8A: Mutations and gene expression

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  • Created by: DBaruch
  • Created on: 06-02-17 10:26

Different types of mutations

  • Any change to the base sequence of DNA is called a mutation. Mutations can be caused by errors during DNA replication. The rate can be increased by mutagenic agents.
  • Substitution- one or more bases are swapped for another
  • Deletion- one or more bases are removed
  • Addition- one or more bases are added
  • Duplication- one of more of the bases are repeated
  • Inversion- a sequence of bases is reveresed
  • Translocation- a sequence of bases is moved from one location in the genome to another. This could be movement within the same chromosome or movement to a different chromosome
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Mutations and proteins

  • Not all mutations affect the order of amino acids in a protein. The degenerate nature of the genetic code means that some amino acids are coded by more than one DNA triplet. This means that not all types of mutation will always result in a change to the amino acid sequence of the polypetide.
  • Some substitutions will still code for the same amino acid.
  • Sometimes, inversion mutations don't cause a change in amino acid sequence either.
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Frameshift mutations

  • Some mutations have a huge effect on the base sequence of a gene. Additions, duplications and deletions within a gene will almost always change the amino acid sequence of a polypeptide. That's because these mutations all change the number of bases in the DNA code. This causes a shift in the base triplets that follow, so that the triplet code is read in a different way.
  • Image result for frameshift mutation (http://study.com/cimages/multimages/16/insertion_mutations1.png)
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What are mutagenic agents

  • Acting as a base- chemicals called base analogs can substitutes for a base during DNA replication, changing the base sequence in the new DNA. For example 5-bromouracil is a base analog that can substitute for thymine. It can pair with guanine (instead of adenine), causing a substitution mutation in new DNA
  • Altering bases- some chemicals can delete or alter bases. For example (alkylating agents can add an alkyl group to guanine, which changes the structure so that it pairs with thymine (instead of cytosine)
  • Changing the structure of DNA- some types of radiation can change the structure of DNA, which causes problems during DNA replication. For example UV radiation can causess adjacent thymine bases to pair up together
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Cell division and cancer

  • Mutations that occur in individual cells after fertilisation are called acquired mutation. If these mutations occur in the genes that control the rate of cell division, it can cause uncontrolled cell division. If a cell divides uncontrollably the result is a tumour- a mass of abnormal. Tumours that invade and destroy surrounding tissue are called cancers. There are 2 types of gene that control cell division- tumour suppressor genes and proto-oncogenes. Mutations in these genes can cause cancer.
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Tumour suppressor genes

  • 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 gene will be inactivated. The protein it codes for isn't produced and the cells divide uncontrollably resulting in a tumour.
  • Image result for tumour suppressor genes
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Proto-oncogenes

  • 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. A mutated proto-oncogene is called an oncogene
  • Image result for proto-oncogenes (http://www.zo.utexas.edu/faculty/sjasper/images/19.13.gif)
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Tumours and cancers

  • Malignant tumours- they are cancers. They usually grow rapidly and invade and destroy surrounding tissues. Cells can break off the tumours and spread to other parts of the body in the bloodstream or lymphatic system
  • Benign tumours- they are not cancerous. They usually grow slower than malignant tumours and are often covered in fibrous tissue that stops cells invading other tissues. They are often harmless, but they can cause blockages and put pressure on organs. Some benign tumours can become malignant
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Tumour cells

  • They differ from normal cells in different ways; the nucleus is larger and darker than in normal cells and may have more than 1 nucleus, they have irregular shape, 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.
  • Image result for tumour cell differences
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Tumour cells

  • They differ from normal cells in different ways; the nucleus is larger and darker than in normal cells and may have more than 1 nucleus, they have irregular shape, 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.
  • Image result for tumour cell differences
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Abnormal methylation

  • Methylation menas adding a methyl group onto something. Methylation of DNA is an important method of regulating gene expression- it can control whether or not a gene is transcribed and translated. When methylation is happening normally it plays a key role in the body
  • When it happens too much (hypermethylation) or too little (hypomethylation) that it becomes a problem. The growth of tumours can be caused by abnormal methylation of certain cancer-related genes
  • When tumour suppressor genes are hypermethylated the genes are not transcrbied- so the proteins they produce to slow cell division aren't made. This means that cells are able to divide uncontrollably, which causes the formation of tumours.
  • Hypomethylation of proto-oncogenes causes them to act as oncogenes- increasing the the production of the proteins that encourage cell division. This stimulates cells to divide uncontrollably, which causes the formation of tumours
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Role of oestrogen in Breast cancer

  • Some women may be exposed to more oestrogen than others. Increased exposure to oestrogen may be the result of starting menstruation earlier than usual, starting menpause later, or taking oestrogen-containing drugs like HRT.
  • Increased exposure is thought to increase the risk of developing breast cancer. It is not known how but there are a few theories.
  • Oestrogen can stimulate certain breast cells to divide and replicate. The fact that more cell divisions are taking place naturally increases the chance of mutations occuring, and increases the chance of cells becoming cancerous
  • Oestrogens ability to stimulate cell division can lead to cancerous cells being assisted in rapid replication and oestrogen can actually introduce mutations directly into the DNA of certain breast cells
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Risk factors for cancer

  • There is no single cause of cancers, however there are lots of different "risk factors". They can either be genetic or environmental
  • Genetic- some cancers are linked with specific inhereited alleles. If you inherit that allele you are more likely to get that type of cancer.
  • Environmental factors- exposure to radiation, life choices such as smoking, alcohol consumption and low exercise have all been linked to an increased chance of developing some cancers
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Preventing cancer

  • If a specific cancer-causing mutation is known, then it is possible to screen for the mutation in a persons DNA- it is possible to screen for the mutated allele of BRCA1 (the tumoour suppressor gene, which increase a womans risk of developing breast cancer)
  • Knowing about the increased risk means that preventative steps can be taken to reduce it- a woman with the BRCA1 mutation may choose to have a mastectomy (removal of the breast) which reduces the risk of breast cancer forming, people with the mutation maybe screened more often to look for early signs.
  • Knowing about specific mutations also means that more sensitive tests can be developed, which can lead to earlier and more accurate diagnoses- people with a mutated APC tumour suppressor gene have frequent colonoscopies to diagnose hereditary colon cancer earlier
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Treating and curing cancer

  • The treatment for cancer can be different for different mutations, so knowing how specific mutations acutally cause cancer can be very useful for developing drugs to effectively target them- breast cancer caused by a mutation of the HER2 proto-oncogene can bre treated with the drug, Herceptin. This drug binds specifically to the altered HER2 protein receptor and suppresses cell division and tumour growth.
  • Some cancer causing mutations require more aggressive treatment than others- if a mutation is known to cause a fast growing cancer, it may be treated with higher doses of radiotherapy or by removing larger areas of the tumour and surrounding tissue
  • Gene therapy- where fautly genes in a persons cells are replaced by working versions of those alleles- if you know that the cancer is being caused by an inactived tumour suppressor genes, it is hoped that gene therapy will be able to provide working versions of the genes
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What are stem cells?

  • Multicellular organisms are made up from many different cell types that are specialised for their function. All specialised cell types orignally came from stem cells. Stem cells are unspecialised cells that can develop into other types of cell. Stem cells divide to become new cells, which then become specialised
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Where are stem cells found?

  • All multicellular organisms have some form of stem cell. Stem cells are found in the embryo and in some adult tissues that need to be replaced. 
  • Stem cells that can develop into any type of body cell in an organism are called totipotent cells. Totipotent stem cells are only present in mammals in the first few cell divisions of an embryo. After this point embryonic stem cells become pluripotent. They can still turn into an cell in the body but lose the ability to become the cells that make up the placenta.
  • The stem cells in adults are either multipotent or unipotent. Multipotent stem cells are able to differentiate into a few different types of cell. Unipotent stem cells can only differentiate into 1 type of cell
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Becoming specialised

  • Stem cells become specialised because during their development they only transcribe and translate part of their DNA. Stem cells all contain the same genes- but during development not all of them are transcribed and translated. Certain genes are switched on and certain genes are switched off.
  • Genes that are expressed get transcribed into mRNA, which is then translated into proteins. These proteins modify the cell. This causes the cell to become specialsed and it is difficult to reverse
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Caridomyocytes

  • They are heart muscle cells that make up alot of the tissue in our hearts. Scientists used to believe that heart muscles couldn't regenerate and that when the heart becomes damaged it cannot repair itself
  • Recent research shows that our hearts have a regenerative capability through a small supply of unipotent stem cells in the heart that make new cardiomyocytes
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Current Stem cell therapies

  • Bone marrow contains stem cells that can form any type of blood cell. Transplants can be used to replace the faulty bone marrow in patients that produce abnormal blood cells.
  • The technique has been used successfully to treat leukaemia and lymphoma. It has also been used to treat some genetic disorders such as sick-cell anaemia and severe combined immunodeficiency (SCID)
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Future stem cell therapies

  • Spinal cord injuries- stem cells could be used to replace damaged nerve tissue
  • Heart tissue and damage caused by heart attacks
  • Bladder conditions- stem cells could be used to grow whole bladders, which are then implanted in patients to replace diseased ones
  • Respiratory diseases- donated windpipes can be stripped down to their simple collagen structure and then covered with tissue generates by stem cells. This can then be transplanted into patients
  • Organ transplants- organs could be grown from stem cells to provide new organs for people on donor waiting lists
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Sources of stem cells

  • Adult stem cells- they can be obtained relatively easily, with very little risk involved. They are not as flexible as they can only specialise into a limited range of cells (they are mutlipotent)
  • Embryonic stem cells- these are obtained in the early stages of development. Embyros are created using IVF- egg cells are fetilised outside the womb. Once the embryos are 4-5 days old, stem cells are removed from them. Embyronic stem cells can divide an unlimited amount of times and develop into all types of body cells (they're pluripotent)
  • Induced pluripotent stem cells (iPS cells)- they are created in labs, the process involves "reprogramming" specialised adult body cells so they become pluripotent. The adult cells are made to express a series of transcription factors that are normally associated with pluripotent stem cells. One way to introduce transcription factors is through infecting adult body cells with modified viruses. The virus has the genes coding for the transcription factors within its DNA. When the adult cell is infected the genes are passed into the adult cells DNA
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Ethical considerations

  • Obtaining stem cells from embryos created by IVF raises ethical issues because the procedure results in the destruction of an embryo that could become a fetus if placed in the womb.
  • Some people believe that at the moment of fertilisation an individual is formed that has the right to life.
  • Some people think that scientists should only use adult stem cells because their production doesn't destroy an embryo. But adult stem cells are not pluripotent
  • With iPS cells they could be made from the patients own cells, which would be genetically identical, they could then be used to grow new tissue or an organ that the patients body wouldn't reject
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Controlling transcription

  • All the cells in an organism carry the same genes but the structure and function of different cells varies. This is because not all the genes in a cell are expressed (transcribed and used to make a protein). Because different genes are expressed, different proteins are made these proteins modify the cell- they determine the cell structure and control cell processes. The transcription of genes is controlled by protein molecules called transcription factors
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The role of transcription factors

  • In eukaryottes, transcription factors move from the cytoplasm to the nucleus. In the nucleus they bind to specific DNA sites called promoters, which are found near the start of their target genes. Transcription factors control expression by controlling the rate of transcription
  • Some transcription factors called activators, stimulate or increase the rate of transcription, for example they help RNA polymerase bind to the start of the target gene and activate transcription. Other transcription factors, called repressors, inhibit or decrease the rate of transcription, for example they bind to the start of the target gene, preventing RNA polymerase from binding stopping transcription
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Oestrogen

  • Oestrogen is a steroid hormone that can affect transcription by binding to a transcription factor called an oestrogen receptor, forming an oestrogen-oestrogen receptor complex
  • The complex moves from the cytoplasm into the nucleus where it binds to specific DNA sites near the start of the target gene. The complex can act as an activator of transcription for example helping RNA polymerase bind to the start of the target gene.
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RNAi- siRNA

  • Once mRNA has been transcribed it leaves the nucleus for the cytoplasm. In the cytoplasm, double stranded siRNA associates with several proteins and unwinds. One of the resulting single strands of siRNA is selected and the other strand is broken down. The single strand of siRNA then binds to the target mRNA. The base sequence of the siRNA is complementary to the base sequence in sections of the target mRNA. The proteins associated with the siRNA cut the mRNA into fragments- so it can no longer be translated. The fragments move into a processing body which contains "tools" to degrade them
  • A similar process happens with miRNA in plants. like siRNA, the base sequence of plant mrRNA is complementary to it target mRNA sequence and so binding results in the cutting up and degradtion of the mRNA,
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miRNA in mammals

  • In mammals, the miRNA isn't usually fully complementary to the target mRNA. This makes it less specific than siRNA and so it may target more than one mRNA molecule. When miRNA is first transcribed, it exists as a long folded strand. It is processed into a double strand, and then into 2 single strands, by enzymes in the cytoplasm. Like siRNA, one strand associates with proteins and binds to target mRNA in the cytoplsms. Instead of the proteins associated with the miRNA cutting mRNA into fragments, the miRNA-protein complex physically blocks the translation of the target mRNA. The mRNA is then moved into a processing body, where it can be either be stored of degraded. When its stored it can be returned and translated at another time
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How does epigenetic control work

  • In eukaryotes, epigenetic control can determine if a cell is turned on or off. It works through the attachment or removal of chemical groups to or from DNA or histone proteins. These epigenetic marks don't alter the base sequence of DNA. Instead, they alter how easy it is for the enzymes and other proteins needed for transcription to interact with and transcribe the DNA
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Inheriting epigenetic changes

  • Organisms inherit their DNA base sequence from their parents. Most epigenetic marks on the DNA are removed between generations, but some escape the removal process and are passed on to offspring. This means that the expression of some genes in the offspring can be affected by environmental changes that affected their parents or grandparents
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Increased methylation of DNA

  • Methylation is when a methyl group is attached to the DNA coding for a gene. The group always attches at a cpG site, which is where a cytosine and guanine base are next to each other in the DNA (linked by a phophodiester bind). Increased methylation changes the DNA structure so that the transcriptional machinery can't interact with the gene, so the gene is not expressed
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Decreased acetylation of histones

  • Histones are proteins that DNA wraps around to form chromatin, which makes up chromosomes. Chromatin can highly condensed or less condensed. How condensed it is affects the accessibility of the DNA and whether or not it can be transcribed.
  • Histones can epigenetically modified by the addition or removal or acetyl groups. When histones are acetylated, the chromatin is less condensed. This means that the transcriptional machinery can access the DNA, allowing genes to be transcribed. When acetyl groups are removed from the histones, the chromatin becomes highly condensed and genes in the DNA can't be transcribed because the transcriptional machinery can't physically access them. Histone deacetylates (HDAC) enzymes are responsible for removing acetyl groups
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Development of disease

  • Fragile-X syndrome- is a genetic disorder that can cause symptoms such as learning and behavioural difficulties, as well as characteristic physical features. It caused by heritable duplication mutation in a gene on the X chromosome called FMR1. The mutation results in the short DNA sequence CGG being repeated more than usual. This means there are more CpG sites in the gene. This leads to increased methylation, which switches the gene off, this means that the protein that it codes for isnt produced.
  • Angelman syndrome- is a genetic disorder that affects the nervous system. It is caused by a mutation or deletion of a region of chromosome 15. In most cases, the maternal allele in the affected region of chromosome 15 is missing. The paternal allele is present but is switched off by methylation so the gene is not transcribed and the protein not produced
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Treating disease

  • Epigenetic changes are reversible, which makes them targets for new drugs for diseases they cause. The drugs are designed to reverese the epigenetic changes. For example, increased methylation is an epigentic change that can lead to a gene being switched off. Some drugs stop this methylation.
  • Decreased acetylation of histones can also lead to genes being switched off. HDAC inhibitor drugs, e.g. romidepsin, can be used to treat diseases that are caused this way. The drugs work by inhibiting the activity of histone deacetylase (HDAC) enzymes, which are responsible for the removing the acetyl groups from the histones. Without the activity of HDAC enzymes, the genes remain acetylated and the proteins they code for can be transcribed. These changes occur normally in a lot of cells so the drugs have to be specific.
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Evaluating data about influences on phenotypes

  • Overeating- It was previously thought that overeating was as a result of environmental factors, however food consumption leads to the release of dopamine and would stop being released when the person stops eating. Researchers found that people with a particular allele had 30% less dopamine receptors and they were more likely to overeat as they wouldn't stop eating as dopamine levels increased.
  • Antioxidants- antioxidants are found in diet and they can prevent chronic diseases. Scientist thought the berries produced by different species of plant contained different levels of antioxidant depending on genetic factors. However experiments carried out show that environmental factors caused a great deal of variation
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Twin Studies

  • Studies of identical twins can be useful for determining the importance of genetic and environmental factors in the development of certain diseases. Comparisons between the prevalence of Alzheimers dieases in identical twins and non-identical twins have shown that the dieases has a genetic risk. However, the disease is not always found in both identical twins, which suggest environmental factors play a part, it is thought that genetics account for about 80% of the risk
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