Mutations

• Mutations

  • In contrast to epigenetic changes, mutations are permanent changes to the actual sequence of DNA bases (A, T, C & G).
  • These changes can lead to alterations or absence of proteins, and can affect the appearance of an organisms offspring (phenotype).
  • Mutations generally occur during DNA replication or during cell division (mitotic or meiotic division).
  • This occurs when DNA is unwound and bases are exposed and vulnerable to damage.
  • Two main reasons for mutations:
  • Damaged during DNA replication/cell division.
  • Incorrect bases are inserted during DNA replication.
• Epigenetics

  • Epigenetics is the study of how external factors affect gene expression.
  • These are generally due to environmental factors.
  • Our DNA develops ‘chemical tags’ called collectively epigenome.
  • Two main types of chemical tags:
  • Methylation of cytosine bases.
  • Acetylation of histone proteins.
  • The chemical tags don’t affect the DNA base sequence (A, C, G, T), but change how cells read the DNA and express genes.
  • These changes can be passed on from one generation to the next if it occurs in gametes (sex cells).
• Mutations

  • It’s thought that each species on Earth evolved from a common ancestor.
  • DNA differs from one species to another due to the accumulation of DNA mutations over millions of years.
  • Mutations are random events and occur spontaneously.
  • Environmental factors can change rate of mutations.
• Impacts of Mutations

  • The impacts of mutations include:
  • Genetic disease: due to the incorrect polypeptide being produced, or a mis-shaped protein being made. If protein is required for cell function and not there, can lead to disease or genetic disorders.
  • Cancer: mutations in proteins that regulate cell division/cycle can lead to uncontrolled cell division, leading to formation of tumours.
• Types of Mutations

  • Point mutations (change in one base pair) occur in human cells every day, usually due to mistakes in DNA replication.
  • These generally occur in non-coding DNA (introns), and have little to no effect on the cell/organism. If mutation occurs to coding DNA (exons), it can have affects to the cell/organism.
  • The three types of point mutations are:
  • Substitution
  • Insertion
  • Deletion
  • Effects of point mutations depend on whether it is: silent, missense, nonsense or a frameshift mutation.
• Base Substitutions

  • Base substitutions occur when one nucleotide (A, T, C or G) is substituted for a different one. An example being guanine being replaced with a cytosine during DNA replication, which codes for a different amino acid (see below image).
• Base Deletions

  • Base deletions occur where one nucleotide is removed from the DNA.
  • These generally cause frameshift mutations, affecting the codon read, amino acid made, and polypeptide produced, of many amino acids.
• Base Insertions

  • Base insertions occur where one nucleotide is inserted/placed into the DNA.
  • These generally cause frameshift mutations, affecting the codon read, amino acid made, and polypeptide produced, of many amino acids.
• Silent Mutations

  • Silent mutations occur when a base substitution results in an altered codon
  • This creates the same amino acid, resulting in the same polypeptide & protein being produced.
• Missense Mutations

  • Missense mutations occur when a base substitution results in an altered codon that codes for a different amino acid, resulting in a different polypeptide and protein being produced.
• Nonsense Mutations

  • Nonsense mutations occur when a base substitution results in an altered codon that codes for stop codon, resulting in a shortened polypeptide
• Large Scale Mutations

  • Often occur during meiosis
  • Mutations are able to make large scale (multiple bases) changes to the structure of, and also number of chromosomes in a cell.
• Types of Large Scale Mutations

  • Deletion: genetic material is broken off a section of chromosome and lost.
  • Duplication: genetic material is duplicated, resulting in extra copies of the gene on the chromosome.
  • Translocation: part of a chromosome detaches and moves to a new chromosome.
  • Inversion: section of broken chromosome is inserted back into chromosome, but in reverse order.
  • Insertion: a section of DNA from one chromosome moves to another.
  • Aneuploidy: chromosome mutations which lead to abnormal number of chromosomes.
• Factors that Increase Rate of Mutations

  • As previously mentioned, mutations occur spontaneously in organisms, but the natural rate is quite low.
  • Rate of mutation can be altered by factor called mutagens.
  • Type of factors include:
  • Physical
  • Chemical
  • Biological
• Ionising Radiation

  • Most common physical agents that affect rate of mutation are high energy radiation like X-rays and UV (ultraviolet) light.
  • Humans are exposed to both natural and other forms of radiation.
  • UV radiation from the Sun can create bonds between DNA bases that don’t normally exist, disrupting transcription and translation.
  • Ionising radiation (e.g. X-rays) may create ions which break the sugar phosphate backbones or base pairs in DNA.
• Mutagenic Chemicals

  • Certain chemicals humans are exposed to can increase mutation rates. Some of these chemicals are:
  • Cigarette smoke
  • Asbestos (used in old buildings)
  • Benzene (in petrols)
  • Vinyl chloride (in plastics)
  • Etoposide (chemotherapy drug)
  • These chemicals generally:
  • Cause chemical changes to particular bases.
  • Mimic shape of normal bases, disrupting DNA replication.
  • Disrupt cell division, leading to chromosomal errors.
  • Cause direct damage to chromosomes, can lead to breaks.
• Viruses

  • Viruses are a type of infectious disease that rely on host cells to survive and reproduce.
  • Viruses are able to induce the usual substitution, insertion and deletion mutations.
  • Viruses generally insert their DNA/RNA into the host cell, which joins in with the host cells genetic material.
  • This can disrupt the way DNA is read.
  • Some viruses also induce the host to secrete chemicals that can lead to mutations.
• Germline vs Somatic Cells

  • Germline Cells
  • Any cells in the testes or ovaries that produce sex cells (gametes), so essentially sperm and egg cells.
  • Germline cell mutations can be inherited by cells in future generations.
  • This means the faulty/mutated gene is replicated in all new cells.
  • Somatic Cells
  • Refers to every cell in the body, excluding gametes.
  • Somatic cell mutations can cause serious diseases, but won’t be inherited by offspring.
• Sickle Cell Anaemia

  • Is causes by a gene on chromosome 11, which codes for the production of haemoglobin protein.
  • A missense mutation provides a single amino acid change, causing abnormally shaped red blood cells.
  • This decreases the amount of oxygen a red blood cell can carry.
• Cystic Fibrosis (CF)

  • A gene (CFTR) on chromosome 7 makes a protein which controls movement of salt and water across cell membranes.
  • People with CF have inherited a mutation which produces a faulty protein which leads to production of thick mucus and salty sweat.
  • This makes breathing and digesting difficult.
• Abnormal Chromosome Numbers

  • Two disorders that occur due to abnormal number of chromosomes is Klinefelter syndrome and down syndrome.
  • Both of these occur due to issues in chromosomes separating during meiosis.
  • Klinefelter syndrome:
  • Contain an extra X chromosome. Children grow with very little testosterone – reduces muscle development, body hair and sterility.
  • Down syndrome:
  • Contain an extra chromosome 21. People with down syndrome are generally short, contain distinct facial appear, intellectual disability, and abnormalities with organs such as heart and thyroid gland.
• Variation

  • As noted, mutations over many generations leads to change in the phenotype (physical characteristics) of organisms, where natural selection can act (Evolution topic).
  • One contemporary mutation in humans is the CCR 5-Delta 32 gene, which results in smaller cell membrane receptors.
  • It’s been found that humans with this mutation are less likely to contract HIV, as the virus cannot use the receptor to enter the cell and replicate.