2.4.2 Mutations

• A gene mutation is a change in the sequence of base pairs in a DNA molecule that may result in an altered polypeptide
• Mutations occur continuously and spontaneously
  • Errors in the DNA often occur during DNA replication
• As the DNA base sequence determines the sequence of amino acids that make up a protein, mutations in a gene can sometimes lead to a change in the polypeptide that the gene codes for
• Most mutations do not alter the polypeptide or only alter it slightly so that its structure or function is not changed
  • This is because the genetic code is degenerate 
• There are different ways that a mutation in the DNA base sequence can occur:
  • Insertion
  • Deletion
  • Substitution
  • Duplication
  • Inversion

Insertion of nucleotides

• A mutation that occurs when a nucleotide is randomly inserted into the DNA sequence is known as an insertion mutation
• An insertion mutation changes the amino acid that would have been coded for by the original base triplet, as it creates a new, different triplet of bases
  • Remember that every group of three bases in a DNA sequence codes for an amino acid
• An insertion mutation also has a knock-on effect on other base triplets by changing the triplets further on in the DNA sequence
  • This means that insertion mutations cause what is known as a frameshift mutation; they don't only change the triplet where the insertion has occurred, but every triplet downstream of the insertion
• This may dramatically change the amino acid sequence produced from this gene and therefore the ability of the polypeptide to function

Insertion mutations occur when a new nucleotide is added into a base sequence

Deletion of nucleotides

• A mutation that occurs when a nucleotide is randomly deleted from the DNA sequence
• Like an insertion mutation, a deletion mutation changes the triplet in which the deletion has occurred, and also changes every group of three bases further on in the DNA sequence
  • This is known as a frameshift mutation
• This may dramatically change the amino acid sequence produced from this gene and therefore the ability of the polypeptide to function

Substitution of nucleotides 

• A mutation that occurs when a base in the DNA sequence is randomly swapped for a different base
• Unlike an insertion or deletion mutation, a substitution mutation will only change the amino acid for the triplet in which the mutation occurs; it will not have a knock-on effect elsewhere in the DNA sequence
• Substitution mutations can take three forms
  • Silent mutations
    • The mutation does not alter the amino acid sequence of the polypeptide; this is due to the degenerate nature of the genetic code
  • Missense mutations
    • The mutation alters a single amino acid in the polypeptide chain, e.g. sickle cell anaemia is caused by a single substitution mutation changing a single amino acid in the sequence
  • Nonsense mutations
    • The mutation creates a premature stop codon, causing the polypeptide chain produced to be incomplete and therefore affecting the final protein structure and function, e.g. cystic fibrosis can be caused by a nonsense mutation
      • Note that a stop codon provides a signal for the cell to stop translation of the mRNA molecule into an amino acid sequence

Substitution mutations involve swapping one nucleotide for another

Duplication

• Duplication is a type of mutation that involves the production of one or more copies of a gene or a region of a chromosome
  • A whole gene or section of a gene is duplicated so that two copies of the gene/section appear on the same chromosome
  • The original version of the gene remains intact and therefore the mutation is not harmful
  • Overtime, the second copy can undergo mutations which enable it to develop new functions
• Gene duplication is an important mechanism by which evolution occurs
• Gene and chromosome duplications occur in all organisms, though they are more common in plants

In duplication mutations entire genes can be duplicated

Inversion

• Inversion mutations usually occur during crossing-over in meiosis
  • The DNA of a single gene is cut in two places
  • The cut portion is inverted 180° then rejoined to the same place within the gene
  • The result is a large section of the gene that is 'backwards' and therefore multiple amino acids are affected
• Inversion mutations frequently result in a non-functional protein
  • In some cases an entirely different protein is produced
• The mutation is often harmful because the original gene can no longer be expressed from that chromosome
  • If the other chromosome in the pair carries a working gene the effect of the mutation may be lessened

Inversion mutations result in the reversal of sections of DNA

• Genes can affect the phenotype of an organism
  • A gene codes for a single polypeptide
  • The polypeptide can affect the phenotype, e.g. it could form part of an enzyme or a membrane transport protein
• Genetic disorders are often caused by a mutation in a gene that results in a differently-functioning or non-functioning protein that alters the phenotype of the individual

Cystic fibrosis

• Cystic fibrosis is a genetic disorder of cell membranes caused by a recessive allele of the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene located on chromosome 7
  • This gene codes for the production of chloride ion channels required for secretion of sweat, mucus and digestive juices
  • A mutation in the CFTR gene leads to production of non-functional chloride channels
  • This reduces the movement of water by osmosis into the secretions
  • The result is that the body produces large amounts of thick, sticky mucus in the air passages, the digestive tract and the reproductive system
• There are many mutations in the CFTR gene that can lead to cystic fibrosis
  • The CFTR gene is large and a mutation in any part of the gene can cause cystic fibrosis
  • Around 1000 different mutations that can lead to cystic fibrosis have been identified, though some only occur very rarely
  • All of the mutations that cause cystic fibrosis are recessive
• Because cystic fibrosis is determined by a recessive allele, this means
  • People who are heterozygous won’t be affected by the disorder but are carriers
  • People must be homozygous recessive in order to have the disorder
  • If both parents are carriers the chance of them producing a child with cystic fibrosis is 1 in 4, or 25 %
  • If only one of the parents is a carrier with the other parent being homozygous dominant, there is no chance of producing a child with cystic fibrosis, as the recessive allele will always be masked by the dominant allele

Cystic fibrosis is a genetic disorder caused by a recessive allele

The respiratory system

• Mucus in the respiratory system is a necessary part of keeping the lungs healthy
  • It prevents infection by trapping microorganisms
  • This mucus is moved out of the respiratory tract by cilia 
• In people with cystic fibrosis, due to the faulty chloride ion channels, the cilia are unable to move as the mucus is so thick and sticky
• This means microorganisms are not efficiently removed from the lungs and lung infections occur more frequently
• Mucus builds up in the lungs and can block airways which limits gas exchange
  
  • The surface area for gas exchange is reduced which can cause breathing difficulties
• Physiotherapy can support people with cystic fibrosis to loosen the mucus in the airways and improve gas exchange

The digestive system

• Thick mucus in the digestive system can cause issues because
  • The tube to the pancreas can become blocked, preventing digestive enzymes from entering the small intestine
    • Digestion of some food may be reduced and therefore key nutrients may not be made available for absorption
  • The mucus can cause cysts to grow in the pancreas which inhibit the production of enzymes, further reducing digestion of key nutrients
  • The lining of the intestines is also coated in thick mucus, inhibiting the absorption of nutrients into the blood

The reproductive system

• Mucus is normally secreted in the reproductive system to prevent infection and regulate the progress of sperm through the reproductive tract after sexual intercourse
• The mucus in people with cystic fibrosis can cause issues in both men and women
  • In men the tubes of the testes can become blocked, preventing sperm from reaching the penis
  • In women thickened cervical mucus can prevent sperm reaching the oviduct to fertilise an egg