Chapter 19

Gene mutations

mutation is a change in the sequence of bases in DNA. Protein synthesis can be disrupted if the mutation occurs within a gene. The change in the sequence is caused by the substitution, deletion or insertion of one or more nucleotidees within a gene. If only one nucleotide is affected it is called a point mutation. The substitution of one nucleotide changes the codon which occurs. If the new codon codes for a different amino acid this will change primary structure of the protein. However, the degenerate nature of genetic code means that the new codon may still code for the same amino acid leading to no change in the protein made. The position and involvement of the amino acid in R group interactions within the protein will determine the impact of the new amino acid on the function of the protein. For example if the protein is an enzyme and the amino acid plays a  role in the active site, the protein may no longer act as a biological catalyst. The insertion or deletion of a nucleotide, or nucleotides, leads to a frameshift mutation. The triplet code means that the sequences are transcribed consecutively in non overlapping groups of 3, which is the reading frame of a sequence of bases, Each triplet corresponds to one amino acid. The addition or deletion of a nucleotide moves, or shifts, the reading frame of the sequence of bases, changing every successuve codon from the point of mutation. The same effect is seen however many nucleotides are added or deleted, unless the number of nucleotdies changed is a multiple of 3, as they code to full codons meaning that the reading frame will not be changed, but the protein formed will still differ due to the addition of a new amino acid.

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Effects and types of different mutations

  • No effect - there is no effect on the phenotype of an organism because normally functioning proteins are still synthesised, this is known as a silent mutation, meaning they have no effect on the protein made. They can occur in introns or code for the same amino acid due to the degenerate code, or may result in changes to the primary structure but don't change the overall structure. A conservative mutation occurs when the amino acid change leads to an amino acid coded for which has similar properties to the orginal so the effect is minimal.
  • Damaging - the phenotype of the an organism is affected in a negative way becuase proteins are no longer synthesised or proteins synthesised are non-functional, which can interfere with processes. For example monsense mututations result in the codon becoming a stop codon instead of coding for an amino acid. The result is a shortened protein which is normally non functional and harms the phenotype. Another type of negative mutation are missense mutations, which result in the incorporation of an incorrect amino acid(s) into the primary structure, and the result of this depends on the role that amino acid has on the structure, which is more likely to be negative if it is a non conservative mutation when the new amino acid coded for has different properties to the original.
  • Beneficial - few mutations result in a new useful characteristic in the phenotype. one example is the mutation in some cell surface membranes that makes some immune to HIV as it cannot bind or enter these cells.
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Causes of mutations

Mutations can occur spontaneously, often during DNA replication, but the rate of mutation is increased by mutagens. A mutagen is a chemical, physical or biological agent which causes mutations. The loss of a purine base (depurination) or a pyrimidine base (depyrimidination) often occurs spontaneously. The absence of a base cna lead to the insertion of an incorrect base through the complementary base pairing during DNA replication. free radicals, which are oxidising agents, cam also disrupt the nase parining during DNA replication. Vitamins A,C and E are known as anticarcinogens because of their ability to negate the effects of free radicals. Mutagens include:

  • Physical mutagens - these include raditions like x-rays which break one or both DNA strands, some can be repaired but mutaiton can occur during the process of repair.
  • Chemical mutagens - deaminating agents can chemically alter bases in DNA such as converting cytosine to uracil in DNA, changing the base sequence.
  • Biological agents - these include alkylating groups where methyl or ethyl groups can attach to bases resulting in the incorrect pairing of bases during replication and so changing the base sequence, base analogs which are incorporated into DNA in place of the usual base during repication, changing the base sequence, or viral DNA which may insert itself into a genome, changing the base sequence.
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Chromsome mutations and sickle cell anaemia

Gene mutations occur in single genes or sectoins of DNA whereas chromosome mutations affect the whole chromosome or numbes of chromosomes within a cell. They can also be caused by mutagens and normally occur during meiosis. As with gene mutatations they can often be silent but often lead to development issues, changes in chromosome structure include deletion, where a section of chromsome breaks off and is lost within the cell, duplication, where sections get duplicated on a chromosome, translocation where a section of one chromosome breaks off and joins another non-homologous chromsome, and inversion where a section of chromosome breaks off, is revered, and then joins back onto the chromosome. 

Sickle cell anaemia is a blood disorder where erythrocytes develop abnormally as is a result of a mutation in the gene coding for haemoglobin, there is a substitution of one base where thymine replaces adenine, making the 6th amino acid valine rather than glutamic acid on the beta haemoglobin chain. Glutamic acid is hydrophillic but valine is hydrophobic, when pO2 is low the hydrophobic valine binds to the hydrophobic region on adjacent Hb molecules, and this aggregation results in deformed erthryocytes which are less efficient in delivering oxygen to tissues. Heterozygous individuals only get mild symptoms of the condition but are resistant to malaira.

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Gene regulation

Enzymes needed as biological catalysts are constanly required and the genes that code for these are called housekeeping genes. Protein based hormones are only required by certian cells are certain points so are coded for by tissue specific genes. The entire genome of an orghanism is present in the nucleus of ebery cells, including genes that are not required by that cell so the expression of genes and the rate of synthesis of protein products has to be regulated. Genes can be turned on or off, and the rate of product synthesis increased or decreased depending on demand. Bacteria are able to respond to changes in their environment because of gene regulation, expressing genes only when the products are needed also prevents vital resources being wasted. Gene regulation is overall the same in prokaryotes and eukaryotes, however stimuli that cause changes in gene expression and the responses produced are more complex in eukaryotes. Multicellular organisms have to respond to changes the external and internal environment, gene regulation is required for cells to specialise and work in a coordinated way. Regulation can be:

  • Transcriptional - genes can be turned on or off. Post transcriptional - 
  • Post transcriptional - mRNA can be modified which regulates the type of proteins produced.
  • Translational - translation can be stopped or started at different points.
  • Post translational - proteins can be modified after synthesis which changes their functions.
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Transcription control

Chromatin remodelling: DNA is a vey long molecule and has to be wound around proteins called histones in eukaryotic cells, in order to be packaged into the nucleus of the cell. The resulting DNA/protein complex is called chromatin. Heterochromatin is tightly wound so they are visible during cell division whilst euchromatic is loosley wound DNA present in interphase. The transcription of genes is not possible when DNA is tightly wound as RNA polymerase cannot access the genes. The genes in euchromatin, however, can be freely transcribed. Protein synthesis does not occur at cell division but during interphase between divisions. This is simple form of regulation ensures the proteins necessary for cell division are synthesised and prevents the complex and energy consuming process of protein synthesis when cells are actually dividing.

Histone modification: DNA coils around histones because they are positively charged and DNA is negatively charged. Histones can be modified to increase or decrease the degree of packaging. The addition of acetyl groups (acetylation) or phosphate groups (phosphorylation) reduces the positive charge on the histones (making them more negative) and this causes DNA to coil less tightly, allowing certain groups to be transcribed. The addition of methy groups (methylation) makes the histones more hydrophobic so they bind more tightly together causing DNA to coil more tightly and preventing the transcription of genes. Epigentics is the term given to describe the control of gene expression by the modification of DNA.

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Transcription control II - Lac operon

An operon is a group of genes that are under the control of the same regulatory mechanism and are expressed at the same time. Operons are far more common in prokaryotes than eukaryotes due to their simpler genome structure. They are also a very efficient way of saving resources because if certain gene products are not needed, then all of the genes involved in their production can be switched off. Glucose is easier to metabolise and is the preferred respiratory substrate of E.coli and many other bacteria. If glucose is in short supply, lactose can be used as a respiratory substrate and different enzymes are needed to metabolise lactose. The lac operon is a group of 3 genes, lacZ, lacY and lacA involved in the metabolism of lactose. They are structural genes which code for 3 enzymes, galactosidase, lactose permease, and transacetylase) and they are transcribed onto a single molecule of mRNA. A regulatory gene, lacI, is located near to the operon and codes for a repressor protein that prevents the transcription of the structural genes in the absence of lactose. The repressor protein is constanly produced and binds to an area called the operator, which is also close to the structural genes. The binding of this protein prevents RNA polymerase binding to DNA and beginning transcription, and this is called down regulation. The section of DNA that is the binding site for RNA polymerase is called thepromotor. When lactose is present it binds to the repressor protein causing it to change shape so that it can no longer bind to the operator. As a result RNA polymerase can bind to the promoter, the 3 genes are transcribed, and the enzymes are synthesised. 

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Lac operon II - Role of cAMP

The binding of RNA polymerase still only results in a relatively slow rate of transcription that needs to be increased or up-regulated to produce the required quantity of enzymes to metabolise lactose efficiently. This is achieved by the binding of another protein, cAMP receptor protein (CRP), that is only possilbe when CRP is bound to cAMP. The transport of glucose into an E.coli cell decreases the levels of cAMP, reducing the transcription of the genes responsible for the metabolism of lactose. If both glucose and lactose are present then it will still be glucose, the preferred respiratory substrate, that is metabolised.

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Post-transcriptional/ pre-translational control

RNA processing: The product of transcription is a precursor molecule, pre-mRNA which is modified to form mature mRNA before it can bind to a ribosome and code for the synthesis of the required protein. A cap (modified nucleotide) is added to the 5' end and a tail (a long chain of adenine nucleotides) is added to the 3' end. These both help to stabilise the mRNA and delay degradation in the cytoplasm. The cap also aids binding of mRNA to ribosomes. Splicing also occurs where the RNA is cut at specific points, the introns (non coding DNA) are removed and the exons (coding DNA) are joined together. Both processes occur in the nucleus. ]

RNA editing: The nucleotide sequence of some mRNA molecules can also be changed through base addition, deletion or substitution. These have the same effect as point mutations and result in the synthesis of different proteins which may which may have different functions. This increases the range of proteins that can be produced from a single mRNA molecule or gene.

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Translational control/Post-translational control

The following mechanisms regulate the process of protein synthesis:

  • Degradation of mRNA - the more resistant the molecule the longer it will last in the cytoplasm, that is, a greater quantity if protein synthesised.
  • Binding of inhibitory proteins to mRNA prevents binding to ribosomes and proteins synthesis
  • Activation of initiation factors which aid the binding of mRNA to ribosomes (the eggs produce mRNA which is not required until after fertilisation when the initiation factors are activated).
  • Protein kinases - these are enzymes that catalyse the addition of phosphate groups to proteins, which changes their tertiary structure and so the function of a protein. Many enzymes are activated by phosphorylation, so protein kinases are therefore important regulators of cell activity, and are often activated themselves by cAMP.

Post-translational control involves modifications to the proteins that have been synthesised, which includes the addition of non-protein groups such as carbohydrate chains, lipids, or phosphates, modifying amino acids and the formation of bonds such as disulfide bridges, folding or shortening proteins, or modification by cAmp, for example in the lac operon cAMP binds to receptor proteins and increases the rate of transcription of the structural genes.

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Body plans

Living organisms come in all shapes and sizes, it is the same group of genes, however, that conrols the growth and developement of vastly different living forms. The regulation of the pattern of anatomical developements is called morphogenesis. These genes were discovered by scientists investiagting mutations in flies, which are small and have short life cycles so are popular choice for use in genetic studies.  

Homebox genes are a group of genes which all contain a homebox. The homebox is a section of DNA 180 base pairs long coding for a part of the protein 60 amino acids long that is highly conserved. This part of the protein, a homeodomain binds to DNA and swtiches genes on or off. Therefore, homebox genes are regulatory genes. The common ancestor of the mouse and humans lived  60 million years ago, and mutations accumulating since and evolution has resulted in two very different organisms, but many of the homebox genes present in the human and mouse still have identical nucleotide sequences. For example pax6 is one of the homebox genes that, when mutated, causes blindness due to the underdevelopment of the retina in mice, flies and humans, suggesting that it is involved in the development of eyes in all 3 species. Hox genes are one group of homebox genes only present in animals which are responsible for the correct positioning of body parts, and the order the genes appear on the chromsome is the order in which their effects are expressed, mammals have 4 clusters on different chromosomes.

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The layout of living organisms

Body plans are usually represented as cross sections through the organism showing the fundemental arrangement of tissue layers. Diplobastic animals have 2 primary tissue layers and tripoblastic animals have 3 primary tissue layers. A common feature of animals is that they are segmented, that is the segments of the vertebrates. These segments have multiplied over time and are specialised to for different functions. Hox genes in the head control the development of mouthparts and in the thorax control the development of wings, limbs or ribs. The individual vertebrae and associated structures have all developed from segments of the embyro called somites, which are directed by Hox genes to develop in a particular way depending on their position in the sequence. The body shape of most animals shows symmetry: Radial symmetry is seen in dipoblastic animals like jellyfish, they have no right or left sides, bilateral symmetry which is seen in most animals means the organisms have both left and right sides and a head and tail, rather than just a top and bottom.Mitosis, which results in cell division and proloferation, and apoptosis, which is programmed cell death, are both essential in shaping organisms.

The role of mitosis is to increase the number of cells leading to growth. The role of apoptosis is to remove unwanted cells and tissues to shape different body parts. Cells undergoing apoptosis can also release chemical signals which stimulate mitosis and cell proliferation leadinf to the remodelling of tissues. Hox genes regulate both mitosis and apoptosis.          

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Factors affecting the expression of regulatory gen

The expression of regulatory genes can be influenced by the environment, both internal and external. Stress can be defined as the condition when the homeostatic balance withing an organism is upset, This can be due to external or internal factors alll of which will impact the growth and development of an organism. Drugs can also affecrt the activity of regulatory genes, for example thalidomide.

The theory of recapitulation states that as organisms develop from a fertilised egg to embryo they repeat the evolutionary process that they have been through, and that is mimics the evolutionary history of an organism. This theory is not accepted as the studies show cancer cells also recapitulate ontolofy, referring to the discovery that genes originally exprfessed in the development of the embryo are expressed by cancerous cells.

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