. In this perspective, we describe the new advances in the fields of transcriptomics and genome organization, focusing on the role of noncoding genomic variants in the predisposition of common diseases. Finally, we propose a new framework for the identification of the next generation of pharmacological targets for common human diseases.

Download Full-text

Molecular Variants in Human Trace Amine-Associated Receptors and Their Implications in Mental and Metabolic Disorders

Cellular and Molecular Neurobiology ◽

10.1007/s10571-019-00743-y ◽

2019 ◽

Vol 40 (2) ◽

pp. 239-255 ◽

Cited By ~ 3

Author(s):

Grazia Rutigliano ◽

Riccardo Zucchi

Keyword(s):

Genetic Variants ◽

Affective Disorders ◽

Metabolic Disorders ◽

Association Studies ◽

Single Gene ◽

Genome Wide Association Studies ◽

Complex Disorders ◽

Linkage Analyses ◽

Genome Wide ◽

Trace Amine

Abstract We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.

Download Full-text

Symposium 2: Modern approaches to nutritional research challenges Targeted and non-targeted approaches for metabolite profiling in nutritional research

Proceedings of The Nutrition Society ◽

10.1017/s0029665109991704 ◽

2009 ◽

Vol 69 (1) ◽

pp. 95-102 ◽

Cited By ~ 18

Author(s):

John K. Lodge

Keyword(s):

Data Analysis ◽

Metabolic Pathways ◽

Present Report ◽

New Technology ◽

Nutrient Status ◽

Tolerance Test ◽

Careful Consideration ◽

Metabolite Profiles ◽

Health And Disease ◽

Isoflavone Metabolism

The present report discusses targeted and non-targeted approaches to monitor single nutrients and global metabolite profiles in nutritional research. Non-targeted approaches such as metabolomics allow for the global description of metabolites in a biological sample and combine an analytical platform with multivariate data analysis to visualise patterns between sample groups. In nutritional research metabolomics has generated much interest as it has the potential to identify changes to metabolic pathways induced by diet or single nutrients, to explore relationships between diet and disease and to discover biomarkers of diet and disease. Although still in its infancy, a number of studies applying this technology have been performed; for example, the first study in 2003 investigated isoflavone metabolism in females, while the most recent study has demonstrated changes to various metabolic pathways during a glucose tolerance test. As a relatively new technology metabolomics is faced with a number of limitations and challenges including the standardisation of study design and methodology and the need for careful consideration of data analysis, interpretation and identification. Targeted approaches are used to monitor single or multiple nutrient and/or metabolite status to obtain information on concentration, absorption, distribution, metabolism and elimination. Such applications are currently widespread in nutritional research and one example, using stable isotopes to monitor nutrient status, is discussed in more detail. These applications represent innovative approaches in nutritional research to investigate the role of both single nutrients and diet in health and disease.

Download Full-text

Mass spectrometry approaches for vitamin E research

Biochemical Society Transactions ◽

10.1042/bst0361066 ◽

2008 ◽

Vol 36 (5) ◽

pp. 1066-1070 ◽

Cited By ~ 5

Author(s):

John K. Lodge

Keyword(s):

Vitamin E ◽

Stable Isotope ◽

Metabolic Pathways ◽

Protective Role ◽

Cigarette Smokers ◽

Metabolite Profiles ◽

Health And Disease ◽

Isotope Studies ◽

Vitamin E Status

Vitamin E is an important nutrient with antioxidant and non-antioxidant functions, and certain evidence suggests that it has a cardiovascular protective role. It is therefore important to maintain an optimal vitamin E status. In the present paper, a number of MS applications to monitor vitamin E status and its interactions, including the use of stable-isotope-labelled vitamin E and metabonomics, are highlighted. Specifically, stable-isotope studies have been used to monitor vitamin E absorption, hepatic processing and lipoprotein transport. As oxidative stress may influence vitamin E status, a number of studies comparing vitamin E biokinetics and metabolism in cigarette smokers and non-smokers have been able to show differences in vitamin E processing in smokers. Metabonomics represents a method to identify changes to metabolite profiles, offering the potential to investigate interactions between vitamin E and metabolic pathways. These applications represent innovative approaches to investigate the role of vitamin E in health and disease.

Download Full-text

Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00294.2007 ◽

2008 ◽

Vol 35 (2) ◽

pp. 182-190 ◽

Cited By ~ 9

Author(s):

Toshimori Kitami ◽

Renee Rubio ◽

William O'Brien ◽

John Quackenbush ◽

Joseph H. Nadeau

Keyword(s):

Gene Expression ◽

Total Cholesterol ◽

Birth Defects ◽

Metabolic Pathways ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Inbred Strains ◽

Serum Folate ◽

Folate Supplementation ◽

Dietary Folate

Dietary folate supplementation can dramatically reduce the severity and incidence of several common birth defects and adult diseases that are associated with anomalies in homocysteine and folate metabolism. The common polymorphisms that adversely affect these metabolic pathways do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test involvement of folate, homocysteine, and other pathways in disease pathogenesis and treatment response, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared with the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE-deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting that homeostasis among the homocysteine, folate and cholesterol metabolic pathways contributes to the beneficial effects of dietary folate supplementation.

Download Full-text