scholarly journals Genome wide analysis in Drosophila reveals diet by gene interactions and uncovers diet-responsive genes

2019 ◽  
Author(s):  
Deanne Francis ◽  
Shila Ghazanfar ◽  
Essi Havula ◽  
James R. Krycer ◽  
Alistair Senior ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Whole Body ◽  
Starvation Resistance ◽  
Nutrient Storage ◽  
Sugar Tolerance ◽  
Genome Wide ◽  
Health Strategy ◽  
Important Health ◽  
Similar Principle ◽  
Genetic And Environmental Factors

AbstractGenetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individual’s genotype. Here, we sought to understand how such gene-diet interactions influenced nutrient storage and utilisation, a major determinant of metabolic disease. We subjected the Drosophila Genetic Reference Panel (DGRP), comprising 200 genetically divergent inbred fly strains, to diets varying in sugar, fat and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilisation that can be robustly measured. Diet influenced the starvation resistance of each strain, but this effect varied markedly between strains. This demonstrates that genetics plays a major role in the response to diet. Furthermore, heritability analysis revealed that the greatest variability arose from diets either high in sugar or high in protein. To uncover the genetic underpinnings of this variation, we mapped 1,239 diet-responsive SNPs in 534 genes, 325 of which have human orthologues. Using whole-body knockdown, we confirmed that 30 candidate genes were required for glucose tolerance, storage and utilization. In particular, we characterised CG4607, a GLUT6/GLUT8 homolog, as a key protein involved in sugar tolerance. Overall, this provides strong evidence that genetics is a major contributor to how individuals respond to diets of varying nutrient composition. It is likely that a similar principle may be applied to metabolic disease in higher organisms thus supporting the case for nutrigenomics as an important health strategy.

scholarly journals Genome wide analysis in Drosophila reveals diet by gene interactions and uncovers diet-responsive genes

2021 ◽  
Author(s):  
Deanne Francis ◽  
Shila Ghazanfar ◽  
Essi Havula ◽  
James R Krycer ◽  
Dario Strbenac ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Inbred Strains ◽  
High Carbohydrate Diet ◽  
Whole Body ◽  
Starvation Resistance ◽  
Nutrient Storage ◽  
Carbohydrate Diet ◽  
High Carbohydrate ◽  
Important Health ◽  
Genetic And Environmental Factors

Abstract Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individual’s genotype. Here, we sought to understand how such gene-diet interactions influenced nutrient storage and utilization, a major determinant of metabolic disease. We subjected 178 inbred strains from the Drosophila Genetic Reference Panel (DGRP), to diets varying in sugar, fat and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilization that can be robustly measured. Diet influenced the starvation resistance of most strains, but the effect varied markedly between strains such that some displayed better survival on a high carbohydrate diet compared to a high fat diet while others had opposing responses, illustrating a considerable gene x diet interaction. This demonstrates that genetics plays a major role in diet responses. Furthermore, heritability analysis revealed that the greatest genetic variability arose from diets either high in sugar or high in protein. To uncover the genetic variants that contribute to the heterogeneity in starvation resistance, we mapped 566 diet-responsive SNPs in 293 genes, 174 of which have human orthologues. Using whole-body knockdown, we identified two genes that were required for glucose tolerance, storage and utilization. Strikingly, flies in which the expression of one of these genes, CG4607 a putative homolog of a mammalian glucose transporter, was reduced at the whole-body level, displayed lethality on a high carbohydrate diet. This study provides evidence that there is a strong interplay between diet and genetics in governing survival in response to starvation, a surrogate measure of nutrient storage efficiency and obesity. It is likely that a similar principle applies to higher organisms thus supporting the case for nutrigenomics as an important health strategy.

Artificial Intelligence for epigenetics: towards personalized medicine

2020 ◽  
Vol 27 ◽  
Author(s):  
Giulia De Riso ◽  
Sergio Cocozza
Keyword(s):  
Biological Sciences ◽  
Artificial Intelligence ◽  
Personalized Medicine ◽  
Molecular Mechanisms ◽  
Genomic Sequence ◽  
Health Care Interventions ◽  
Genome Wide ◽  
Genetic And Environmental Factors ◽  
Opening Up ◽  
Omic Data

: Epigenetics is a field of biological sciences focused on the study of reversible, heritable changes in gene function not due to modifications of the genomic sequence. These changes are the result of a complex cross-talk between several molecular mechanisms, that is in turn orchestrated by genetic and environmental factors. The epigenetic profile captures the unique regulatory landscape and the exposure to environmental stimuli of an individual. It thus constitutes a valuable reservoir of information for personalized medicine, which is aimed at customizing health-care interventions based on the unique characteristics of each individual. Nowadays, the complex milieu of epigenomic marks can be studied at the genome-wide level thanks to massive, highthroughput technologies. This new experimental approach is opening up new and interesting knowledge perspectives. However, the analysis of these complex omic data requires to face important analytic issues. Artificial Intelligence, and in particular Machine Learning, are emerging as powerful resources to decipher epigenomic data. In this review, we will first describe the most used ML approaches in epigenomics. We then will recapitulate some of the recent applications of ML to epigenomic analysis. Finally, we will provide some examples of how the ML approach to epigenetic data can be useful for personalized medicine.

scholarly journals Generation and characterization of iPSC-derived renal proximal tubule-like cells with extended stability

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vidya Chandrasekaran ◽  
Giada Carta ◽  
Daniel da Costa Pereira ◽  
Rajinder Gupta ◽  
Cormac Murphy ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Retinoic Acid Receptor ◽  
Renal Proximal Tubule ◽  
Whole Body ◽  
Proper Function ◽  
Genome Wide ◽  
Glomerular Filtrate ◽  
Proximal Tubular ◽  
Induced Pluripotent

AbstractThe renal proximal tubule is responsible for re-absorption of the majority of the glomerular filtrate and its proper function is necessary for whole-body homeostasis. Aging, certain diseases and chemical-induced toxicity are factors that contribute to proximal tubule injury and chronic kidney disease progression. To better understand these processes, it would be advantageous to generate renal tissues from human induced pluripotent stem cells (iPSC). Here, we report the differentiation and characterization of iPSC lines into proximal tubular-like cells (PTL). The protocol is a step wise exposure of small molecules and growth factors, including the GSK3 inhibitor (CHIR99021), the retinoic acid receptor activator (TTNPB), FGF9 and EGF, to drive iPSC to PTL via cell stages representing characteristics of early stages of renal development. Genome-wide RNA sequencing showed that PTL clustered within a kidney phenotype. PTL expressed proximal tubular-specific markers, including megalin (LRP2), showed a polarized phenotype, and were responsive to parathyroid hormone. PTL could take up albumin and exhibited ABCB1 transport activity. The phenotype was stable for up to 7 days and was maintained after passaging. This protocol will form the basis of an optimized strategy for molecular investigations using iPSC derived PTL.

scholarly journals Genetic Determinants of Telomere Length in African American Youth

2018 ◽  
Author(s):  
Andrew M. Zeiger ◽  
Marquitta J. White ◽  
Sam S. Oh ◽  
Jonathan Witonsky ◽  
Maria G. Contreras ◽  
...  
Keyword(s):  
African American ◽  
Telomere Length ◽  
Genome Wide Association Study ◽  
African Ancestry ◽  
African American Youth ◽  
Genetic Associations ◽  
Disease States ◽  
Genome Wide ◽  
Pediatric Populations ◽  
Genetic And Environmental Factors

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

scholarly journals Epigenetic Aspects of Posttraumatic Stress Disorder

2011 ◽  
Vol 30 (2-3) ◽  
pp. 77-87 ◽  
Author(s):  
Ulrike Schmidt ◽  
Florian Holsboer ◽  
Theo Rein
Keyword(s):  
Posttraumatic Stress Disorder ◽  
Posttraumatic Stress ◽  
Stress Disorder ◽  
Treatment Options ◽  
Adverse Life Events ◽  
Genome Wide ◽  
Recent Developments ◽  
Covalent Modifications ◽  
Genetic And Environmental Factors ◽  
And Control

Development of psychiatric diseases such as posttraumatic stress disorder (PTSD) invokes, as with most complex diseases, both genetic and environmental factors. The era of genome-wide high throughput technologies has sparked the initiation of genotype screenings in large cohorts of diseased and control individuals, but had limited success in identification of disease causing genetic variants. It has become evident that these efforts at the genomic level need to be complemented with endeavours in elucidating the proteome, transcriptome and epigenetic profiles. Epigenetics is attractive in particular because there is accumulating evidence that the lasting impact of adverse life events is reflected in certain covalent modifications of the chromatin.In this review, we outline the characteristics of PTSD as a stress-related disease and survey recent developments revealing epigenetic aspects of stress-related disorders in general. There is also increasing direct evidence for gene programming and epigenetic components in PTSD. Finally, we discuss treatment options in the light of recent discoveries of epigenetic mechanisms of psychotropic drugs.

scholarly journals Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

2020 ◽  
Author(s):  
Youwen Qin ◽  
Aki S Havulinna ◽  
Yang Liu ◽  
Pekka Jousilahti ◽  
Scott C Ritchie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Microbial Communities ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Dietary Habits ◽  
Population Based ◽  
Genome Wide ◽  
Scale Population ◽  
Important Health ◽  
Disease Analysis

Co-evolution between humans and the microbial communities colonizing them has resulted in an intimate assembly of thousands of microbial species mutualistically living on and in their body and impacting multiple aspects of host physiology and health. Several studies examining whether human genetic variation can affect gut microbiota suggest a complex combination of environmental and host factors. Here, we leverage a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial shotgun metagenomes, dietary information and health records up to 16 years post-sampling, to characterize human genetic variations associated with microbial abundances, and predict possible causal links with various diseases using Mendelian randomization (MR). Genome-wide association study (GWAS) identified 583 independent SNP-taxon associations at genome-wide significance (p<5.0×10-8), which included notable strong associations with LCT (p=5.02×10-35), ABO (p=1.1×10-12), and MED13L (p=1.84×10-12). A combination of genetics and dietary habits was shown to strongly shape the abundances of certain key bacterial members of the gut microbiota, and explain their genetic association. Genetic effects from the LCT locus on Bifidobacterium and three other associated taxa significantly differed according to dairy intake. Variation in mucin-degrading Faecalicatena lactaris abundances were associated with ABO, highlighting a preferential utilization of secreted A/B/AB-antigens as energy source in the gut, irrespectively of fibre intake. Enterococcus faecalis levels showed a robust association with a variant in MED13L, with putative links to colorectal cancer. Finally, we identified putative causal relationships between gut microbes and complex diseases using MR, with a predicted effect of Morganella on major depressive disorder that was consistent with observational incident disease analysis. Overall, we present striking examples of the intricate relationship between humans and their gut microbial communities, and highlight important health implications.

138. GENOME-WIDE LINKAGE SCAN FOR FAMILIAL DIZYGOTIC TWINNING

2010 ◽  
Vol 22 (9) ◽  
pp. 56
Author(s):  
J. N. Painter ◽  
G. Willemsen ◽  
D. R. Nyholt ◽  
C. Hoekstra ◽  
D. Duffy ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Complex Trait ◽  
Potential Candidate ◽  
Chromosome 2 ◽  
Family Work ◽  
Linkage Analyses ◽  
Genome Wide ◽  
A Genome ◽  
The Usa ◽  
Genetic And Environmental Factors

The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning we have conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism (SNP) marker panels. Non-parametric linkage analyses including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL) produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential (exp)LOD score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (p = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family-specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5’ untranslated region of FSHR that segregated with the DZ twinning phenotype in the UT family. Work is continuing screening candidate genes. Our data provide further evidence for complex inheritance of familial DZ twinning.

scholarly journals Microarray Based Functional Analysis of Myricetin and Proteomic Study on Its Anti-Inflammatory Property

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Tao Li ◽  
Jihe Zhu ◽  
Fangming Deng ◽  
Weiguo Wu ◽  
Zhibing Zheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Disease ◽  
Microarray Data ◽  
Inflammatory Cytokine ◽  
Gene Expressions ◽  
Genome Wide ◽  
Proteomic Study ◽  
Anti Inflammatory ◽  
First Time

Myricetin has been reported as a promising chemopreventive compound with multiple biofunctions. To evaluate its influence on gene expressions in genome-wide set and further investigate its anti-inflammatory property, the present study performed Gene Ontology and Ingenuity Pathway Analysis (IPA) to describe the basic gene expression characteristics by myricetin treatment in HepG2 cells, confirmed its multi-biofunction by real-time fluorescent quantitative PCR (RT-qPCR), and further verified its anti-inflammatory property by Western blotting and bio-plex-based cytokines assay. The IPA data showed that 337 gene expressions (48% of the top molecules) are disturbed over 2-fold, and the most possible biofunctions of myricetin are the effect on “cardiovascular disease, metabolic disease, and lipid metabolism,” via regulation of 28 molecules with statistic score of 46. RT-qPCR data confirmed the accuracy of microarray data, and cytokines assay results indicated that 6 of the total 27 inflammatory cytokine secretions were significantly inhibited by myricetin pretreatment, including TNF-α, IFN-γ, IL-1α, IL-1β, IL-2, and IL-6. The present study is the first time to elucidate the multi-function of myricetin in genome-wide set by IPA analysis and verify its anti-inflammatory property by proteomics of cytokines assay. Therefore, these results enrich the comprehensive bioactivities of myricetin and reveal that myricetin has powerful anti-inflammatory property, which provides encouragement for in vivo studies to verify its possible health benefits.

scholarly journals Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk

2018 ◽  
Author(s):  
Luca A. Lotta ◽  
Liang Dong ◽  
Chen Li ◽  
Satish Patel ◽  
Isobel D. Stewart ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Fine Mapping ◽  
Fat Distribution ◽  
European Ancestry ◽  
Metabolic Risk ◽  
Genetic Associations ◽  
Metabolic Complications ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Scan

AbstractDifficulties in identifying causal variants and genes underlying genetic associations have limited the translational potential of genetic studies of body fat distribution, an important, partly-heritable risk factor for cardio-metabolic disease. Rare variant associations facilitate fine-mapping of causal alleles, but their contribution to fat distribution is understudied. We performed a genome-wide scan of rare nonsynonymous variants for body mass index-adjusted waist-to-hip-ratio (BMI-adjusted WHR; a widely-used measure of fat distribution) in 450,562 European ancestry individuals, followed by systematic Bayesian fine-mapping at six genome-wide (p<5×10−08; main-analysis) and two subthreshold signals (significant at a Bonferroni-corrected p<1.3×10−06). We found strong statistical evidence of causal association for nonsynonymous alleles in CALCRL (p.L87P, pconditional=5.9×10−12; posterior-probability of association [PPA]=52%), PLIN1 (p.L90P, pconditional=5.5×10−13; PPA>99%), PDE3B (p.R783X, pconditional=6.2×10−15; PPA>99%), ACVR1C (p.I195T; pconditional=5.4×10−12; PPA>99%), and FGF1 (p.G21E, pconditional=1.6×10−07; PPA=98%). Alleles at the four likely-causal main-analysis genes affected fat distribution primarily via larger hip-rather than smaller waist-circumference and six of nine conditionally-independent WHR-lowering index-variants were associated with protection from cardiovascular or metabolic disease. All four genes are expressed in adipose tissue and have been linked with the regulation of intracellular lipolysis, which controls fat retention in mature cells. Targeted follow-up analyses of key intracellular-lipolysis genes revealed associations for a variant in the initiator of intracellular lipolysis PNPLA2 (p.N252K) with higher BMI-adjusted-WHR and higher cardio-metabolic risk. This study provides human genetic evidence of a link between intracellular lipolysis, fat-distribution and its cardio-metabolic complications in the general population.

Sign in / Sign up

Export Citation Format

Share Document