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http://creativecommons.org/licens es/by-sa/2.0/ Metagenomics Prof:Rui Alves [email protected] 973702406 Dept Ciencies Mediques Basiques, 1st Floor, Room 1.08 Website of the Course:http://web.udl.es/usuaris/pg193845/Courses/Bioinformatics_2007/ Course: http://10.100.14.36/Student_Server/ Studying an organism …ACTG… >Dna MAACTG… Measure Response Find signatures for physiological dynamics in genomic data >DNA Pol MTC… Diversity of Life on Earth Described species: ~1.5 millions Predicted to exist: >30 millions Cultivate in the lab: ~thousands How do we know the genome of the species we can not cultivate? How can we know if the genes that are expressed in nature follow the same patterns as those in the lab? Metagenomics Metagenomics (also Environmental Genomics, Ecogenomics or Community Genomics) is the study of genetic material recovered directly from environmental samples. Sampling in Metagenomics Take a sample off of the environment Isolate and amplify DNA/mRNA Sequence it Shotgun Sequencing Restriction Enzymes Computer assembly ACT…GTC CTA …ATC … …GGGG How do we know which genes belong to which genome???? How do we assemble them??? The Best Case Scenario Coverage is enough to assemble independent genomes What normally happens Coverage is not enough and assembly is fragmentary Worst Case Scenario: Some fragments can not be assigned Down Side of Metagenomics Often fragmentary Often highly divergent Rarely any known activity No chromosomal placement No organism of origin Ab initio ORF predictions Huge data Marine Metagenomics Microbes account for more than 90% of ocean biomass, mediate all biochemical cycles in the oceans and are responsible for 98% of primary production in the sea. Metagenomics is a breakthrough sequencing approach to examine the open-space microbial species without the need for isolation and lab cultivation of individual species. PI Larry Smarr Paul Gilna Ex. Dir. PI Larry Smarr Marine Genome Sequencing Project Measuring the Genetic Diversity of Ocean Microbes Sorcerer II Data from this area has already reach to 10% of GenBank. The Entire Data Will Double Number of Proteins in Embank! Sample Metadata from GOS Site Metadata Location (lat/long, water depth) Site characterization (finite list of types plus “other”) Site description (free text) Country Sampling Metadata Sample collection date/time Sampling depth Conditions at time of sampling (e.g., stormy, surface temperature) Sample physical/chemical measurements (T (oC), S (ppt), chl a (mg m-3), etc) “author” Experimental Parameters Filter size Insert size Calit2’s Direct Access Core Architecture Will Create Next Generation Metagenomics Server Sargasso Sea Data Moore Marine Microbial Project NASA Goddard Satellite Data Community Microbial Metagenomics Data DataBase Farm Flat File Server Farm 10 GigE Fabric Request + Web Services JGI Community Sequencing Project W E B PORTAL Sorcerer II Expedition (GOS) Traditional User Dedicated Compute Farm (1000 CPUs) Response Direct Access Lambda Cnxns Local Environment Web (other service) Local Cluster TeraGrid: Cyberinfrastructure Backplane (scheduled activities, e.g. all by all comparison) (10000s of CPUs) Source: Phil Papadopoulos, SDSC, Calit2 Marine Metagenomics Metabolic pathway discovery Drug discovery Microbial genetic survey Symbiosis Environmental survey Who is there? Endosymbiosis Microbial genomic survey Evolution study Organism discovery Bioenergy discovery Biogeochemistry mapping Marine conservation http://creativecommons.org/licens es/by-sa/2.0/ 7/17/2015 19 Nutrigenomics Prof:Rui Alves [email protected] 973702406 Dept Ciencies Mediques Basiques, 1st Floor, Room 1.08 Website of the Course:http://web.udl.es/usuaris/pg193845/Courses/Bioinformatics_2007/ Course: http://10.100.14.36/Student_Server/ What is Nutrigenomics? Nutrigenomics is the science that examines the response of individuals to food compounds using post-genomic and related technologies. The long-term aim of nutrigenomics is to understand how the whole body responds to real foods using an integrated approach. Studies using this approach can examine people (i.e. populations, sub-populations - based on genes or disease - and individuals), food, lifestage and life-style without preconceived ideas. 7/17/2015 21 Why is Nutrigenomics important? Most non-genetic diseases are behaviorally related. E. g. Last year in the world, heart disease was responsible for a fraction of deaths comparable to that caused by infectious diseases. Diabetes, obesity growing!!! Of course genes are a factor. Finding the right combination of nutrients for each genotype can help in changing behavior and preventing many of these diseases. This combination may change with age, sex!! 7/17/2015 22 Problem 1: Nutrition – tasty + complex 7/17/2015 23 Genes – Lifestyle – Calories 7/17/2015 24 The same genes – The changed diet Paleolithic era Modern Times 1.200.000 Generations between feast en famine % Energy 100 50 0 2-3 Generations in energy abundance % Energy Low-fat meat Chicken Eggs Fish Fruit Vegetables (carrots) Nuts Honey 100 50 0 Grain Milk/-products Isolated Carbohydrates Isolated Fat/Oil Alcohol Meat Chicken Fish Fruit Vegetables Beans Molecular nutrition 7/17/2015 26 Problem 2: Our “gene passports” and nutrition Optimal Nutrition Individual genotype Functional phenotype AA AB BB Lifestyle Improvement of Health Maintenance “Eat right for your genotype??” 7/17/2015 27 Personalized diets? 7/17/2015 28 Nutrients acts as dietary signals Nutritional factors Transcription factors Gene transcription Energy homeostasis Cell proliferation Nutrient absorption 7/17/2015 29 Transcription-factor pathways mediating nutrient-gene interaction 7/17/2015 30 A key instrument in Nutrigenomics research: The GeneChip® System 7/17/2015 31 Nutritional Systems Biology Gene Sample Types: protein index metabolite index Protein ge ne ind ex • 10 ApoE3 mice • 10 wildtype mice • liver tissue • plasma • urine Biostatistics Biostatistics Bioinfomatics Bioinfomatics Metabolite 9 8 7 6 5 4 3 2 1 0 ppm Targets Targets and and Biomarkers Biomarkers Figure 1. A typical Systems Biology strategy for study of atherosclerosis [1] using a transgenic ApoE3 Leiden mouse model. Onset of disease Predisposition Genotype Surrogate Biomarkers Late biomarkers of disease Early biomarkers of disease Diagnostic markers Prognostic markers Changes in pathway dynamics to maintain homeostasis 7/17/2015 32 Nutrigenomics Target Genes Mechanisms Pathways Foods Nutrition Molecular Nutrition & Genomics Signatures Profiles Biomarkers Nutritional Systems Biology •Identification of dietary signals •Identification of dietary sensors •Identification of target genes •Reconstruction of signaling pathways •Measurement of stress signatures •Identification of early biomarkers Large research consortia Big money Small research groups Small budgets Complexity 7/17/2015 33 “Molecular Nutrition & Genomics” The strategy of Nutrigenomics 50000 (?) metabolites 80-100000 proteins 100000 transcripts 20-25000 7/17/2015 genes 34 Integration of enabling technologies in nutrigenomics Microarray & SAGE 7/17/2015 35 Two Strategies (1) The traditional hypothesis-driven approach: specific genes and proteins, the expression of which is influenced by nutrients, are identified using genomics tools — such as transcriptomics, proteomics and metabolomics — which subsequently allows the regulatory pathways through which diet influences homeostasis to be identified . Transgenic mouse models and cellular models are essential tools . provide us with detailed molecular data on the interaction between nutrition and the genome . (2) The SYSTEMS BIOLOGY approach: gene, protein and metabolite signatures that are associated with specific nutrients, or nutritional regimes, are catalogued, and might provide ‘early warning’molecular biomarkers for nutrient-induced changes to homeostasis. Be more important for human nutrition, given the difficulty of collecting tissue samples from ‘healthy’ individuals. 7/17/2015 36 Linking to other EU programs NuGO DIOGENES obesity (EU, 12M€) Proliferation Differentiation Apoptosis Absorption Host-microbe interaction Carotenoids Metabolic stress Gut Health Metabolic health Life stage nutrition Risk Benefit analysis Adipocyte fat oxidation Periconceptual nutrition Inflammation Muscle insulin resistance Systems biology Nutrigenetics Genetic epidemiology Toxicogenomics EARNEST early life nutrition (EU, 14M€) 7/17/2015 Lipid metabolism Early biomarkers Nuclear transcription factors LIPGEN Lipids & genes (EU, 14M€) Diabetes II Innovative Cluster Nutrigenomics Chronic metabolic stress (Dutch, 21M€) 37 Conclusion and future perspective (1) Nutrigenomics researchers must know the challenge of understanding polygenic diet related diseases. (2) Short-term goals: 1. to identify the dietary signals. 2. to elucidate the dietary sensor mechanisms. 3. to characterize the target genes of these sensors. 4. to understand the interaction between these signalling pathways and pro-inflammatory signalling to search for sensitizing genotypes. 5. to find ‘signatures’ (gene/protein expression and metabolite profiles). 7/17/2015 38 (3) Long-term goals: Nutrigenomics is to help to understand how we can use nutrition to prevent many of the same diseases for which pharmacogenomics is attempting to identify cures. SNP database will be effect on disease risk. Future 7/17/2015 personalized diets 39