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NUTRITIONANDGENETICS Mapping individual health

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ILSI Europe

by Janice I. Harland

NUTRITION AND GENETICS Mapping individual health

© 2005 International Life Sciences Institute

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ISBN 1-57881-195-3

CONTENTS

FOREWORD .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. NUTRITION DEVELOPMENTS .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. GENE STRUCTURE AND FUNCTION .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3. THE NEW TECHNOLOGIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

4. VARIATION IN HUMAN POPULATIONS .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

5. RELATIONSHIP BETWEEN NUTRITION, GENES AND HEALTH .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

6. CONSEQUENCES AND POTENTIAL .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

7. ETHICS AND SOCIAL ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

GLOSSARY .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

FURTHER READING .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Author: Janice I. Harland, Harlandhall (UK)Scientific Editor: Ruan Elliott, Institute of Food Research (UK)

Scientific Referees: Judy Buttriss, British Nutrition Foundation (UK), Bruce German, Nestlé Research Centre (CH), John C. Mathers, University of Newcastle (UK)

Concise Monograph Series Editor: Ron Walker, University of Surrey (UK)

Nutrition and genetics – mapping individual health 1

FOREWORD

Characterisation of the human genome and identificationof the pivotal role that nutrients play in gene expressionevolved into the science of nutrigenomics.

As a new science “nutrigenomics” brings with it newterminology, novel experimental techniques and afundamentally new approach to nutrition research suchas high throughput technologies that enable the globalstudy of gene expression in a cell or organism. Thismonograph aims to provide the reader with anintroduction to the new science and its potential.

Until recently, nutrition research concentrated onnutrient deficiencies and impairment of health. Theadvance of nutrigenomics has created unprecedentedopportunities to deepen our understanding of hownutrients modulate gene expression, protein biosynthesisand metabolism. Scientists face the challenge to providecomprehensive answers to questions such as:

• Which components of the diet have important healthpromoting effects?

• How, where and when are these effects exerted?

• Can some of these components also have adverseeffects?

• How much and in what form and combination do weneed to eat such components to obtain the maximumhealth benefit with minimum risk?

• How do individuals’ dietary recommendations varydepending on their genetic profile, age, gender andlifestyle?

Nutrigenomics-aided research should ultimately providea sound basis for dietary management of maintenanceand protection of health, eventually positioning nutrientsin the context of individual genetic background.

This may sound somewhat futuristic and the relativeimportance of gene-nutrient interactions on polygenicdiseases is still at a very early stage as well as theunderstanding of the complexity of genetic regulation,including redundancy of pathways and the role ofepigenetic modifications.

The greatest potential for benefit from dietarymodification is likely to be the protection of health.Nutrigenomics will facilitate the identification ofbiomarkers that play a role in the initial physiologicalchanges at the onset of disease providing indicators tomeasure the effectiveness of dietary interventions.

We are confident that this Concise Monograph will helpreaders to gain insight into the exciting area ofnutrigenomics, its terminology, its technology, and itspotential for nutrition science.

Els de GroeneUnilever

1. NUTRITIONDEVELOPMENTS

The 20th century is the period during which nutrition‘came of age’. Many significant developments took placethat commenced with the isolation and coining of theword ‘vitamin’ in 1912 and the appreciation of theimportant role that vitamins play in nutrition.

In 1929, linoleic acid was shown to be the first essentialfatty acid in experiments with rats. Later, linolenic andarachidonic acids were shown to partially relievedeficiency symptoms. The group subsequently becameknown as the essential fatty acids. As the centuryprogressed, roles for fibre, antioxidants and othermicronutrients were discovered. The concept ofreference intakes of nutrients developed (determined onthe basis of the average population requirement plustwice the standard deviation) and recommended dailyamounts were established for the main nutrients acrossall age groups.

Just as important as the development in nutrition scienceis the change that has occurred in people’s nutritionalstatus. In the early part of the 20th century, the majorconcern was under-nutrition with overt deficiencysymptoms frequently seen. In the second half of thecentury, in Western societies, the major concern hadmoved towards over-nutrition with the rising incidenceof obesity and diabetes. In addition, there was animproved understanding of the links between nutritionand chronic disease(s), for example heart disease, strokeand cancer. As these diseases overtook infectiousdiseases as the major causes of death, a greater awarenessof the need for moderation in food intake developed.

The last decade of the 20th century saw a furthernutritional development. This was the use of nutrients orfoods - the so-called functional foods - to promote ahealthy body and to help avoid disease.

A key realisation has been that nutrients are now not onlyimportant to ensure nutritional adequacy, but can alsohelp to maintain and improve health.

The development of functional foods, and nutritionists’improved understanding of the potential role of these inthe diet, has helped informed consumers to makehealthful dietary interventions that contribute topreventive healthcare.

The 21st century will witness a major step forward innutrition science prompted by the recent characterisationof the human genome. The identification of genes andgene sequences can help unlock a whole new area ofnutrition research.

Nutrient or nutrient/metabolic signals hold a pivotal rolethat governs the expression of genes encoding theproteins required for energy metabolism, celldifferentiation and cell growth.

Possibly, future generations will be able to identify thelink between an individual’s genetic code andpredisposition to dietary related illness and/or sub-optimum physiological performance, in essence enablingthem to map their own individual health and makingnutrition interventions to help maintain it.

2 Concise Monograph Series

2. GENE STRUCTURE ANDFUNCTION

2.1 IntroductionThe genetic material that we acquire from our parentsconsists of a collection of DNA nucleotide sequences thatmake the back-bones of the 23 pairs of chromosomes (seeBox 1: Chromosomes and Figure 1) present in the nucleus ofthe cells throughout our body. Within each chromosome,the genetic material is organised into sequences knownas genes (see Box 4: Gene).

Genes encode the proteins responsible for our structureand metabolic functions (see Box 4: Genetic Code).

Genes are turned on and off according to metabolicsignals that the nucleus receives from internal factors, forexample hormones, and external factors, for examplenutrients, which are among the most influential ofenvironmental stimuli.

Early in evolutionary development, the nutrients thatorganisms ingested functioned as primitive signals thatturned on and off pathways of synthesis or storageduring periods of starvation or excess. As simple


Chromosomes

Chromosomes are linear double stranded DNA moleculespresent in the nuclei of eukaryotic cells. Different organismshave different numbers of chromosomes. A normal humancell contains 46 chromosomes - two copies of each ofchromosomes 1 to 22 - plus, in the case of a cell from awoman, two copies of the X chromosome or, in a cell from aman, one copy of the X chromosome and one copy of the Ychromosome.

The human chromosomes vary in length from 47 million to246 million base pairs of deoxyribonucleic acid (DNA)sequence (see Box 2: DNA).

The DNA in the chromosomes is normally present in thenuclei in the form of chromatin – DNA complexed withproteins. Prior to cell division the entire sequence of theDNA in each chromosome is replicated, so that for eachchromosome two identical sister chromatids are present.During mitosis (cell division) the chromatin structure of eachchromosome becomes highly condensed forming discretestructures, visible by microscopy, which possess distinctcharacteristic morphologies, and structurally and functionallydistinct regions.

BOX 1 FIGURE 1. Human chromosomes

Reproduced with permission from Applied Imaging Corporation.

organisms developed into more complex forms of lifethey retained the ability to respond to nutrient ornutrient/hormonal signals that govern the expression ofgenes encoding the proteins of energy metabolism, celldifferentiation and cell growth.

The central role that nutrients play in governing the cellcontent of different proteins has been further investigatedand a recognition of their role as regulators of genetranscription, nuclear RNA processing, mRNA stabilityand mRNA degradation (see Box 3: Ribonucleic Acid) hasemerged (see Chapter 5).


Deoxyribonucleic acid (DNA)

Deoxyribonucleic acid (DNA) is the repository of all geneticinformation in the cell. It is a long linear polymeric moleculemade up of nucleotide building blocks. Each nucleotidecomprises a deoxyribose (a sugar) and phosphate group andone of four different bases, adenine (A), guanine (G),cytosine (C) or thymine (T). The deoxyribose and phosphategroups form the backbone of the polymer. It is the sequenceof the bases that carries the genetic code. In most cells DNAis present in a double-stranded form and the two strands areheld together by hydrogen bonding between bases (basepairing) on opposite strands. The nucleotides always pair as Cand G or A and T. The two strands are twisted round acommon axis to form a double helix.

BOX 2

FIGURE 2. DNA double helix

1 - Deoxyribose and phosphate back bone; 2 - Hydrogen bonds; 3 - Nucleotide bases, adenine, guanine, cytosine or thymine; 4 - Double helix.

Source: Elliott, R.M., Bacon, J.R. and Bao,Y-P. (2004). Chapter 1 "Nutritional Genomics", pp 1-25, in "Phytochemicals in Health and Disease",Editors Bao, Y-P. and Fenwick, R. with permission from Taylor and Francis Group.

2.2 The GenomeThe genome is essentially the genetic fingerprint of anorganism.

The genome is the entire DNA sequence of an organism.It is the palette of information that an organism can callon to ensure its own survival and growth, and that it canpass on to its own progeny.

The Human Genome Project is the largest everinternational collaboration in biology. The result has beenthat the sequence of three billion chemical coding units inhuman DNA is now known. The next challenge is toidentify each of the sequences of codes that areresponsible for a specific activity or outcome.

Although the just fewer than three billion base pairs havebeen sequenced, most genes have not yet beendefinitively identified. It has been estimated that in

human cells some 30-40,000 genes exist, although morerecent estimates suggest 24,500 – and even this may be anover-estimate. This number is surprisingly small, as asimple worm is considered to have 17,000 genes.

There are sequence similarities between many genes ofrelated functions in different species, and these oftenappear in a similar order along chromosomes. Forexample, organisational similarities are apparentbetween the human and mice genomes. The sequence ofthe human chromosome 22 has been compared to that ofthe mouse chromosome. It was found that over 80% ofthe human sequence that contains genes includes regionsthat have direct counterparts on the mouse chromosome.

Genomic similarities also exist between plant species.When wheat and rice were compared, many of the genesand their order on the chromosomes were identical,although the wheat genome is 40 times greater than thatof rice.

The genomes of many organisms contain more than justsets of genes. Within the entire genomic sequence therecan be stretches of DNA that are not known to code foranything. Such non-coding DNA appears to account for90-95% of human DNA. DNA which has no knownfunction in the cell or that does not appear to code forproteins is known as “junk DNA”, but this designationmay become inappropriate as future research mayidentify its role.

Genomes are not completely static. Genes may mutateduring the reproductive process and genes from parentsare shuffled and produce a new combination in theiroffspring. These new and different sequences andcombinations may confer specific advantages, forexample, encourage taller offspring which may be anadvantage in crops or animals. For thousands of yearsfarmers and latterly plant breeders have been identifying

Ribonucleic Acid (RNA)

RNA is a nucleic acid that is structurally similar to DNA, butit differs in three principal ways. Firstly, the sugar componentof the nucleotide building blocks is a ribose rather than adeoxyribose. These molecules include two –OH groups,which make them more reactive, but less flexible. Secondly,the base uracil is used in place of thymine, so that the codeconsists of A,C,G and U rather than the A,C,G and T in DNA.Thirdly, unlike DNA, RNA is generally single stranded, butcan form a duplex with a complementary strand of eitherDNA or RNA. In eukaryotic cells the major RNAs areinvolved in all stages of protein synthesis and many types ofRNA are involved in regulatory, catalytic and other processesin the cell.

BOX 3


As well as the natural processes by which spontaneousgenetic differences arise, a range of technologies areavailable that permit specific targeted changes to bemade in genomes.

Genetic modification (see Box 5: Genetic Modification) isone technique that can be used to remove, modify or add

and cultivating specific crops that have a competitiveadvantage through their changed genome.

Not all changes in the genome are beneficial; somechanges will result in immediate death, or othersengender poor growth and premature death of the plant,animal or organism.


Gene

A gene is defined as the smallest indivisible unit of heredity.

The totality of an organism’s genes provides the instruction book for all inheritable characteristics and directs the production ofspecific proteins. In molecular terms, a gene consists of a sequence of DNA that carries all the genetic information necessary toproduce the specific product (contained within the coding region) for that gene and to do so in an appropriately regulated manner(controlled by the non-coding region of the gene). The non-coding regions, called promoter regions, can respond to factors such asdiet and determine how much RNA is made from that gene.

The number and order of the nucleotides in the coding sequence determine the individuality and the functionality of the gene andalso the identity of the product it encodes, either a functional polypeptide chain or RNA molecule.

In some cases a gene may share a similar or identical region of sequence(s) with another gene. If the similar sequences lie in the non-coding sequence, this may indicate similarities in the way these genes are regulated or the product processed. If the similar sequencesare within coding regions, this may indicate that the gene products share some common function such as a common enzymic activityor the ability to bind to DNA.

Genetic Code

The “code” in which information for the synthesis of proteins is contained lies in the nucleotide sequence of the coding region of agene. Prior to protein synthesis this coded information is first reproduced by the process of gene transcription in messenger RNA, alsocalled mRNA. The code carried by the mRNA is then translated into one or more polypeptides. Each amino acid of a polypeptide isencoded by a particular sequence of three nucleotides (called a codon) in the mRNA. The polypeptide synthesis begins at an initiatorcodon in the mRNA and the translating machinery (ribosome) reads the information in adjacent non-overlapping triplets moving alongthe mRNA from this point. The codon does not interact directly with the corresponding amino acid, as the amino acid to be added tothe growing polypeptide must be linked through an adapter molecule transfer RNA, also called tRNA. A number of tRNAs areproduced that are specific for each type of amino acid. Each of these contains a triplet sequence (anti-codon) complementary to oneof the possible codons for that amino acid.

The four bases A,C,G,U can generate 64 possible triplet combinations; 61 of these encode 20 amino acids (which means in essencemost amino acids are encoded by two or more triplets). For example, the amino acid phenylalanine is coded by UUU and UUC andvaline by GUU, GUC, GUA and GUG. The remaining three codons UAA, UAG and UGA are nonsense, “stop” or “termination”codons, which signify the end of the polypeptide chain.

BOX 4


gene(s) to a living organism to create a new combinationof DNA codes.

There are two main ways in which the genetic makeupcan be modified. Directly, by altering the expression ofexisting genes. For example, it is possible to prevent, orknockout, the normal expression of some existing genes.This allows investigations of the function of particulargenes. For instance, knockout mice are being widely usedin research on cystic fibrosis, breast cancer, colon and

other cancers in humans. Secondly, by adding new(foreign) sequences of DNA. Physically inserting theDNA coding for a gene with a desired effect into theDNA of another animal, is termed gene transfer and theanimals receiving the foreign DNA are called transgenicanimals. DNA is chemically identical across species, andthe genetic codes for producing particular proteins arethe same across species. This means that it is possible totransfer genes not only within species, but also betweenspecies, and sometimes even between different classes oforganism. For instance, bacterial and viral DNA has beenintroduced to a range of food crops to confer insect andvirus resistance.

Looked at another way, modification is the specific effectof man’s intervention on gene structure, where genomicsstudies the expression of the genes and the sequencing ofthe whole genome.

Once the genome sequence has been modified, theresulting new combination of DNA replicates itself in thesame natural way that all organisms cut and copy theirDNA and therefore becomes an integral part of thebuilding blocks of the organism.

The study of genomics is acquiring knowledge not onlyof the gene sequences, but also determining what genesdo. Genetic modification relates more specifically to thealteration of gene(s) and the impact of that alteration.

The definition that is used throughout this document isthat genomics refers to “the holistic study ofbiomolecules” and comprises the study of all nucleotidesequences including structural genes, regulatorysequences and non-coding DNA sequences of thechromosome.

Genetic Modification

Genetic modification (also called genetic engineering orgene technology) is used to describe the process by whichthe genetic make-up of an organism can be altered byremoving, modifying or adding gene(s) to a living organismto create a new combination of DNA codes. This may beachieved by introducing genetic material from a differentspecies, by adding additional copies of a gene or genesoriginating from the same organism (sometimes engineeredso that they can be regulated by different processescompared with the original genes), or by deleting copies ofgenes. GM technologies have proven to be extremelypowerful tools for fundamental research in addition to theiruse in crop production. Current genetically modified cropsinclude soya, maize and tomatoes.

Not all genetic modification technology involves insertingDNA from other organisms. Plants and microorganisms maybe modified by removing or “switching-off” particular genes.Genes can be “switched off” (alternately known as genesilencing) by inserting an inactive or partial copy of a genealready present or by inserting an “antisense” copy of thegene. Research is underway to use this methodology toswitch off genes that encode allergenic (allergy-causing)proteins in foods.

BOX 5

Transcription can be regulated by dietary componentsand their metabolites that can influence the cellenvironment. The location of these products within thecell, any of the intermediates of their synthesis and theirsubsequent rate of degradation can also influence thetranscription process.

Initiation and termination of transcription are importantcontrol points for the regulation of gene expression.

With any one gene, normally only one of the two strandsof DNA acts as a template. The transcriptome containsthe totality of RNA species produced from the genome ofan organism. The transcriptome can be separated intoseveral different types of RNA including mRNA, asdescribed above.

The role of tRNA during protein synthesis is to act as theadapter molecule matching amino acids to their codonson the mRNAs (see Box 4: Gene).

Ribosomal RNAs (rRNA) combine with ribosomalproteins to form ribosomes, the cellular machines thatread the code carried by mRNAs and work with tRNAsto produce proteins from this code.

In addition to these three main categories of RNA, anumber of, generally small, RNA molecules have beenrecognized, which possess novel regulatory or enzymaticactivities.

2.5 Translation and proteinWhile the DNA may be the information archive of thecell, it is the proteins that do the work of the cell andultimately dictate biological processes and cellular fates.


2.3 DNA replicationDNA replication is the first step in cell division. Theprocess of DNA replication starts with a new strand ofDNA being synthesised on each of the pre-existingstrands. Each of these pre-existing strands acts as atemplate. Each new strand is complementary to, not acopy of, the original strand.

Initiation of the DNA replication begins at one or morespecial sites known as an ori (origins). Initiation ofreplication involves the recognition of an ori site byvarious initiation factors and enzymes. As no knownDNA polymerase can initiate synthesis of a new DNAstrand there is a requirement for a starter series ofnucleotides known as a primer.

DNA synthesis is usually primed by a short strand ofRNA, which is transcribed on to the DNA template.During this process, ribonucleotides in the RNA strandbase pair with nucleotides in a template strand andinorganic phosphate is released.

Termination of DNA synthesis occurs when the entireduplex is replicated. Replication is a complex andcarefully regulated process involving a number ofdifferent proteins; incorrect replication can lead to e.g.cell death or cancer.

2.4 Transcription and RNATranscription conveys the message from DNA (“thelibrary”) to the cell factory making proteins.

Transcription is the process by which a RNA strand isformed from a DNA template. Where messenger RNA(mRNA) is the RNA that is produced, this subsequentlyacts as the template on which amino acids are assembledfor the purpose of protein synthesis.


Protein regulation is a factor of major importance intranslating the genome into function. Rates of proteinsynthesis, localisation of proteins within and outside thecell, degree and positions of phosphorylation and/orglycosylation, rates of degradation and many otherprocesses determine the activity of different proteins.

Generally the proteins in the cell do not exist in isolation,but form a cellular protein network that consists ofprotein interactions and pathways that connect in finelytuned orchestration. Proteins coalesce into networks andcircuits in response to specific stimuli.

As stimuli fluctuate and feedback loops returninformation, newly formed protein networks rapidlybreak apart. Consequently the population state of proteinnetworks is constantly changing within each living cell.

The amino acid sequence of a protein is the primarydeterminant of its (3-D) shape. It is this shape and thesurface presentation of amino acids that enable highlyselective lock and key recognition between proteinpartners and metabolites in the communication circuit, aswell as substrate specificity and enzyme activity.

Examples of post-translational modifications that alter 3-D protein structure are phosphorylation, cleavage,glycosylation and lipidation.

As multiple stimuli impinge on the living cell, hundredsof protein-signal networks are constantly changing.However, it is possible to map the state of key nodes inknown protein networks and relate this back to cellfunction. Investigators measure the ratio betweenactivated (e.g. phosphorylated or cleaved) and theinactivated form of the key signal proteins and from thiscan be estimated the status of a signal node at the timethe proteins are extracted from the cell.

For example, a fast growing tumour cell may have ahigher proportion of activated signal proteins withinpathways that stimulate cell growth or suppress celldeath.

In a diseased cell the protein network is disrupted,deranged or locally hyperactive compared with that in ahealthy cell.

2.6 Metabolic processes in the cellProcesses and metabolic regulation in individual cells ortissues give rise to a complete set of metabolites in thecell. These are generally low molecular weight moleculesand include the intermediates of metabolism in the cell(the totality of all such metabolites is termed themetabolome).

Metabolomics investigates metabolic regulation andfluxes in individual cells or tissues. The metabolitesderive from a broad range of functions in the cell and arethe final stage of biological activity along the line fromgene to mRNA, to protein, to function, to phenotype. Themetabolites are usually rapidly converted in enzyme-controlled or chemical reactions and provide the buildingblocks for larger molecules or transient energy storage.

The identification and quantification of the metabolitesand the reactions they are involved in are important inthe context of systems biology. Metabolic profiles can bederived from tissue, cellular and extra-cellular fluidsamples, and because of the literally thousands ofcompounds involved, pose the greatest analyticalchallenge to the investigator. One of the strategiesadopted is the sub-division of the metabolome intoclasses of compounds with similar chemical properties,while undertaking parallel analysis to help to visualise agreater portion of the metabolome.


3. THE NEW TECHNOLOGIES

The sequencing of the human and other genomes has ledto the development of a whole new scientificmethodology. These new areas of scientific study usuallyinclude the ‘omics’ suffix (see Figure 3).

The characterisation of one gene can immediatelyprovide an insight into the gene function in a relatedspecies. The deposition of the draft sequence of themouse genome in 2002 has been particularly useful inthis respect. Sequences from this and other organisms canbe compared in order to find commonality; other tools fordeveloping an understanding of gene function are underdevelopment. Once it became apparent that there was a large number ofgenes with unknown functions, the development of largescale, high throughput technologies that could assignfunctions to genes was necessary.

Definitions for the technologies adopted are: • Transcriptomics is the study of activity of all the genes

in response to changing conditions and, in essence, isa study of gene expression at the level of the mRNA.

DNA arrays are the most widely used tool formeasuring the relative amounts of the thousands ofRNA species within cellular or tissue samples (seeDNA Microarray: Box 6 and Figure 4).

• Proteomics is the study of the totality of the proteinsthat can be expressed within an organism.

Currently, the most widely used technologies forproteomics are two-dimensional gel electrophoresis (2Dgel electrophoresis) to separate the proteins in acomplex mixture isolated from cells or tissues, andspecialised mass spectrometry techniques as proteinidentification tools (See Figure 5).

FIGURE 3. The steps in gene expression and the‘omics’ descriptor

Reproduced with permission from Peter D. Karp and Suzanne Paley, SRI International, lower part only.

Genomics

Transcriptomics

ProteomicsCell metabolites and processes

Metabolomics

Template strand

Transcription

Translation

Codon

{DNA

mRNA

Protein(aminoacid chain)

GENE EXPRESSION


FIGURE 4. DNA chip or Microarray (A small device for detecting the presence or activity of many genes simultaneously)

Source: Elliott, R.M., Bacon, J.R. and Bao, Y-P. (2004). Chapter 1 "Nutritional Genomics", pp 1-25, in "Phytochemicals in Healthand Disease", Editors Bao, Y-P. and Fenwick, R. with permission from Taylor and Francis Group.

RNASample 2

False colour scale

RNASample 1

cDNA(green)

cDNA 2(red)

Microarray analysis. DNA or oligonucleotides are printed onto specially coated slides (1) and covalently bound. Two RNAsamples are reversed transcribed (2) and either green or red fluorescent dyes incorporated into the cDNA products. The twofluorescent cDNA populations are combined and hybridized to the array under a cover slip (3). The slide is washed andfluorescence imaged using a microarray laser scanner (4). The fluorescent signals from the two dyes are presented together with afalse colour scheme (5) in which cDNA present in only one of the two samples appear red or green and those present in bothappear in varying shades of orange and yellow.

New techniques under development include proteinarrays, “two-dimensional” column chromatographyand one-dimensional protein separation technologies.

• Metabolomics is the study of the complete set ofmetabolites that an organism produces. It investigatesmetabolic regulation and fluxes in individual cells ortissues, in response to specific environmentalchanges.

In common with transcriptomics and proteomics itinvolves the non-targeted determination of allmetabolites present under specific environmentalconditions. The analysis and interpretation of the datathat is derived from the comparison of different cellconditions is achieved by the use of bioinformatics (seeBox 7: Bioinformatics).

Some researchers use the term metabolomics to refer toboth simple (cellular) and complex (whole tissue ororganism) systems, others distinguish betweenmetabolomics studies that are in simple systems onlyand metabonomics in complex systems. Inmetabonomics, systematic biochemical profiles andregulation of function are determined in wholeorganisms by analysing biofluids and tissues.

A metabolomics experiment provides quantitativeinformation on which pathways are being used by anorganism, and whether they are operational in a specificcompartment.

As the turnover of many metabolites is very fast withhalf-lives of less than a second, it is important that themetabolism in the cell is stopped instantaneously at themoment of sampling. Regulation of transcription,translation and enzyme activities are only directlyaffected by the metabolite in its immediateenvironment. Therefore, to obtain an accurate picture,


DNA Microarrays

DNA microarrays or gene chips allow the activity of a largenumber of genes at the level of the mRNA to be measuredsimultaneously.

DNA chips contain multiple short DNA sequences, eachunique to one gene, synthesised directly on silicon chipsenabling the expression analysis of thousands of genes withina single experiment. The production of these slides is anindustrial process, which provides good reproducibility.

The material investigated is the mixed RNA population orcan be isolated RNA extracted from the cells or tissue ofinterest. Labelled copies of these RNA molecules areproduced enzymatically in vitro. These bind to theircorresponding DNA sequence on the DNA chip where theyare detected using fluorescent reagents. This type ofexperiment provides a “snapshot” of gene activity.

For other microarray formats, scientists generally producetheir own DNA arrays derived from known or unknownDNA clones. A commonly used method for copying specificsequences of DNA nucleotides is polymerase chain reaction(PCR). Typically PCR products or synthetic oligonucleotidesfor thousands of genes are deposited on one microarray. RNAis isolated from two samples – a control and treated. DNAreverse copies of these RNA samples are produced (each ofthe two carrying a different fluorescent label) and both arehybridised to the same microarray. Fluorescent densities ofboth markers are then measured for each separate spotresulting in thousands of data points. Analysis of the largedata set results in an overview of the activities of mostmetabolic pathways and biological processes.

The microarray allows researchers to determine which genesare active at that specific time and under specificcircumstances. Microarray techniques have been very usefulin understanding how bacteria work. For example, DNAcorresponding to all of the few thousand genes that abacterial genome contains can be placed on a singlemicroarray to demonstrate which genes are active duringinfection. The information obtained can be used to designnew antibiotics or treatments to combat the infection.

BOX 6

metabolites need to be determined separately in thedifferent compartments of the cell, for example, incytoplasm, mitochondria, extra-cellular matrix, cellmembrane etc.

Ideally, the metabolome of a cell is determined by non-invasive techniques such as NMR or IR. Althoughcurrent techniques are not very sensitive and do notalways separate individual metabolites, there will nodoubt be future advances in the technology. In themeantime, conventional analytical methods like HPLC,GC and gel electrophoresis using a combination ofdifferent columns and detectors are used for the analysisof the metabolome.

At the present time, there is only a limited number ofresearchers with the facilities required to do such specificstudies, so until now there are few reported examples ofmetabolomics in human subjects. Most examples haveinvolved the metabolic profiling of individuals, wherelarge-scale analyses of body fluids have been used todiagnose for metabolic disorders or exposure toxenobiotics.

With the development of computer algorithms it is alsopossible to correlate other physiological parameters withthe physiological status of the organism. In this way,metabolomics is being expanded and can incorporatephysiological parameters such as pH, oxido-reductionpotential and growth characteristics in the computeranalysis. This approach may then be used to understandthe secondary effects of changes in metabolism, forexample to identify secondary metabolites that mayinduce food spoilage, pathogenic bacteria, or enzymeinduction that may have adverse effects.


FIGURE 5. Proteomics Process

Proteomics process. 2D gel electrophoresis first separates proteinsalong a strip gel and a second gel separates proteins by size. The aim isto produce a protein map for a particular cell or tissue. Protein extractsare subjected to isoelectric focusing on strip gel (1). Each strip gel isthen placed onto a slab gel and the samples subjected to denaturinggel electrophoresis at right angles (second dimension) to the directionof isoelectric focusing (2). The protein is visualised using a suitablestaining method (3). Individual protein spots of interest are identified,excised from the gel (4) and transferred into a tube (5) for treatmentwith proteolytic enzymes (6). The peptide fragments produced areanalysed by mass spectrometry to determine their amino acid content(and if necessary sequence) (7). This information is used to searchprotein databases (8) to identify each excised protein.

Source: Elliott, R.M., Bacon, J.R. and Bao,Y-P. (2004). Chapter 1"Nutritional Genomics", pp 1-25, in "Phytochemicals in Health andDisease", Editors Bao, Y-P. and Fenwick, R. with permission from Taylorand Francis Group.

Databasesearching

Massspectrometry

Anode Cathode

pH gradientLow High

Denaturing gelelectrophoresis

This range of technologies is just beginning to be usedin nutrition science, but their potential is demonstratedby the rapid adoption of the technologies bypharmaceutical and clinical research.

The final ‘omics to mention at this stage is nutritionalgenomics or nutrigenomics.

• Nutrigenomics is the all-encompassing study of thegenome-wide influences of nutrition.

This area of study is likely to be extensive, as thenutritional environment of the cell is constantlychanging thereby posing an additional challenge forresearchers. It is likely that this area of research willidentify the key to understanding such crucial questionsas inter-individual variations in food intake andresponse to nutrients, providing the information “tomap” individual health.


Bioinformatics

Bioinformatics is the science that handles the huge demand for the analysis and interpretation of biological data and is essential for themanagement of data in modern biology and medicine.

It is specifically defined as the application of the tools of computation and analysis to the capture and interpretation of biological data.The bioinformatics toolbox includes computer software programs and the internet. The ever-increasing amount of data from the humangenome project necessitated the development of computer databases that can assimilate large amounts of data quickly, and transformthem into formats that can be interrogated by non-specialists. A key requirement is for sequence analysis of DNA and proteins. Twosignificant websites that provide freely available access are detailed below:

The National Centre for Biotechnology (www.ncbi.nlm.nih.gov) provides BLAST (basic local alignment search tool), which is anintegrated database retrieval system that is capable of searching databases for genes with similar nucleotide structure and hence allowscomparison of an unknown DNA or amino acid sequence with thousands that are already logged within the database. The resultingsearch is sorted on the basis of maximum similarity.

The European Bioinformatics Institute archives all gene and protein genome study data from all studies on all organisms. As part of ajoint venture with the Sanger Centre they provide free access to the database Ensembl (www.ensembl.org). This database produces andmaintains automatic annotation of the human and other genomes and can assemble and analyse genes and other features of interest tomedical or nutritional researchers.

It is considered that bioinformatics will make a major contribution in identifying susceptibility genes and illuminate the pathways of thepathogenesis involved in illness. These susceptibility genes may be influenced by environmental or nutritional factors that will providean opportunity for targeted therapy. Potential targets in cancers were recently developed from gene expression profiles. An example ofa therapeutic advance was the development of the novel designer drug – imatinib mesylate (Gleevec), which interferes with anabnormal protein made in chronic myeloid leukaemia. The ability to identify and target specific genetic markers by using bioinformatictools facilitated the development of this drug.

Already the study of genetic disorders is shifting from investigation of single genes in isolation to the understanding of cellular networksof genes and their complex interactions. Bioinformatic tools will help molecular scientists and clinical researchers integrate their skills tocapitalise on the huge biological databases now available.

BOX 7

4. VARIATION IN HUMANPOPULATIONS

4.1 Introduction

Since the time of Gregor Mendel, an understanding ofpatterns of inheritance has been established. Thevariation between individuals within a population can berelated to the package of genes they have inherited fromtheir parents. For example, the probability of having blueeyes or blond hair can be related to our parents’ genes,just like other obvious physical traits such as skin colour,stature and hair type can be linked to heritage.

In some cases, a trait will only be present in an individualif the specified gene or genes is present in the form ofidentical alleles (see Box 8: Allele); such a condition isknown as homozygous.

In the 19th century, Charles Darwin introduced theconcept of the survival of the fittest, indicating that somealleles may provide a selective advantage compared to

others. We are all too familiar with the disappearance ofthe dinosaurs and the many other animal and plantspecies unable to compete in the changing world theyfound themselves in.

Genetic polymorphism (see Box 9: Single NucleotidePolymorphisms) is the basis of this variation fromindividual to individual. DNA polymorphism is definedas a difference from the generally accepted genesequence, and occurs in at least 1% of the generalpopulation.

Genetic variance can readily be identified among humanpopulations. An example of this is the survival of a fewindividuals in isolated tribes where most died followingexposure to the colds, flu and measles viruses brought bypioneers and travellers from the West.

Differences in genetic susceptibility exist between certainindividuals or populations with regard to the majorcauses of ill health - diabetes, coronary heart disease andcancers. For example, it has been established that there isa significantly higher incidence of Type II diabetes amongPima Indians. The offspring of Pima Indians, particularly


Allele

An allele is two or more alternative forms of a given gene.Alleles are concerned with the same trait or characteristic,but the product or function coded by a particular allelediffers from that coded for by other alleles of that gene.When the members of an allelic pair occupy correspondingpositions (loci) on a pair of homologous chromosomes andthe alleles are genetically identical, it is said to behomozygous. If the alleles are genetically different, theorganism is heterozygous with respect to that particular gene.

BOX 8Single Nucleotide Polymorphisms (SNPs)

Single Nucleotide Polymorphisms (SNPs, pronounced ‘snips’)are the commonest form of genetic variability and relate to asingle nucleotide substitution in a DNA sequence, forexample, ACGT could be replaced by AGGT. SNPs occurroughly every 1000-2000 nucleotides in the human genome,and to date 22,000 have been sequenced and theirrelationship to the gene determined.

BOX 9

those that are obese have a 50%, or greater, chance of alsobecoming diabetic, and worryingly are doing so at ayounger age than their parents.

There is evidence that obesity is influenced by geneticfactors. The obesity gene map includes over 300 genes,markers and chromosomal regions that have beenassociated or linked to human obesity.

There are also well-established genetic links to conditionssuch as haemophilia, sickle cell anaemia and familialhypercholesterolemia where one or more SNPs havebeen identified.

Other aspects of metabolism may be influenced bygenetic factors. An example is the control of energyexpenditure in infants and the extent of suppression ofinflammatory response following fish oil supplemen-tation are both dependent on a SNP that affects genotypefor pro-inflammatory cytokine TNF-α.

Recently, several extensive genetic polymorphismdatabases have been developed that allow highthroughput genetic screening. These not only enable thestudy of inter-individual genetic screenings, but can alsohelp to identify future areas for closer scrutiny innutrition and clinical research.

4.2 Finding genes associated withdisease Some of the initial research carried out has been in thesearch for genes associated with complex diseases. Thiscommences by finding the chromosomal location of thegenes for disease susceptibility using linkage analysis.The principle of this approach is shown in Figure 6.

Initially families in which sibling pairs are affected withthe disorder are typed with DNA polymorphisms(common variations in the DNA sequence), in order to


FIGURE 6. Linkage analysis

Linkage analysis. Genes in the demonstration data set weresubjected to hierarchical clustering:

(A) average linkage(B) complete linkage(C) single linkage

Genes that are up-regulated appear mid-blue (1). Those in lightblue colour are down-regulated (2). This method of clusteringgroups/genes by reordering the expression matrix allows patternsto be easily visualised.

Source: Reproduced with permission from Nature PublishingGroup. © Quakenbush, 2001 Nature June 2001, vol 2, p424.

(1) up-regulated

(2) down-

regulated

identify a polymorphism that is co-inherited with thedisease. If a substantial number of the alleles of thepolymorphism are shared in the affected sibling pairsthen the polymorphism is probably linked (closely) to agene that engenders susceptibility to that disease. To findpolymorphisms requires 200-300 sibling pairs in which300-400 polymorphisms that are evenly spaced along thehuman genome are evaluated. This process is known asa genome scan.

This approach has been used to map susceptibility genesfor a number of chronic diseases. However, there is somedegree of inconsistency in the results, with linkages beingreported by one research group not being replicated byanother group. This may be due to lack of statisticalpower in the studies undertaken or a false positive in theoriginal data set. It may also be a consequence of thegene/environment interaction, which may altersusceptibility in one population and not another. Theremay also be different susceptibility genes in differentpopulations. Until a study has been replicated by at leastone other independent large-scale population study, adegree of caution is required.

Once a linkage has been confirmed, the search for thecritical gene in a region of 20-30 million base pairs canbegin – a little like looking for a needle in a haystack.

5. RELATIONSHIP BETWEENNUTRITION, GENES ANDHEALTH

5.1 IntroductionThe importance of the role that nutrients play inmodulating the expression of genes encoding theproteins of energy metabolism, cell differentiation andcell growth has already been described above.

Dietary-derived regulators of gene expression may benutritive (e.g. fatty acids, iron or selenium) and non-nutritive (e.g. phytochemicals) components of food,metabolites of food components (e.g. eicosanoids,retinoic acid) result from the cooking process (e.g.heterocyclic amines in cooked meats), or end products ofintestinal bacterial metabolism (e.g. short-chain fattyacids).

The simplest interpretation of nutrient control of geneexpression is that the reading of the genomic blueprintand its translation into functional proteins can bemodulated by a single food component.

In most cases, relationships are more complex and ofteninvolve diet-diet (e.g. fatty acid and retinoids) or diet-hormone (e.g. fatty acids and thyroid hormone)interactions.

Regardless of the type of diet-gene interaction, nutritiveand non-nutritive components of food influence theabundance and function of cellular proteins by governinggene expression at a variety of levels (see Table 1 andFigure 7).



FIGURE 7. Pathway of protein expression showing where regulation occurs by nutrients

Shown in blue are where nutrients can impact

Source: Clarke, S.D. (2001). The Human Genome and Nutrition. In Bowman, B.A. and Russell, R.M. ed. Present Knowledge inNutrition, 8th ed., ILSI Press, Washington, DC. Reproduced with permission from ILSI Press.

NUTRITIONAL IMPACT

BLUEPRINTDNA

TEMPLATESRNA Synthesis and degradation

BUILDING BLOCKS OR TOOLSmRNA translation = Proteins

PROTEIN ACTIONSPosttranslational modifications

PHENOTYPE OUTCOME

High saturated fatOxidised lipidRedox stressExcess energyHeterocyclic amines

Low essential amino acids

Low folateLow antioxidants

Retinoidsn-6/n-3 PUFAPhytosterolsEnvironmental oestrogensSelenium Iron

IronLeucine

IronLeucine

High disease risk Reduced disease risk

5.2 Diet and gene transcriptionOne key determinant of protein abundance is the rate atwhich the mRNA template is synthesised. This rate isdetermined by the binding of transcription factors tospecific DNA recognition sequences generally locatedwithin a specific region known as the 5’-flanking regionof the gene.

An example of nutrient regulation of the abundance of atranscription factor is the cholesterol regulation of sterolregulatory element-binding protein-2 (SREBP-2) and thepolyunsaturated fatty acid (PUFA) regulation of SREBP-1.

Precursor-SREBP molecules are located in the membraneof the endoplasmic reticulum. The active form of themolecule is released by a two-stage cleavage. The releaseof the mature SREBP is highly dependent on cholesterolconcentration and possibly the fatty acid composition ofthe endoplasmic reticulum.

When the cholesterol or PUFA content of theendoplasmic reticulum is high the release of SREBP isslow, but when the endoplasmic reticulum is depleted ofcholesterol or PUFA, release of mature SREBP increases.

Changes in the release of SREBP are paralleled bycomparable changes in the transcription ofcholesterogenic and lipogenic genes.

Dietary constituents also exert a strong influence on theaffinity that a transcription factor has for its DNArecognition sequence. Lipophilic factors and theirmetabolites frequently modulate transcription factorDNA-binding activity. A broad family of steroid-likereceptors that include retinoid receptors, vitamin D3receptor, and peroxisome proliferator-activated receptors(PPARs) has attracted attention due to their role asregulators of genes involved in cell differentiation, lipidand energy metabolism, inflammatory response,atherosclerotic plaque formation and cancer. Activationfactors for PPAR include n-3 and n-6 fatty acids,conjugated linoleic acids, prostaglandins, leukotrienesand oxidised fatty acids. A generalised scheme for thePPAR signalling pathway is given in Figure 8.

Protein phosphorylation and dephosphorylation,regulated by the activity of specific protein kinases andphosphatases, also modulate the DNA activity of manytranscription factors. In addition to functioning directlyon kinases and phosphatases, dietary factors mayinfluence DNA-binding activity by affecting the redoxstate of the cell. Anti-oxidants such as vitamin E mayprotect the cell against oxidative stress and prevent theinitiation of the kinase stress pathway. Alternatively,antioxidants such as glutathione may increase the DNA-binding activity of transcription factors by protectingtheir oxidative status.


Targeted Site Examples of Nutrient Regulator

Gene transcription Fatty acids, glucose, cholesterol,

retinoids, vitamin D

mRNA stability Fatty acid, glucose, selenium, iron

mRNA processing Polyunsaturated fatty acids,

glucose

mRNA translation Iron, amino acids

Post-translational Vitamins and minerals

modification

TABLE 1Points in the pathway of protein expression regulatedby dietary constituents

Some nutrients appear to regulate the movement ofmRNA into the cytosol. Glucose and PUFA are at leasttwo of the nutrients found to modulate the mechanismsof mRNA processing.

5.3 Diet and mRNA stabilityThe cellular content of mRNA transcripts depends oncytosolic signals that determine the stability of a givenmRNA.

Dietary examples of this regulation include thestabilisation of fatty acid synthetase mRNA by glucose,glutathione peroxidase by selenium and destabilisationof the transferrin receptor mRNA by iron. For example,when cellular levels of iron are low, the iron regulatory

proteins bind iron and increase transcript stability.Conversely, the binding of iron accelerates degradation ofthe transferrin receptor mRNA.

5.4 Diet and mRNA translationSynthesis of a protein from the mRNA template requiresbinding of ribosomes and subsequent reading of themessage. Some dietary factors affect this process byblocking the ribosome binding which will alter theaffinity for the initiation site or the rate of peptideelongation. Amino acid scarcity is one of the key factorsthat may slow or terminate peptide elongation.

As detailed above, iron status can also inhibit thetranslation of the ferritin transcript.


FIGURE 8. A generalised scheme for the PPAR signalling pathway

A general scheme of PPAR signaling pathway. Agonists for the system include free fatty acids, deriving from glucose or lipid intermediarymetabolism, and retinoic acid and retinoids, binding to PPAR and RXR, respectively. The heterodimeric complex bound to the respectiveagonists is thus able to bind PPRE in the promoter region of responsive genes, thus driving transcription. See text for further details.

Source: De Caterina, R.D., Madonna, R., Hassan, J. and Propcopio, A.D., (2001). Nutrients and Gene Expression, in Nutrition and Fitness: Diet,Genes, Physical Activity and Health. ed Simopoulos, A. P. and Pavlou, K.N. World Rev Nutr Diet. 89,23-52. Reproduced with permission fromS. Karger AG.

Lipids Glucose

Intermediate metabolism

cytoplasmRA FFA

transcription

nucleus

PPREPromoter

RA = retinoic acidand retinoids

FFA = free fatty acids

PPAR = peroxisomeproliferator-activatedreceptors

PPRE = peroxisomeproliferators responseelements

Gene coding region

PPARRXR

▲ ▲ ▲▲ ▲ ▲

▲

● ●

● ● ●

● ●

●

Research defining the full scope of the role that diet canplay in mRNA translation is in its infancy and attentionto date has focused on individual amino acids. However,as the translation of the transcript relies on a wide arrayof proteins, including enzymes such as kinases andphosphatases, and ribosomal proteins, a wider dietaryrole is implicated.

5.5 Diet and post-translationalmodification of proteinsOnce translated, many proteins undergo furthermodification. The array of post-translational modifica-tions includes proteolytic cleavage, phosphorylation-dephosphorylation, acetylation, acylation, methylationand glycosylation. Each of these processes has thepotential to be regulated by dietary constituents, and anydefects in the post-translational mechanism may result inmajor changes in cellular functioning or metabolism.

The binding of a vitamin or mineral cofactors to a proteinand the subsequent conversion from an inactiveapoenzyme to an active holoenzyme is another commonpost-translational modification for a number of enzymes.Examples include thiamin addition to pyridoxinedehydrogenase and manganese insertion in arginase.

5.6 Nutrition and gene polymorphism The function and relative abundance of a protein can bealtered by genetic mutations that may affect any of thenumerous steps involved in converting the genetic codeinto a protein.

The most obvious outcome of gene polymorphism iswhen a change in a nucleotide sequence occurs thatresults in the protein product of the mRNA templatelosing its function or having altered substrate affinity(Section 5.6.1).

A more subtle but potentially just as, or even more,important gene polymorphism occurs when the variationin DNA sequence is in the non-transcribed region of agene where the control switches for governing genetranscription, mRNA stability, or rate of translation areaffected (Section 5.6.2).

Several genetic polymorphisms with a nutritionalsignificance have already been identified; some of theseare detailed in Table 2.

5.6.1 Gene polymorphisms affecting proteins

A SNP (see Box 9: SNP) has been identified that influencesthe dietary folate requirement.

The affected gene codes for a key enzyme methylene-tetrahydrofolate reductase (MTHFR) and the poly-morphism replaces a single cytosine with thymidine.This in turn changes a codon that encodes alanine insteadof valine. This single and apparently minor change inamino acid sequence reduces the thermostability of theenzyme. Those individuals homozygous for the alleledemonstrate lowered MTHFR activity and elevatedplasma homocysteine. Folate supplementation appearsto lower plasma homocysteine levels, which is beneficial,as elevated homocysteine levels have been associatedwith atherosclerosis.

This finding is important, as it demonstrates that singlenucleotide changes may have a significant effect on theexpression and function of protein.

One of the most common inherited disorders withnutritional implications is familial hypercholesterolaemia,caused by mutations in the low-density lipoprotein (LDL)receptor gene template.


The mutations lead to impaired LDL clearance andindividuals display elevated cholesterol levels of greaterthan 7.76 mmol/L. Approximately 1 in 500 people areheterozygous (one allele mutated) for these mutationsand individuals that are homozygous have exceedinglyhigh cholesterol levels very early in life and shortenedlife spans.

A second common polymorphism related to lipoproteinsis the apolipoprotein (apo)-E gene. Apo-E is involved inlipid transport and the receptor-mediated uptake ofchylomicron and very low density lipoprotein (VLDL)remnants. Apo-E synthesis and secretion is increasedwhen diets high in saturated fat are consumed. Anexample of the impact of polymorphisms in this gene isdetailed below.

There are three major variants of apo-E; the normal formis apo-E3. In apo-E2, a cysteine has replaced arginine 158and in the apo-E4 variant, cysteine 112 is replaced byarginine. The relative occurrence in the US population iscirca 60% for the homozygous allele, 56%, 1% and 2% foralleles E3, E2 and E4 respectively. Population studiesindicate that heterozygous allele is carried by 23% in thecase of E3/E4, 12% for E3/E2 and 3% for E2/E4. Both E2and E4 homozygotes demonstrate impaired lipoproteinmetabolism. In the case of E2 hyperlipoproteinemiaresults due to defective binding to the apo-E receptor andwith E4 elevated total cholesterol and LDL levels areseen.


Cellular Process Gene with known polymorphisms Nutrition/health ImpactFolate metabolism Methylene tetrahydrofolate reductase, cystathione beta- Risk of neural tube defect,

synthase, methionine synthase, Down’s syndrome, CVD and cancerglutamate carboxy-peptidase III

Iron homeostasis Hereditary haemochromatosis, linked gene HFE Effect on iron requirements, anaemia,and transferrin receptor and iron overload

Bone health Vitamin D receptor, oestrogen receptor, type I collagen Effect on bone metabolism, osteoporosis, mediation of calcium and phosphorus translocation

Lipid metabolism Apolipoprotein (AIV, B, C3, E), low density Effect on blood cholesterol and other lipoprotein receptor, lipoprotein lipase cardiovascular risk factors

Immune function HLA (MHC), tumour necrosis factor α and other cytokines Susceptibility to various food allergies (such as coeliac disease) and modified susceptibility to cancer through diet

TABLE 2

Examples of known cellular processes and genetic polymorphism with direct consequences for nutrition

Source: Derived from Elliott, R. and Ong, T.J. (2002). Nutritional genomics, BMJ 324, 1438-42, with permission from BMJ Publishing Group.

LDL receptor, apo-E and MTHFR are only three of themany gene polymorphisms that affect human health andthe development of heart disease.

5.6.2 Gene polymorphisms affecting the level ofprotein expression

The polymorphisms that occur in the untranscribedregion of the gene produce more subtle effects becausethey limit the level of expression of a protein rather thanaltering the protein per se.

Polymorphisms of this type have been identified byDNAase foot-printing and simple DNA sequencecomparisons. A common example of this change is in theapo-B gene, where cytosine may be replaced bythymidine at position 516. This substitution increasedgene transcription by 40% and healthy middle-aged menwho were homozygous for the thymidine allele have12% higher LDL levels.

A polymorphism in the regulation of the hepatic lipasegene is caused by a SNP at the 514 nucleotide; a changefrom cytosine to thymidine results in a major differencein the response of HDL to dietary fat intake.

Similarly, a single nucleotide change at position 491 of theapo E gene significantly increased gene transcription,which was associated with an increased risk of thedevelopment of Alzheimer’s Disease.

5.7 Nutrition and EpigeneticsEpigenetics refers to modifications of the genome, notinvolving alterations in the primary DNA sequence, butincluding an alteration of the DNA itself by, for example,methylation and posttranslational modification of theoctet of histone proteins around which the DNA iswrapped.

DNA methylation occurs on cytosines (C) within themolecule, particularly where the cytosine base isfollowed by a guanine base and the dinucleotide may bemethylated at the 5’ position of cytosine. When DNAmethylation occurs in assemblies of cytosine/guaninedinucleotides in the promoter region of the gene, oftengene silencing results with no subsequent mRNA orprotein production.

Rogue methylation is part of the ageing process and isinvolved in the development of a number of diseasesincluding cancers, cardiovascular disease and nerve cellor tissue degenerative disorders such as Alzheimer’sdisease and Parkinson’s disease.

Rogue methylation is influenced by dietary factors anddrugs and is shown to be reversible, although the impactthat food components may have is not yet understood.At some future time it may be possible to developnutrition regimes that help to maintain normalmethylation and so promote longer-term health.

Chemical modification of the protein (histone) tails thatprotrude from the histone bundles, around which DNA iswrapped within the chromatin, has been described ashistone “decoration”. Although not fully understoodthese chemical modifications are thought to be epigeneticsignals that regulate gene expression. There is a closeinterplay between histone decoration and DNAmethylation. It is believed that histone decoration is oneof the ways in which the genome integrates both intrinsicand extrinsic signals that result in the modulation of geneexpression and modification of the phenotype.


6. CONSEQUENCES ANDPOTENTIAL

6.1 Introduction The application of genomic technologies to nutrition andbiochemical research techniques provides a powerfultool to understand the mechanisms by which individualfoods or nutrients modulate processes occurring withinthe tissues of the body.

Scientists face the challenge to provide comprehensiveanswers to questions such as:• Which components of the diet have important health

promoting effects?

• How, where and when are these effects exerted?

• Can some of these components also have adverseeffects?

• How much and in what form and combination do weneed to eat such components to obtain the maximumhealth benefit with minimum risk?

• How do individuals’ dietary recommendations varydepending on their genetic profile, age, gender andlifestyle?

Answering these questions will require collaborationbetween groups of scientists with diverse specialismssuch as molecular biologists, geneticists, nutritionists,clinicians and bioinformaticians. In fact, the subject is sohuge that in many cases a global approach to data useand sharing will be required to increase the scope ofunderstanding.

This poses one of the challenges to the development ofthis area, as groups of traditional and ‘omics scientistsmust learn to collaborate and communicate within multi-skilled teams of scientists.

Another barrier will be the high cost of entry into thisspecialist field. This is due to the immense requirementfor data handling, integration of data from differentsources and techniques, the lack of sufficientlysophisticated tools for data interrogation and modellingand logistical difficulties between co-operating groups

There are, however, specific areas where progress hasalready been made.

6.2 Nutrition and gene polymorphismDefining nutrient requirements from DNA sequencesmay be somewhat futuristic. However, DNA sequencingcould be used to screen for specific gene polymorphismse.g. the Apo-E alleles. Effective dietary advice for thosewith the E3 allele that have elevated cholesterol would bedifferent to the dietary advice given to those with eitherthe E2 or E4 alleles. Using this technology would allownutrient requirements of particular groups of individualsto be tailored more specifically.

As many polymorphisms identified appear to be linkedto increased disease susceptibility, better understandingof the mechanisms involved would allow scope for bettertargeting of more appropriate dietary advice to therelevant population sub-groups.

However, understanding the relative importance of gene-gene and gene-environment interactions for polygenicdiseases is still at an early stage.


For example, in osteoporosis, twin and sibling studiesindicate that genetic factors are the main determinants ofbone mineral density and structure, typically accountingfor 50-85% of phenotypic variance, with environmentalfactors accounting for the rest. Although some geneticpolymorphisms have been linked to variations in bonemineral density, these associations are still contentiousand it seems more likely that several genetic poly-morphisms each make a small contribution to the geneticcomponent of osteoporosis.

Identifying appropriate candidate genes that markdisease risk in these circumstances becomes substantiallymore complicated and the risk of finding spurious resultsis increased.

The best strategy for resolving the genetic andenvironmental contributors to such polygenic disordersremains unclear at this stage.

Future use of DNA polymorphisms could be toinvestigate the genome for sequence information thatdefines the variation in nutrient absorption and use.However, the bioinformation requirements of such anapproach are enormous and still in the relatively earlystages of development.

A second requirement is for basic biological research thatcan correlate nutritional outcome with the genepolymorphism.

Where links are established between nutrients or dietarypractice and SNP, it is conceivable that people at riskcould be identified early in life, if rapid and inexpensivescreening methods were available. This would enable alifelong dietary approach that may improve bothlongevity and quality of life.

6.3 Gene and food bioactivesFood bioactives such as naturally occurringphytochemicals found in many fruits, vegetables, spices,and tea can also play a significant role in gene expression.Functional genomics techniques could effectively be usedfor identifying the effect of the novel functional food orfood component (often described as nutraceuticals) onglobal gene expression and cell function, without havingto make assumptions about what to look for in terms ofrisk.

The same approach is being used to establish the safety ofgenetically modified food and food ingredients.

Research is already underway to identify thechemopreventive effect of model food components bycomparing the effect on protein and RNA expressionwithin the relevant cell lines. It is anticipated that thesemodel food components will affect different mechanismsinvolved in colon carcinogenesis. Once a mechanism andmarker genes are linked, it should be possible to gain anunderstanding of the prophylatic mechanism of the foodcomponent under study.

6.4 Genomics in the development ofbiomarkersThe greatest potential for benefit from dietarymodification is likely to be in terms of the maintenance orprotection of health.

At the present time, biomarkers of disease risk rely on themeasurement of a single or few nutrients, genes, proteinsor metabolites and often measure parameters thatindicate that the degenerative process is underway if notwell advanced. For example, an elevated bloodcholesterol concentration may indicate that considerableatherosclerosis has already taken place. In addition, as


many biological processes are multifactorial, a singlebiomarker may not accurately reflect the process understudy.

Nutritional genomics offers the possibility of measuringgenome-wide changes in gene expression resulting fromchanges in diet or possibly a single food component.Specific effects on gene expression would provide thefocus to seek for links in the disease developmentprocess.

Alternatively, the disease state could be monitored toidentify the genes involved in its early development. Thiswould involve studying various tissues at differentstages of disease development, which will allow morerelevant markers at the DNA, RNA or protein level to beidentified. These molecular biomarkers will permit earlyidentification of pivotal changes between healthmaintenance and disease onset and progression.

This work may be complicated by the fact that somecomponents in foods may be protective in one area at aspecific time and cause adverse effects at another. Anexample of such a food is soya protein and its componentphytoestrogens, which appear to offer varying degrees ofprotection to the breast health at different life stages andat different stages of breast cancer development.

7. ETHICS AND SOCIALISSUES

Crucial to consumer acceptance of the products, orservices resulting from nutrigenomic developments, isthe way in which they are communicated and by whom.

The information needs to clearly identify consumerbenefits and to address any of their concerns and shouldbe communicated by individuals or groups that theconsumers trust to inform them on scientific issues.

Communicating any diet health message is an areafraught with difficulty, requiring much consideration tobe given to the actual words used to communicate themessage. Even after paying attention to how the messageis communicated there is often poor uptake in largesectors of the population, who seem unwilling or unableto relate to the notion that today’s diet will influencefuture health and well-being.

A barrier to greater exploitation of genetics in the area ofnutrition and health is likely to be consumer-led fear oruncertainty about the consequences of characterisation ofthe genome and the identification of mutations of highlypenetrant genes, e.g. those responsible for familial formsof cancer, and specific SNPs known to impact on health.This fear is based on the assumption that suchconsequences may have implications on an individual’sability to obtain employment, finance or insurance. It isimportant that those involved in the technologies addressthese concerns and communicate the benefits and thesafeguards that are in place.


Clearly advantages for the individual can be identifiedand there is the potential for positive action throughnutrition, for example, as detailed previously in thosecarrying the Apo-E3 allele (see Section 6.2). Under thesecircumstances genotyping is likely to be lesscontroversial. Gene-specific advice or products could beused with responders or non-responders as appropriateto allow better targeting of resources and effort.

The greater benefit would be in the context of diseaseprevention where the knowledge of an individual’sgenetic profile, encoded by their unique pattern of SNPs,could be used to tailor specific risk-reducing actionsinvolving diet or other factors that could reduce the riskof disease and improve the quality of life.

However, although an attractive proposition, there islittle research to support the proposition that individualtargeting would provide the motivation for change.Further research is required into factors that motivatebehaviour change and whether these are in themselvesinfluenced by genotype before this approach could berecommended.

The confidentiality of data relating to individuals’ geneticmap is also an area for concern; some people willquestion the extent to which such information should orcan remain anonymous.

Clearly, as advances are made in nutrigenomics, all ofthese issues need to be addressed and reviewed on aregular basis. This will ensure that the innovativetechnologies and products that develop take due accountof changing public reaction, consumer concerns andethical issues. A further concern must be to maintain thevalue of this emerging science while it is still in itsinfancy. Over-promising the ability of nutrigenomicscould cause it to be undermined or dismissed byconsumers.

There is also a greater need for a holistic view as moreand more detailed information is generated and a globalapproach will be desirable.


GLOSSARY

Allele: Two or more alternative forms of a given gene.All alleles are concerned with the same trait orcharacteristic, but the product or function coded by aparticular allele differs from that coded for by otheralleles of that gene.

Amino acids: Building blocks of proteins. Typically 20different amino acids are commonly used by the cellsto make proteins.

Atherosclerosis: A degenerative disease of arteries inwhich there is a thickening caused by an accumulationof material (plaque) beneath the inner lining,eventually restricting blood flow. The materialcharacteristically contains cholesterol and macrophagecells.

Bioinformatics: The evolving science that handles thehuge demand for the analysis and interpretation ofbiological data.

Cardiovascular disease: Any one of numerous abnormalconditions characterised by dysfunction of the heartand blood vessels.

Cholesterol: A lipid (sterol) made in the body fromacetyl-CoA and present in the diet; a constituent of cellmembranes (especially in nervous system tissues)blood and atherosclerotic plaques.

Chromosomes: In the cell nucleus, DNA is tightlypacked with particular proteins into structures calledchromosones. Different organisms have differentnumbers of chromosomes. A normal human cellcontains two pairs of 23 chromosomes. Packaging intochromosomes enables the organised assortment ofgenes into daughter cells upon cell division, as well asplaying a role in controlling gene expression.

Codon: The sequence of three nucleotides in mRNA thatencodes for each amino acid of a protein.

Coronary heart disease (CHD): A condition in which themain coronary arteries supplying the heart are blockedor restricted and are no longer able to supply blood,and therefore oxygen to the heart muscle(myocardium), which may then quickly die. The maincause of reduced blood flow is the accumulation ofplaques in the arterial walls, a disease known asatherosclerosis. The blockage of an already narrowedartery is thrombosis.

Deoxyribonucleic acid (DNA): Deoxyribonucleic acid(DNA) is the repository of all genetic information inthe cell. It is a long linear polymeric molecule made upof nucleotide building blocks. Each nucleotidecomprises a deoxyribose (a sugar) and phosphategroup and one of four different bases, adenine (A),guanine (G), cytosine (C) or thymine (T). Each DNAmolecule consists of two strands in the shape of adouble helix.

DNA Microarrays: DNA microarrays or gene chips allowthe activity of a large number of genes at the level ofthe mRNA to be measured simultaneously.

Enzyme: A protein produced by living cells that regulatesthe speed of chemical reactions that are involved in themetabolism of living organisms, without itself beingaltered in the process. Also called a “biologicalcatalyst”.

Epigenetics: Modifications to the genome, not involvingalterations in the primary DNA sequence, butincluding alteration of the DNA by processes such asmethylation.

Gas chromatography (GC): a technique for separating amixture of molecules that involves the vaporising ofthe sample in a suitable carrier gas, often helium,hydrogen or nitrogen.


Gene: The segment of DNA on a chromosome thatcontains the information necessary to make oneprotein. A gene is the smallest indivisible unit ofheredity.

Genetic code: The “code” in which information for thesynthesis of proteins is contained. It lies in thenucleotide sequence of the coding region of a gene.

Genetic: Inherited; a genetic disease is one that isinherited and potentially transmitted through a faultygene.

Genetic modification: The techniques for removing,modifying or adding genes to a living organism. Alsocalled “gene splicing”, “recombinant DNA (rDNA)technology” or “genetic engineering”. “Within-species” genetic modification is essentially similar totraditional breeding methods (except that it is muchspeedier and much less haphazard). Through “trans-species” modification, results are obtained that wouldnot be obtained by traditional breeding methods.

Genome: The genetic fingerprint of an organism thatcontains all the nucleotide sequences includingstructural genes, regulatory sequences and non-coding DNA sequences of the chromosome.

Genomics: “The holistic study of biomolecules” andcomprises the study of all nucleotide sequencesincluding structural genes, regulatory sequences andnon-coding DNA sequences of the chromosome.

Heterozygous: Where the members of an allelic pair aregenetically different, it is heterozygous with respect tothat particular gene.

High performance liquid chromatography (HPLC): Atechnique for separating a mixture of molecules thatinvolves using very high pressures to force a liquidsample through a tightly packed column of particles;separation occurs on the surface of the particles by anadsorption process.

Histone: Protein bundles rich in the amino acids arginineand/or lysine around which DNA is wrapped withinthe chromatin.

Homozygous: Where the members of an allelic pairoccupy corresponding positions (loci) on a pair ofhomologous chromosomes and the alleles aregenetically identical, it is said to be homozygous.

Hypercholesterolaemia: Concentrations of cholesterol inthe blood higher than normal (or reference) values.Causes include dietary and genetic.

Infra-red absorption spectroscopy (IR): A technique thatmeasures the vibrations of molecules; each moleculehas a unique internal frequency that can be used todetermine what functional groups are in a sample.

Lipoproteins: Particles composed of specialised proteinsand lipids including triglycerol, cholesterol andphospholipid. They enable (water-insoluble) lipids tobe carried in the blood plasma. LDL and HDL arelipoproteins.

Low density lipoprotein (LDL): Plasma lipoproteinscontaining high concentrations of lipids (so lowdensity compared to that of water), includingcholesterol. Increased concentrations are a risk factorfor coronary heart disease.

Metabolome: The complete complement of lowmolecular weight molecules including theintermediates of metabolism in the cell.

Metabolomics: The study of the entire complement ofmetabolites in the cell including those involved inmetabolic regulation and fluxes.

Metabonomics: A variant of metabolomics described as asystems approach to examining the changes in thehundreds or thousands of low molecular weightmetabolites in an intact tissue or biofluid.


Mutation: The change in DNA sequence caused bydamage by a mutagen, or by errors in cellularprocesses that may occur during cell division. Somemutations have no effect on the function of the genesin which they occur, while others inactivate or changethe activity of the genes. Some mutations aredetrimental to the organism, a few are beneficial.Mutations are a source of variation betweenindividuals and are a driving force of evolution.

Nuclear Magnetic Resonance (NMR): A technique thatuses an electromagnet or superconducting magnet todetermine the structures, confirmations andinteractions of molecules, usually small moleculeswith a molecular weight <2000.

Nutrigenomics: The study of the genome-wideinfluences of nutrition – the application of genomicstechnologies in nutritional sciences and foodtechnology.

Ori: The special site(s) on the chromosome where theinitiation of DNA replication begins.

Promoter: A nucleotide sequence within the non-transcribed region of the DNA of a gene that regulatesthe process of transcription. Transcription iscommonly initiated at a position within the promotersequence.

Protein: Polymers (chains of linked units) of amino acids.The uniqueness of individual proteins depends ontheir length and the order of amino acids within theproteins.

Proteome: The full cellular content of proteins.

Proteomics: The study of proteomes.

Ribonucleic Acid (RNA): A nucleic acid that isstructurally similar to DNA involved in all stages ofprotein synthesis and in regulatory, catalytic and otherprocesses in the cell. It differs in three main ways: thesugar component of the nucleotide building blocks is aribose, the base uracil is used in place of thymine, sothat the code consists of A, C, G and U, and it isgenerally single stranded.

Ribosomes: The cellular machines that read the codecarried by mRNAs and work with tRNAs to produceproteins from this code.

RNA: The RNA that combines with ribosomal protein toform ribosomes.

mRNA: Any RNA that functions as a template for theassembly of amino acids during protein synthesis.

tRNA: The RNA that during protein synthesis acts as theadapter molecule matching amino acids to theircodons on mRNA.

Reverse transcription polymerase chain reaction (RT-PCR): An experimental method used forunderstanding gene expression and that providesinformation on RNA quantification and conformation.

Single Nucleotide Polymorphisms (SNPs): Thecommonest and smallest form of genetic variability,where a single nucleotide substitution occurs in aDNA sequence.

Transcription: Transcription is the process by which aRNA strand is formed from a DNA template.

Transcriptome: The complete complement of RNAspecies produced from the genome of an organism.

Translation: The stage where mRNA guides the assemblyof the polypeptide chain that results in proteinsynthesis.


FURTHER READING

Clarke, S.D. (2001). The Human Genome and Nutrition.In Bowman, B.A. and Russell, R.M. ed. PresentKnowledge in Nutrition, 8th ed., ILSI Press,Washington, DC, p. 750-760.

Corthésy-Theulaz, I., den Dunnen, J.T., Ferré, P., Geurts,J.M.W., Müller, M., van Belzen, N. and van Ommen, B.(2005). Nutrigenomics: The Impact of BiomicsTechnology on Nutrition Research. Ann Nutr Metab. 49,355-365.

De Caterina, R.D., Madonna, R., Hassan, J. andPropcopio, A.D. (2001). Nutrients and Gene Expression,in Nutrition and Fitness: Diet, Genes, Physical Activityand Health. ed Simopoulos, A.P. and Pavlou, K.N.World Rev Nutr Diet. 89, 23-52.

Elliott, R. and Ong, T.J. (2002). Nutritional genomics.BMJ 324, 1438-42.

Elliott, R.M., Bacon, J.R. and Bao, Y-P. (2004) Chapter 1"Nutritional Genomics", pp 1-25, in "Phytochemicals inHealth and Disease" Editors Bao, Y-P. and Fenwick, R.Marcel Dekker, Inc. New York.

International Human Genome Sequencing Consortium(2001). Initial sequencing and analysis of the HumanGenome. Nature 409, 860-921.

Quackenbush, J. (2001). Computational Analysis ofMicroarray Data. Nature Rev. 2, 418-27.

Obesity Gene Map: http://obesitygene.pbrc.edu

Van der Werf, M.J., Schuren, E.H.J., Bijlsma, A.C. Tas.and van Ommen, B. (2001). Nutrigenomics: Applicationof Genetics Technologies to Nutritional Sciences andFood Technology. J. Food Sci. 66, 772-780.

Various authors (2004) British Nutrition SocietySymposium: How and Why Measure Individualvariability; Implication of Dietary Guidelines of GeneticInfluences on Requirements, Proc Nut Soc. 63, 1-20; 167-185.



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This publication is made possible by support from the ILSI Europe Nutrition and Genetics Task Force, which is under the umbrella of theBoard of Directors of ILSI Europe. ILSI policy mandates that the ILSI and ILSI branch Boards of Directors must be composed of at least 50%public sector scientists; the remaining directors represent ILSI’s member companies. Listed below are the ILSI Europe Board of Directors andthe ILSI Europe Nutrition and Genetics Task Force members.

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