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Chapter 4-Nutrigenomics and Nutrigenetics

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<ul><li><p>INTRODUCTION</p><p>A revolution in nutrition is underway. Through newly availablescientific methods and technologies, dramatic advances inunderstanding the role of nutrition in health and disease arewithin reach. These new tools include:</p><p>1. Complete or partially sequenced genomes of many animal,plant and microbial species (Bell et al, 2001; Lander et al,2001; Waterson et al, 2002; Kirkness et al, 2003; Seshadriet al, 2006).</p><p>2. Ample historical evidence suggests nutrients providepotent dietary signals via gene control that influence cellu-lar metabolism and homeostasis, either positively or nega-tively (Clarke and Abraham, 1992; Muller and Kirsten,2003; Straus, 1994).</p><p>3. Laboratory and computer technologies that allow for theanalysis of the molecular response of entire biologic sys-tems to nutrients (Muller and Kirsten, 2003).</p><p>This chapter will acquaint readers with the current status ofemerging nutritional technologies and provide insight aboutthe future potential of these tools. When applied to nutrition,</p><p>these technologies are collectively referred to as nutritionalgenomics.</p><p>NUTRITIONAL GENOMICS AND OTHER OMICS</p><p>Because nutritional genomics is a relatively new science, thefollowing discussion includes a review of relevant, but perhapsunfamiliar, terminology. Table 4-1 summarizes definitions andother related terms.</p><p>Genome refers to the full set of an individuals genes (i.e.,its genotype). Phenotype refers to the entire physical, bio-chemical and physiologic makeup of an animal as determinedby its genome and the animals environment. Genomicsdescribes the mapping, sequencing and analysis of all genespresent in the genome of a given species (Mutch et al, 2005).Numerous genomes are available to the public at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj. Theterm genomics is sometimes used loosely to refer to sequenceanalysis, gene expression analysis and single nucleotide poly-morphism analysis (the last two are discussed below).</p><p>Chapter</p><p>4Nutrigenomics and</p><p>Nutrigenetics: Nutritional Genomics in</p><p>Health and DiseaseSamer Al-Murrani</p><p>Craig D. Thatcher</p><p>Michael S. Hand</p><p>It is from the progeny of this parent cell that we all take our looks; we stillshare genes around, and the resemblance of the enzymes of grasses to</p><p>those of whales is in fact a family resemblance.Lewis Thomas</p></li><li><p>Nutritional genomics includes nutrigenomics and nutrige-netics. Nutrigenetics refers to the study of how genetic varia-tions, such as single nucleotide polymorphisms, are associatedwith an individuals response to nutrients or specific foods(Corella and Ordovas, 2005). That is, nutrigenetics attempts toexplain how, and to what extent, nutrition-related disorders areinfluenced by genetic variation (Mariman, 2006). Nutrigeneticshas the potential to provide for personalized dietary recom-mendations based on genetic makeup, by which the onset of adisorder will be prevented or delayed, thereby optimizinghealth. The information generated from a nutrigeneticsapproach can be used to identify individuals, but more impor-tantly, groups that are most likely to benefit from a specially for-mulated dietary regimen.</p><p>The importance of genetic variation in the physiologic orpathophysiologic response to nutrition is already well describedin principle, and examples continue to be published. A few ofthese examples include studies in people that link genetic vari-ation to insulin resistance, type II diabetes mellitus and cardio-vascular disease. These studies also demonstrate how an indi-vidual genotype affects appropriate dietary management fordisease prevention (Mutch et al, 2005). Similar examples inanimals with genetic variations that respond to special feedingregimens include obesity and diabetes mellitus (Snyder et al,2004). It is likely that, in some cases, the increased risk for obe-sity in dogs may be related to breed-associated genetic varia-tion. Another example in dogs includes large- and giant-breedpuppies with genetic variation that responds to diet for the pre-</p><p>Small Animal Clinical Nutrition44</p><p>Table 4-1. Glossary of nutritional genomics terminology. </p><p>Bioinformatics The application of computerized statistical tools (informatics) to biologic data. In genome projects, informaticsincludes the development of methods to search databases quickly, analyze DNA sequence information andpredict protein sequence and structure from DNA sequence data.</p><p>Dietary signature The repeatable pattern of gene expression, protein expression and metabolite production in different tissues inresponse to one or more food components.</p><p>Gene expression The process of converting the genetic code into mRNA and subsequently the translation of mRNA sequencesinto protein.</p><p>Genome All the genetic material in the chromosomes of an organism; its size is generally given as its total number ofbase pairs; the term is derived from gene + chromosome.</p><p>Genomics The mapping, sequencing and analysis of all genes present in the genome of a given species.Genotype The genetic makeup of an individual, in contrast to its physical appearance or phenotype.Metabolome The complete set of metabolites synthesized by a biologic system; all the substances except DNA, </p><p>RNA and protein.Metabolomics The study of the influence of the genome on an organisms entire metabolite profile, at a given time.Microarray technology A laboratory technique that permits the simultaneous detection of thousands of genes in a small sample and</p><p>analyzes the expression of those genes.Nutrigenetics The effect of genetic variation of an individual on the interaction between diet and disease.Nutrigenomics The effects of nutrients on the genome, proteome and metabolome.Nutritional genomics An umbrella term that includes nutrigenomics and nutrigenetics.Phenotype The visible properties of an organism that are produced by the interaction of the genotype and the environment.Probes Single stranded DNA sequences of varying lengths (depending on the technology platform) that represent indi-</p><p>vidual genes that are immobilized onto a solid support. Proteome The entire complement of proteins, and their interactions, in cells, tissues, organs and physiologic fluids.Proteomics The study of the protein products of gene expression with the goal of identifying the proteins and </p><p>understanding their role in the functioning of an organism.Single nucleotide A variation of a genes normal sequence, in which a single nucleotide in the genetic material is altered andpolymorphism the specific alteration occurs in more than 1% of the population. It is the most common form of polymorphism.Systems biology The study of entire biologic systems using transcriptomics, proteomics and metabolomics (Figure 4-1).Transcription The process whereby mRNA is synthesized from a DNA template.Transcriptome The sum of all the mRNA expressed by the genome of an organism.Transcriptomics The study of the relative amounts of mRNA expressed in cells or tissues at a given time.Translation The process of protein synthesis whereby the primary structure of the protein is determined by the nucleotide</p><p>sequence in mRNA.</p><p>Figure 4-1. A schematic overview of the relationships between nutrigenomics, transcriptomics, proteomics, metabolomics and systems biology. </p><p>Nutrigenomics</p><p>Nutrients</p><p>Transcriptomics Proteomics Metabolomics</p><p>Systems biology</p><p>Gene expression(RNA) Protein Metabolites</p><p>Healthor</p><p>disease</p></li><li><p>vention of developmental orthopedic disease.Nutrigenomics relates to the study of genome-wide influ-</p><p>ences of nutrition (Figure 4-1). Nutrigenomics explores theeffects of nutrients on the genome, proteome and metabolome(the last two are discussed below). From a nutrigenomics per-spective, nutrients are dietary signals that are detected by cellu-lar sensor systems that influence gene and protein expressionand, subsequently, metabolite production. Repeatable patternsof gene expression, protein expression and metabolite produc-tion in response to particular nutrients or foods can be viewedas dietary signatures. Nutrigenomics studies these signaturesin specific cells, tissues and complete organisms to understandhow nutrition influences homeostasis and resultant health ordisease (Muller and Kersten, 2003). The potential outcomefrom nutrigenomics research is a much clearer, more completeunderstanding of the effects and mechanisms of diet on health.To do this, researchers use genomics tools that include tran-scriptomics, proteomics and metabolomics to generate data andsubsequently analyze, link and mine the data using bioinfor-matics tools and approaches.</p><p>Transcriptomics studies the effects of nutrients on geneexpression. Because messenger RNA (mRNA) results fromthe process of transcription, the total pool of mRNA in a cellis referred to as the transcriptome. In nutrigenomics, transcrip-tomics examines nutrients that influence the expression of spe-cific genes and the transcription of the corresponding mRNA.This is one of the first steps in the regulatory process that con-trols the flow of information from genes. The field of tran-scriptomics is based on the examination of gene expressionpatterns quantifying the abundance of mRNA copied from abasic nucleic acid blueprint contained in the genome (Dawson,2006). Thus, the level of mRNA in a cell or tissue at any onetime is a reflection of whether a gene is activated or inactivat-ed. Thanks to powerful new tools that have been developedover the past decade, RNA can be measured. For example,total RNA or mRNA is extracted from a cell or tissue and usedto create either a complementary labeled strand of DNA calledcDNA, or, alternatively, unlabeled cDNA can be used togenerate a complementary labeled strand of RNA calledcRNA. This labeled material is then hybridized with knowncomplementary strands of DNA sequences that are attached toa solid support such as a glass or plastic slide or a nylon sub-strate. These fixed sequences are called probes. Probes areoften organized as an array of small dots on the solid supportmatrix. In some cases, arrays of probes are called microarraysor chips because the probes are only micrometers apart andmany of them will fit on a solid platform of only 1 to 3 cm2.It is possible to display a whole genome on a microarray.Commercial forms of microarrays are available (Figure 4-2). Ifthe original cRNA sample is labeled with a fluorescent dye, thehybridized array can be scanned with a laser scanner in whichthe light or signal that results from the hybrid of the labeledsample and the immobilized probes is directly related to theamount of specific mRNA present in the tissue sample andrepresents the level of gene expression in that tissue. Thus, it ispossible to determine if a specific nutritional manipulation</p><p>switched a gene on or off using this technology (Debusk,2005; Dawson, 2006). Figure 4-3 shows a scanned image of aglass-based cDNA array.</p><p>However, gene transcription is only one step in the regulato-ry pathway that leads to functional protein formation. Thus, itis not always possible to correlate the increased or decreasedpresence of mRNA in tissues with specific protein changes.Even with this shortcoming, however, transcriptomics is a verypowerful tool for determining and clarifying importantprocesses in metabolic regulation because it broadly evaluatesthe initial regulatory steps of gene expression (Dawson, 2006).</p><p>Transcriptomics is a relatively mature technology comparedwith proteomics and metabolomics. Currently, it is possible toobtain an overview of the expression of essentially all genes ina single microarray or GeneChip experiment. However, it is notyet possible to measure the whole proteome or metabolome(Afman and Muller, 2006).Transcriptomic studies have alreadyyielded exciting results, examples of which are discussed below.</p><p>Proteome describes the entire complement of proteins, andtheir interactions, in cells, tissues, organs and physiologic fluids.The number of proteins in a cell far exceeds the number ofgenes due to alternative gene splicing mechanisms and post-translational modifications of expressed proteins. Furthermore,because protein amounts differ widely in a cell at any given</p><p>45Nutritional Genomics </p><p>Figure 4-2. Affymetrix GeneChip probe array used for expressionprofiling of experimental tissues. (Courtesy Affymetrix, reprinted withpermission).</p><p>Figure 4-3. Example of the signal generated from a hybridized glassslide cDNA microarray. </p></li><li><p>moment, with expression levels that span many orders ofmagnitude, there is no single technology platform that canmeasure all the protein in the cell. Therefore, proteomics andthe corresponding proteomic technologies are not as widelyused or as standardized as the gene-based studies and tech-nologies described above. However, because protein expres-sion is the functional outcome of gene transcription andtranslation, it has long been a focus of extensive research.Using proteomics tools (the analysis of the proteome),researchers can simultaneously display and determine thou-sands of proteins in a study sample and identify their changesin response to nutritional inputs. Research methods in pro-teomics are progressing rapidly. Proteome analysis holds greatpromise for discoveries in nutrition research (Afman andMuller, 2006).</p><p>One of the newest omics is metabolomics. Metabolomicstechnology measures the level of all substances, other thanDNA, RNA or protein, present in a sample. Metabolitesinclude such things as intermediates of metabolism and a vari-ety of low molecular weight molecules (e.g., lactic acid, carbondioxide, ketones, ATP, ADP, prostaglandins, prostacyclins andthromboxanes). The metabolome represents the complete setof metabolites synthesized by a biologic system. Studyingmetabolites is important because of the simplistic, often incor-rect belief that one gene leads to the formation of one protein,which creates one metabolite (Munoz et al, 2004). The studyof a cells complete set of metabolites is much more complexthan transcriptomics and proteomics. Besides the huge varietyand number of potential metabolites, many cellular metabo-lites have a very rapid turnover. For example, ATP has a half-life of less than 0.1 second. Also, metabolites need to be deter-mined separately in the different compartments of a cell (e.g.,cytoplasm, mitochondria, extracellular matrix) (van der Werfet al, 2001).</p><p>Unlike transcriptomics, proteomics and metabolomics arenot yet routinely performed, do not have standardized proce-dures and continue to face challenges such as sample prepara-tion, technological sensitivity and lack of standardized statisti-cal methods (Mutch et al, 2005). However, the potential fornutritional applications of metabolomics is considerable and anumber of research teams are addressing the current shortcom-ings (Afman and Muller, 2006).</p><p>Systems biology refers to a merging of the previously dis-cussed omics technologies. Together, transcriptomics, pro-teomics and metabolomics allow for nutrition studies to con-currently observe and quantify a significant fraction of all reg-ulated genes, gene expres...</p></li></ul>