20 - Gene Expression

• What are Mutations?

  Any change to the base (nucleotide) sequence of DNA. It can be caused by errors during DNA replication. The rate of mutation can be increased by mutagenic agents.
• What is a Substitution Mutation?

  One or more bases are swapped for another e.g. ATCG becomes ATTG. There are 3 possible consequences:

  1. Formation of a Stop Codon (Nonsense Mutation) - this would prematurely end the production of the polypeptide.
  2. Formation of a Codon for a different Amino Acid (Missense Mutation) - alters the structure
  3. Formation of a different codon for the SAME amino acid (Silent Mutation) - Can occur as genetic code is degenerate, so mutation has no effect
• What are Deletion Mutations?

  One or more bases are removed. One deleted base causes left frame shift, all bases shift to the left e.g. ATGCAT becomes ATCATG
• What are Addition Mutations (Insertion)?

  One or more bases are added. Right frame shift occurs, but if the bases added are a multiple of 3, effects are minimised e.g. ATGCCT become ATGACCT
• What are Duplication Mutations?

  One or more bases are repeated, Produces a right frame shift e.g. ATGCCT becomes ATGCCCCT
• What are Inversion Mutations?

  A group of bases become separated from the DNA sequence & rejoin at the same position but in inverse order e.g. ACT become TCA
• What are Translocation Mutations?

  A sequence of bases become separated from the DNA sequence & are inserted either within the same chromosome or moved onto a different chromosome. Has massive effects such as cancer & reduced fertility.
• How do mutations alter protein structure?

  • Changes the base sequence
  • Which changes the codon sequence & therefore sequence of complementary anticodons change
  • Changes the amino acid sequence, coding for a different polypeptide. It has a different tertiary (3D) structure by changing the bonds meaning it cannot function properly
• Causes of Mutations:

  
  

  Mutagenic Agents

  • High energy ionising radiation (e.g. α (alpha) & β (beta), UV light, X-rays)
  • Chemicals (Nitrogen dioxide disrupts DNA, Benzopyrene - found in tobacco smoke - is a powerful mutagen that inactivates a tumour-suppressor gene)
• Mutations Pros:

  • Produce genetic diversity for natural selection & speciation
  • Could be advantageous
• Mutations Cons:

  • They're usually harmful
  • Can make an organism less adapted to their environment
  • They can occur in body cells, impacting normal cellular activity, such as cell division causing cancer
• What is the Start Codon?

  AUG -> Methionine
• How many Stop Codons are there?

  3/64 amino acids
• Mutations in Genes can cause Uncontrolled Cell Growth:

  1. Mutations that occur after fertilisation (e.g. in adulthood) are called acquired mutations
  2. If mutations occur in genes that control cell division, it can cause uncontrolled cell division, resulting in a tumour (a mass of abnormal cells)
  3. Cancers are tumours that invade & destroy surrounding tissue
• Tumour Suppressor Genes:

  • Tumour Suppressor Genes can be inactivated if a mutation occurs in the DNA sequence
  • When functioning normally, tumour suppressor genes slow cell division by producing proteins that stop cells dividing or cause them to self-destruct (apoptosis)
  • If a mutation occurs in a tumour suppressor gene, the protein isn't produced. The cells divide uncontrollably, resulting in a tumour

  
• Proto-Oncogenes:

  • The effect of a proto-oncogene can be increased if a mutation occurs in a DNA sequence.
  • A mutated proto-oncogene is called an oncogene
  • When functioning normally, proto-oncogenes stimulate cell division by producing proteins that make cells divide
  • If a mutation occurs in a proto-oncogene, the gene can become overactive. This stimulates the cells to divide uncontrollably, resulting in a tumour

  
• What are Malignant Tumours?

  • Malignant tumours are cancerous
  • They grow rapidly & destroy surrounding tissue
  • Cells can break off tumours and spread to other parts of the body in the bloodstream or lymphatic system
• What are Benign Tumours?

  • Benign tumours are not cancerous
  • They grow slower & are often covered in fibrous tissue that stops cells invading other tissues.
  • Benign tumours are often harmless, but they can cause blockages and put pressure on organs.
  • Some Benign tumours can become Malignant
• How do Tumour Cells differ from normal cells?

  • They have an irregular shape
  • Nucleus is larger & darker
  • They don't produce all the proteins needed to function correctly
  • They have different antigens on their surface
  • They don't respond to growth regulating processes
  • They divide more frequently than normal cells

  
• How does Methylation cause Tumour Growth?

  1. Methylation means adding a methyl (-CH3) group onto something
  2. Methylation of DNA controls whether or not a gene is transcribed (copied into mRNA) and translated (turned into a protein)
  3. Hypermethylation = too much & Hypomethylation = too little
  4. The growth of tumours can be caused of abnormal methylation of certain cancer-related genes
• How does Methylation affect Tumour Suppressor Genes?

  When Tumour Suppressor Genes are hypermethylated, the genes are not transcribed - so the proteins they produce to slow cell division aren't made. This means cells divide uncontrollably by mitosis & tumours can develop
• How does Methylation affect Proto-Oncogenes?

  Hypomethylation of proto-oncogenes causes them to act as oncogenes - increasing the production of the proteins that encourage cell division. This stimulates cells to divide uncontrollably, causing the formation of tumours
• Oestrogen:

  • Increased exposure to oestrogen over an extended period of time is thought to increase a woman's risk of breast cancer.
  • This exposure can be due to starting menstruation early, menopause late or by taking oestrogen-containing drugs
• How does Oestrogen contribute to breast cancer?

  1. It can stimulate breast cells to divide & replicate. This naturally increases the probability of mutations occurring & cancer developing
  2. This stimulated division means that if a cell does become cancerous, oestrogen may further assist replication of the cancerous cells
  3. Other research suggests is able to introduce mutations directly into the DNA of breast cells, increasing chance of cancer developing.
• Risk Factors of Cancers:

  • Genetic Factors - some cancers are linked to specific inherited alleles. If you inherit that allele, you're more likely to get that type of cancer (not 100% of the time)
  • Environmental Factors - exposure to radiation, lifestyle choices such as smoking, alcohol consumption & a high-fat diet all increase chance of developing certain cancers
• Why is it difficult to interpret relative contributions of Genes & Environment to cancer?

  The data is polygenic, being affected by many different genes and environmental factors. This makes it hard to draw conclusions about which factors are having the greatest effect.
• The Effects of Genetic & Environmental Factors on Breast Cancer:

  • There's positive correlation between relatives affected & incidence rate of women with cancer
  • The effect of family history decreases with age, but incidence rate is always higher in women with close family history of the disease
  • Suggests a genetic link

  
• Incidence Rate of Breast Cancer in women compared to number of alcoholic drinks consumed:

  • Incidence of breast cancer increases with age, positive correlation
  • There is also a positive correlation between the number of alcoholic drinks consumed and incidence of breast cancer
  • Alcohol consumption is an environmental factor

  
• How Knowing the Mutation prevents cancer:

  1. If a specific cancer-causing mutation is known, we can screen for it in the person's DNA (E.g. mutated allele of BRCA1 tumour suppressor gene)
  2. Meaning preventative steps can be taken (E.g. getting a mastectomy or having regular screenings)
  3. Knowing about specific mutations can develop more sensitive tests, leading to earlier accurate diagnosis
• How Knowing the Mutation treats & cures cancer:

  1. The treatment for cancer differs with each mutation, so knowing the specific mutation helps to develop drugs to effectively target them
  2. Some cancer-causing mutations require more aggressive treatment, so it's beneficial to produce the best treatment plan (e.g. if a mutation is known to cause aggressive cancers, doctors can proactively attack it with radiotherapy or surgery)
  3. Gene therapy is where faulty alleles in a person's cell are replaced with working alleles.
• What are Stem Cells?

  Unspecialised cells develop into other types of cells. They divide to become new cells, which then become specialised.
• What are Totipotent stem cells?

  They are located in the early mammalian embryo. They are only present in mammals in the first few cell divisions of an embryo & they can develop into any type of body cell in an organism, including the cells that make up the placenta
• What are Pluripotent stem cells?

  They are located in embryos. After Totipotent stem cells have divided a few times, they become Pluripotent. They can still specialise into any cell in the body, but lose the ability to become the cells that make up the placenta.
• What are Multipotent stem cells?

  They are found only in mature mammals, in the bone marrow. They are able to differentiate into a few different types of cell. For example, both red & white blood cells can be formed from multipotent stem cells found in bone marrow.
• What are Unipotent stem cells?

  They are found in mature mammals. They can only differentiate into one type of cell. For example, there is a type of unipotent stem cell that can only produce epidermal skin cells.
• How are stem cells specialised?

  1. They all contain the same genes - but during development, not all are transcribed & translated
  2. Under the right conditions, some genes are expressed & others are switched off
  3. mRNA is only transcribed from specific genes
  4. The mRNA from these genes is then translated into proteins
  5. These proteins modify the cell - they determine the cell structure & control cell processes (including the expression of more genes, which produces more proteins)
  6. Changes to the cell produced by these proteins cause the cell to become specialised. These changes are irreversible.

  
• Example of Cell Specialisation:

  1. Red blood cells are produced from a type of stem cell in the blood marrow. They contain lots of haemoglobin & have no nucleus (to make room for more haemoglobin)
  2. The stem cell produces a new cell in which the genes for haemoglobin production are expressed. Other genes, i.e. genes to remove the nucleus, are also expressed. Many other genes are switched off, resulting in a specialised red blood cell.
• Cardiomyocytes:

  1. Cardiomyocytes are heart muscle cells that make up of lots of heart tissue. In mature mammals, everyone thought this couldn't be regenerated -which is a problem in the case of heart damage
  2. Recent research suggests our hearts have some regenerative capability
  3. They think a small supply of unipotent stem cells in the heart can replace old or damaged cardiomyocytes

  • Some think it's a slow process & that it's possible some cardiomyocytes are never replaced in a person's life
  • Others think it occurs quickly & that every cardiomyocyte is replaced several times in a lifetime
• Stem Cell Therapies:

  1. Bone marrow contains stem cells that can specialise to any type of blood cell. Bone marrow transplants can replace a faulty bone marrow that produces abnormal blood cells
  2. This has been used to treat leukaemia & lymphoma
  3. It has also treated some genetic disorders such as sickle-cell anaemia & severe combine immunodeficiency (SCID)
• How is SCID treated by Bone Marrow transplants?

  • People with SCID have a poor immune system as their white blood cells are defective, so they can't defend against/are very susceptible to infections
  • Bone marrow transplants replace the faulty bone marrow with one containing functional stem cells
  • They differentiate to produce functional white blood cells, that can identify & destroy pathogens, allowing the immune system to function properly