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1 Unit 7: Molecular biology and genetics We all start off as one stem cell (a fertilised ovum) that divides to give a ball of cells. These cells then differentiate and become specialised to carry out specific functions. Not all genes in differentiated cells need to be expressed (making their products – usually proteins). Cells carrying out a particular function will only need certain enzymes to catalyse the relevant metabolic reactions. Hence in differentiated cells many genes will be switched off and only those needed to encode enzymes and other proteins needed by those cells will be switched on. Also genes are not always either on or off but may be making smaller or larger amounts of the product – some gene switches are like dimmer switches. How do you think the gene expression in a β-cell in an islet of Langerhans differs from the gene expression in mammary gland cells? On successful completion of this topic you will: understand factors involved in the regulation of gene expression (LO2). To achieve a Pass in this unit you will need to show that you can: discuss the structure of operons (2.1) explain the features of positive and negative control (2.2). Regulation of gene expression 7 . 2

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  • 1

    Unit 7: Molecular biology and genetics

    We all start off as one stem cell (a fertilised ovum) that divides to give a ball of cells. These cells then differentiate and become specialised to carry out specific functions. Not all genes in differentiated cells need to be expressed (making their products – usually proteins). Cells carrying out a particular function will only need certain enzymes to catalyse the relevant metabolic reactions. Hence in differentiated cells many genes will be switched off and only those needed to encode enzymes and other proteins needed by those cells will be switched on.

    Also genes are not always either on or off but may be making smaller or larger amounts of the product – some gene switches are like dimmer switches.

    How do you think the gene expression in a β-cell in an islet of Langerhans differs from the gene expression in mammary gland cells?

    On successful completion of this topic you will: • understand factors involved in the regulation of gene expression (LO2).

    To achieve a Pass in this unit you will need to show that you can: • discuss the structure of operons (2.1) • explain the features of positive and negative control (2.2).

    Regulation of gene expression7.2

  • 2

    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    1 The purpose of genesThe purpose of genes is to cause proteins, or one of the types of RNA, to be produced when required to meet the needs of the cell. The production process, expression, is regulated by a molecular gene switch called an operon. An example of the operation of an operon, the lac operon, was discovered in 1961 by Francois Jacob and Jacques Monod.

    In E. coli, cells may need to metabolise lactose if it is the only source of sugar available as a nutrient. The enzymes needed for metabolism of lactose are β-galactosidase and lactose permease. Production/synthesis of these enzymes is triggered, or induced, by the addition of lactose to the nutrient medium. The enzymes are said to be ’inducible‘. Lactose is the operon, the lac operon, which induces their production.

    The lac operon

    I P O Z Y

    controlsites

    regulatorygene

    The E. coli lac operon and its regulator gene. The operon consists of the structural genesencoding the enzymes needed for lactose metabolism (hence the name lac operon), andthe control regions, O and P. O and P control the expression of the structural genes, Z andY. Z codes for the enzyme β-galactosidase. Y codes for the enzyme lactose permease

    structuralgenes

    (a)

    (b)

    I P O Z Y

    mRNA

    ribosome

    Repressor protein binds to operator,preventing transcription of gene bystopping RNA polymerase binding tothe promoter region

    How the lac operon works by stopping RNA polymerase binding to the promoter regionwhen lactose is absent from the growth medium

    repressor protein

    RNA polymerase

    I P O Z Y

    mRNA mRNA

    ribosome

    genestranscribed

    lactosepermease

    β-galactosidaseinducer(lactose)

    repressorprotein

    inducer-repressor complexcannot bind to operator

    repressorproteinleaves

    operator

    (c) How the lac operon works when lactose is present

    Key termOperon: A length of DNA consisting of structural genes, coding for proteins such as enzymes, and control sites consisting of an operator region and a promoter region. The operator and promoter are both genes but their products are not proteins.

    Figure 7.2.1: The E. coli lac operon (Z, Y, O and P) and its regulator gene.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    The lac operon (see Figure 7.2.1) is a length of DNA and it consists of structural genes – Z codes for ß-galactosidase and Y codes for lactose permease – plus the operator region, O, next to the structural genes, which O can switch on and off. P is the promoter region – the length of DNA to which RNA polymerase binds to initiate transcription of the structural genes.

    When lactose is absent

    In the absence of lactose: • the regulator gene is transcribed and translated, producing a repressor

    protein • the repressor protein uses one of its binding sites to bind to the operator

    region of the operon, blocking the recognition/binding site of the promoter region for RNA polymerase

    • so Z and Y are not transcribed and cannot be expressed.

    When lactose is present

    In the presence of lactose: • lactose binds to the other binding site of the repressor protein • this causes the protein to change its configuration and leave the operator region.

    This exposes the RNA polymerase binding site on the promoter region and transcription of Z and Y can begin.

    Lactose permease enables the bacteria to take up lactose and β-galactosidase converts the disaccharide lactose to the monosaccharides glucose and galactose for use in respiration.

    Negative and positive controlNegative control

    Negative control is when genes are expressed unless they are switched off, either at transcription or translation level. The default position for these genes is ON.

    Genes under negative control are expressed unless they are switched off by a repressor protein. Such control provides a fail-safe mechanism because, if the regulator protein is inactivated, the gene is expressed and the cell is not deficient in its enzyme products.

    This lac operon is an inducible operon and is an example of negative control. It regulates gene expression at transcription initiation and uses negative feedback; the gene product downregulates its own production. In this case the cell does not waste amino acids and energy synthesising enzymes that are not needed. Its structural genes are switched off except when molecules of lactose (the inducer) are present. When there is no inducer the genes are not transcribed because the repressor protein is active and bound to the operator.

    Repressible systems are also examples of negative control. E. coli synthesises the amino acid tryptophan using an enzyme, tryptophan synthetase. If tryptophan is added to its nutrient medium, production of tryptophan synthetase is halted. Tryptophan is described as a corepressor because it represses production of an enzyme that would synthesise more of it (tryptophan) than the cell now needs.

    Key termsOperator: Region (length of DNA) of a chromosome that is able to interact with a specific repressor and thereby control the function of adjacent genes.

    Promoter: A region on a gene (length of DNA) to which RNA polymerase binds to initiate transcription.

    Repressor protein: Protein product of the regulator gene associated with an operon, which bonds to the operator and prevents RNA polymerase binding to the adjacent promoter region, thereby preventing transcription of the structural genes.

    Inducers: Small molecules that cause production of enzymes able to metabolise them.

    Corepressors: Small molecules that prevent the production of enzymes able to synthesise them.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    The tryptophan (trp) operon

    This was the first repressible operon discovered. It functions only in the absence of the corepressor molecule, tryptophan.

    • It consists of five structural genes: trp E, trp D, trp C, trp B and trp A that code for the components of tryptophan synthetase (see Figure 7.2.2).

    • There is a promoter where RNA polymerase binds and a repressor gene that codes for a protein that, in the presence of tryptophan, binds to the operator and blocks transcription.

    • If no tryptophan (the corepressor) is present, the repressor protein cannot bind to the operator.

    R P O type E type D type C type B type A

    repressormonomers

    binds topromoter

    leader

    attenuator

    repressortetramer tryptophan

    If tryptophan is high a smalllength of mRNA is transcribed,

    but not for structual genes

    activatedrepressor

    structual genes fortryptophan synthetase

    mRNA

    mRNA

    1 2 3 4

    If tryptophan is low all mRNAis transcribed, so structual

    genes can be made

    Leader region of mRNAhas 4 regions

    Also on this operon are a leader region and an attenuator region that allow gradations of gene regulation.

    The leader region is transcribed to RNA, which contains four regions.

    Region 2 is complementary to sequences 1 and 3.

    Region 3 is complementary to regions 2 and 4.

    This allows various hairpin loops to be made in the RNA.

    Within sequence 1 are two adjacent codons for tryptophan. The attenuator sequence is a UUU codon that acts as a stop codon when areas 3 and 4 form a hairpin loop.

    Figure 7.2.2: Transcription of the trp operon.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    Ribosome starts at area 1 ofleader mRNA. Areas 2 and 3

    form a loop. There is no termination loop and

    all mRNA is transcribed.

    (i) low tryp

    (ii) high tryp

    Ribosome starts at area 2 longenough for areas 3 and 4 to form

    a termination loop. Structuralgene mRNA is not translated.

    1

    1 4

    2

    2 3

    3

    two codensfor tryp

    4

    In prokaryotes, because their DNA is not in a nucleus, translation begins as soon as a length of mRNA has been made by transcription, so transcription and translation can be happening together.

    If tryptophan is low: • the ribosome pauses at area 1 of the leader RNA while it waits for two tRNA-

    tryptophan complexes to arrive. • the ribosome is shielding area 1 so areas 2 and 3 form a hairpin loop.

    This means area 3 cannot bind to area 4 and no terminator loop is formed.

    Once the ribosome starts moving again it can progress to the mRNA for the structural genes and these genes are translated, making the enzyme to catalyse the synthesis of tryptophan (see Figure 7.2.3 (a)).

    If tryptophan is high: • the ribosome moves along area 1 and then pauses, shielding area 2,

    preventing it from making a loop with area 3.

    This leaves area 3 free to form a termination loop with area 4 and the structural genes are not translated (see Figure 7.2.3(b)).

    Negative translational control in eukaryotic cells

    Translation repressor proteins bind at the 5’ end of mRNA where translation would begin.

    An example is in eukaryotic liver cells when: • exposure to iron switches ferritin mRNA from inactive to active (ferritin is a

    protein that stores iron in liver cells) • near the 5’ end of the ferritin mRNA is an iron-response element that binds to

    a regulatory iron-binding protein, when that protein is not bound to iron.

    In this state the mRNA cannot be translated.

    When iron is present it binds to the protein causing it to move away from the mRNA and translation proceeds.

    Figure 7.2.3: (a) Transcription of the trp operon when tryptophan level is

    low. (b) Transcription of the trp operon when tryptophan level is high.

    Activity: Making modelsMake a model of the lac operon and of the trp operon.

    Use modelling clay, drinking straws, pieces of string or wool and anything else that you think will make a useful model.

    If possible attach your model to a piece of card to make a 3D poster.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    Positive control

    Positive control is when genes are only expressed when they are switched on by, for example, transcription factors or by catabolite activator protein (CAP).

    The default setting for these genes is OFF.

    Genes that are under positive control can only be expressed when an active regulator protein is present. Here the regulator protein does not interfere with initiation – it is essential for it to happen. It interacts with DNA and with RNA polymerase. The regulator protein must be present for transcription to occur.

    CAP-cAMP complex When E. coli has both glucose and lactose available as a respiratory substrate it metabolises glucose and represses use of lactose by repressing several operons including the lac operon. This is called catabolite repression and it is set in motion because glucose reduces the level of cyclic AMP (cAMP) in the cell. Figure 7.2.4 and the ensuing text explain how this happens.

    • cAMP binds to the product, CAP (catabolite activator protein), of the cap gene. • This protein is a positive control factor and its presence is needed to initiate

    transcription at dependent promoters. • CAP is only active in the presence of cAMP, which behaves as a small molecule

    inducer. • When glucose reduces cellular levels of cAMP, CAP becomes inactive and is

    unable to bind to the control region. • This in turn prevents RNA polymerase from initiating transcription of the

    β-galactosidase and lactose permease genes. • In the presence of cAMP the CAP factor can bind to it and to DNA and form

    complexes of cAMP-CAP-DNA. • CAP interacts directly with RNA polymerase and with DNA, changing its

    structure so that RNA polymerase can bind to the promoter. • In the lac operon the CAP-binding site is adjacent to the promoter but in other

    operons the CAP-binding site is well upstream of the promoter.

    Transcription factors

    In eukaryotes a common method of regulating gene expression is by transcription factor proteins that activate a promoter.

    Transcription factors contain one or more DNA-binding domains (DBDs) that attach to specific sequences of DNA, either enhancer or promoter regions, adjacent to the genes they regulate. Some genes have several binding sites for many different transcription factors that work together to regulate the expression of those genes. Some transcription factors lead to upregulation (increasing transcription) and some to downregulation (decreasing transcription).

    Transcription factors, each coded by a gene and present in various combinations, regulate our genes that enable us to make all the proteins for development and control of metabolism. They read and interpret our genetic code (think about how two actors can interpret the same script quite differently in different productions of the same play) so even identical twins with the same genome can have phenotypic differences due to differences in gene regulation.

    Key termsTranscription factors: Proteins that regulate transcription by helping or inhibiting binding of RNA polymerase.

    Catabolite: A compound/molecule generated by a catabolic (metabolic breakdown) reaction.

    CH2OO

    O

    PO

    O

    Adenine

    Deoxyribosesugar

    Figure 7.2.4: Cyclic AMP (cAMP) has a single phosphate (phosphoryl) group attached to both the 3’ and 5’

    positions of the sugar molecule.

    Activity: Making a flow chartMake a large flow diagram to show how the CAP-cAMP complex brings about catabolite repression.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    Taking it further: Some examples of how transcription factors workSome transcription factors are general and bind with RNA polymerase. Some differentially regulate the expression of genes by binding to enhancer regions of DNA.

    • Many are involved in development and can switch genes on or off as needed to direct the differentiation of cells.

    • The Hox transcription factors direct development of the basic body plan. • The transcription factor encoded by the SRY (sex-determining region) on the Y chromosome

    plays a major role in allowing XY mammals to develop as males. • Some, such as proto-oncogenes and tumour suppressor genes, are involved in regulating the

    cell cycle, cell division and apoptosis (programmed cell death). • Steroid hormones such as oestrogen can pass through the cell membrane and combine with

    oestrogen-receptor transcription factor which then passes into the nucleus and initiates transcription of certain genes involved in the bodily changes brought about by these hormones. The oestrogen receptor also attracts various epigenetic enzymes that alter the histone protein modifications.

    • Some pathogenic bacteria produce proteins that act as transcription activators and make host cells easier to infect.

    • Mutations in genes for transcription factors are responsible for some genetic disorders such as maturity onset diabetes of the young (MODY), a neurological disorder called Rett syndrome, developmental verbal dyspraxia, Li-Fraumeni syndrome, multiple cancers and some forms of breast cancer.

    RNA as gene regulators

    In every female cell, one of the X chromosomes is inactivated. This happens during early development and all the descendants of that cell have the same X chromosome inactivated. The chromosome in question transcribes a very long non-coding piece of RNA (ncRNA) containing many stop sequences, which then smothers the chromosome, inactivating nearly all of its genes.

    There are also short (about 21 bases long) ncRNAs that target mRNAs to prevent translation. This is called post-transcriptional gene silencing. These miRNAs (microRNAs) bind to the 3’ untranslated region (UTR) end of an mRNA molecule. If the base pair binding of the miRNA is perfect for all 21 bases, then the mRNA is degraded. If only some of the base triplets match, then translation is prevented. Because the match is not always perfect, one type of miRNA can regulate several types of mRNA, and hence several genes (see Figure 7.2.5 for an example of a use for a microRNA).

    Consider genetic diseases where a chromosome or piece of it is duplicated (for example, trisomy 21) – not only are more proteins encoded, but more regulatory pieces of RNA are encoded. These will disrupt cell metabolism and organ development. Over-expression of some miRNAs is associated with some cancers.

    Small interfering RNAs (siRNAs) work in much the same way as miRNAs. They are short lengths of antisense RNA that are complementary to, and can therefore bind to, the mRNA (copies of sense strands) of other genes, preventing translation and thus silencing genes. Researchers use them to add to cells and silence a particular gene to see the effects and find out more about the role of that gene.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    Some pharmaceutical companies have explored the idea of using siRNAs, but using nucleic acids as drugs is difficult as the molecules are large and more likely not to remain intact when introduced into patients’ bodies. However, some have applications in treating cancers.

    Abel is a freelance journalist and science correspondent. His first degree was in biochemistry from the University of Liverpool and he then gained a Masters in Science Journalism at City University London. This course gave him a thorough grounding in health, science and environmental journalism and he writes for many national newspapers as well as for National Geographic and popular magazines. He plans to write a book on landmark events in molecular genetics. He has recently reported on the ENCODE project.

    In this project, scientists in Japan, Spain, Singapore, the US and the UK have collaboratively worked on the Encyclopedia of DNA elements (ENCODE) and have found that 80% of the human genome is performing a specific function. Two % of the genome codes for proteins and the rest of the active DNA works like a control panel to regulate the expression of those protein-encoding genes or to regulate the regulatory genes. Many of these switches are linked to changes in risk for conditions such as heart disease, diabetes and mental illness. Researchers will target these switching genes to try to find out more about the underlying mechanisms involved in these chronic conditions and to develop new treatments for these conditions.

    Many transcription factors are either tumour suppressor genes or proto-oncogenes so mutation in their genes can lead to cancer – therefore research into these will have important clinical implications.

    In 2007, a paper in the journal Science revealed that the severe neurological developmental disorder, Rett syndrome, could be reversed in mice by giving them a chemical that activated the Mecp2 gene. These results were astonishing and offer hope that in the future there may be treatments for complex neurological disorders previously regarded as untreatable. In November 2010, a research paper published in the prestigious journal Nature showed that Rett syndrome can be caused by transposons or jumping genes – genes that copy and paste themselves elsewhere in the genome and disrupt gene regulation.

    Abel also does some work for the BBC and is hoping in the near future to present a programme about gene regulation.

    Science correspondent

    Figure 7.2.5: Biomedical illustration of human let-7b stem-loop.

    Researchers have reversed the growth of lung tumours in mice

    using a naturally occurring tumour suppressor microRNA let-7.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    Case study: Mutations to genes involved with speech in humansIn the 1990s scientists studied a family in London, known as the KE family, to try to find the cause of their speech problems. Over many generations, several members of this family had severe speech difficulties and could not move their mouths and facial muscles in order to talk, and also had some comprehension difficulties. By studying unaffected and affected members of the family they found that the inability to speak was caused by a mutation to the FOXP2 (forkhead box protein P2) gene – one of the FOX family of genes that code for transcription factors. FOXP2 is on chromosome 7.

    Other research indicates that mutations in the FOXP2 gene may regulate more than 100 other genes, including some that control development of the brain in embryos, and genes involved in growth of nerve cells and in nerve signalling. Mutations in this gene have been linked to switching off the CNTNAP2 gene, leading to language impairment as manifested in autism.

    • Explain why one of the symptoms of autism may be speech impairment.

    Taking it further: Epigenetics Genetically identical organisms are not always phenotypically identical. Environmental factors can influence gene expression without altering the genes themselves, and sometimes that expression is permanently changed and inherited by future generations.

    When one identical twin develops schizophrenia, rheumatoid arthritis or cancer, the chances of the other twin developing it are 50%.

    • Why are they not 100%?

    It is because of the way environmental factors have interacted with one twin’s genes and altered their expression without altering their base triplet sequence.

    Chemical groups can be added to some parts of DNA molecules and we have already seen that proteins affect gene expression. Methyl groups added to cytosine molecules within DNA inactivate genes, because certain proteins can now bind and suppress gene action, whereas acetyl groups added to lysine (amino acid) in histone protein tails activate genes. However, genes are rarely just on or off – this type of regulation can act like a dimmer switch or a volume control switch. Some histone modifications drive gene expression up and some drive it down. Either way, histone proteins are more than just packaging proteins, as was once thought.

    Although it is difficult to remove methyl groups from genes, adding an –OH group to the methyl group activates the gene again as the –OH group prevents the regulatory proteins binding. The silencers can themselves be silenced.

    In most cases of Rett syndrome (a severe neurological developmental disorder) the mutation is in a gene, MeCP2 on the X chromosome, that encodes a protein, MeCP2, that reads methylated DNA. The symptoms of Rett syndrome are severe, showing that molecular reading of the epigenetic code is important.

    Very few boys are born with Rett syndrome because if they have the mutated form of the gene, as they only have one X chromosome, they have no normal MeCP2 protein and the fetuses fail to develop.

    Girls have two X chromosomes and, although in each cell one X is inactivated, this inactivation is random so the one without a mutation is active in some cells. However, in this case all cells need sufficient amounts of the protein so when some body cells lack enough of it the fetus develops but with severe neurological disorders.

    Several studies have shown that what a woman eats during pregnancy affects the health of that offspring for the rest of its life, and may affect the health of the child’s offspring. A fungicide, vinclozolin, if given to pregnant rats when male fetuses are developing testes, produces testicular abnormalities and reduced fertility in the offspring and in their offspring’s offspring for the next three generations.

    An egg and a sperm are both specialised cells. However, when their two nuclei fuse, the fertilised egg becomes a totipotent stem cell. Soon after a sperm has penetrated the egg, methyl groups are stripped from paternal DNA; they are also removed from the maternal DNA but more slowly. This wipes epigenetic memory from the new individual’s genome. New epigenetic modifications are added as cells in the embryo become differentiated and the epigenome is being reprogrammed. However, some epigenetic modifications do get transmitted and these help cells to recognise which chromosomes are of maternal origin and which are of paternal origin – a phenomenon known as imprinting.

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    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    ActivityResearch one of the following topics and present your findings to the rest of your class:

    • data gathered during and after The Dutch Hunger Winter and its contribution to the study of epigenetics • how differentiated cells can be reprogrammed to become stem cells called iPS cells – induced pluripotent

    cells • Prader-Willi syndrome, Angelman syndrome and chromosomal imprinting • retrotransposons and their role in development of cancer • X chromosome inactivation (Lyonisation).

    Case study: Identical twins are not always genetically identicalIn one pair of monozygotic twin girls, one girl was healthy and the other severely affected by Duchenne muscular dystrophy where the muscle protein dystrophin, a large protein that acts as a shock absorber, is abnormal. The gene for dystrophin is on the X chromosome and has a recessive inheritance pattern. Females with one abnormal allele are usually symptomless carriers as they have enough X chromosomes with the normal allele for dystrophin protein switched on throughout their muscle cells. Remember that muscle is a syncytial tissue with many fused cells sharing many nuclei. The affected twin in this case had skewed X chromosome inactivation as during early development, in cells destined to become muscle tissue, nearly all her X chromosomes with the normal dystrophin allele became inactivated.

    1 What is the mechanism where one X chromosome in female cells is inactivated?

    More recent research has shown that sequences of DNA known as jumping genes (transposons or retrotransposons) are active in the brain during development and can make copies of themselves that are then inserted elsewhere in the genome. (Retrotransposons make their copies by first making RNA and then DNA.) Jumping genes are implicated in neurological developmental disorders such as autism, schizophrenia and Rett syndrome. They may also be responsible for some of the differences between people’s mental capacities, behaviour and attitudes.

    Using the information above:

    2 Suggest how in identical twins, reared under identical environmental conditions, (a) one may suffer from autism or schizophrenia and the other does not; (b) they may not always think the same or gain identical scores in cognitive ability tests.

    3 How do you think this information will affect traditional psychology studies that try to find out how much of our behaviour is genetic and how much is environmental by using twin studies, where they assume that identical twins are genetically identical in all aspects?

    ChecklistAt the end of this topic guide you should be familiar with the following ideas:

    much more of our DNA than was previously thought is known to be active; much of it acts to regulate other genes by affecting gene expression, which may be regulated by positive or negative control

    negative control is when genes are expressed unless they are switched off, acting at transcription or translation level – the default position for these genes is ON

    positive control is when genes are only expressed when they are switched on by, for example, transcription factors or by catabolite activator protein (CAP) – the default setting for these genes is OFF

    genetically identical individuals can have different levels of gene expression producing varied phenotypes

    gene regulation is key for cell differentiation and mutations to regulatory genes are associated with many health problems including cancers, diabetes, heart disease, mental health, and neurological and speech disorders.

    Activity: Flavr savr tomatoesResearch and find out the mechanism used for genetically modified Flavr Savr tomatoes.

  • 11

    Unit 7: Molecular biology and genetics

    7.2: Regulation of gene expression

    AcknowledgementsThe publisher would like to thank the following for their kind permission to reproduce their photographs:

    Corbis: MedicalRF.com; Science Photo Library Ltd: Carol & Mike Werner / Visuals Unlimited Inc 8

    All other images © Pearson Education

    We are grateful to the following for permission to reproduce copyright material:

    Figure 7.2.1: The E. coli lac operon (X, Y, O and P) and its regulator gene, from OCR A2 Biology, Pearson, page 112 and 113. Used with permission of Pearson Education Ltd.

    Every effort has been made to trace the copyright holders and we apologise in advance for any unintentional omissions. We would be pleased to insert the appropriate acknowledgement in any subsequent edition of this publication.