MUTATIONS AND DISEASES

1 EJC H2 Biology T3W3 Mutations & Diseases Mutations & Diseases 1. Overview of Topic We have, thus far, learnt about the processes of DNA replication and cell division. These processes are fundamental in an organism’s life cycle as they ensure that normal cellular activities can be continually carried out by new cells which originate from existing ones. However, as with most systems, perfection is hard to come by. Gene mutations and chromosomal mutations occur in cells during DNA replication and cell division. Though there are repair mechanisms which can correct such errors in eukaryotes, in some cases, cells could still end up with such mutations. These mutations could manifest in the phenotypes of organisms and lead to diseases. In this chapter, we will be taking a closer look at the types of mutations which can occur in cells and examples of diseases which could be brought about due to these mutations. 2. Learning Outcomes a. Explain what is meant by the terms gene mutation and chromosome aberration. For gene mutation, knowledge of how substitution, addition, deletion could change the amino acid sequence (e.g. frameshift) is required. For chromosomal aberration, knowledge of numeral (e.g. aneuploidy, as in the case of trisomy 21, i.e. Down syndrome) and structure (e.g. translocation, duplication inversion, deletion) aberration is required. b. Explain how gene mutations can result in diseases (including sickle cell anaemia). 3. References Campbell, N.A. and Reece, J.B. (2008). Biology, 9th edition. Pearson. Jones & Jones. (1997). Advanced Biology. Hoh Yin Kiong (2003). Longman A-Level Course in Biology, Vol. 1. Longman Green, Stout and Soper (1990). Biological Sciences, Vol 1. Cambridge Raven, Johnson, Losos, Mason & Singer (2008). Biology, 8th edition. McGraw-Hill.

2 EJC H2 Biology T3W3 Mutations & Diseases Contents 1. Overview of Topic ...................................................................................................... 1 2. Learning Outcomes.................................................................................................... 1 3. References ................................................................................................................. 1 4. Gene mutations ......................................................................................................... 3 Example of disease: Sickle Cell Anaemia ................................ ................................ ........ 6 Example of disease: Cystic Fibrosis ................................ ................................ ................ 9 7. Chromosomal mutations ......................................................................................... 11 (I) Variation in the chromosomal structure ................................ .............................. 11 Examples of diseases: ................................ ................................ ................................ .. 12 (II) Variation in chromosomal number ................................ ................................ ...... 14 Examples of diseases: ................................ ................................ ................................ .. 15

3 EJC H2 Biology T3W3 Mutations & Diseases 4. Gene mutations Definition: A gene mutation arises as a result of a change in the sequence of nucleotides in the DNA of a gene. A mutation could be caused by a mutagen – a chemical or physical agent that interacts with DNA causing a mutation. E.g. UV, gamma radiation, carcinogens (cancer causing chemicals). An alteration in the sequence of nucleotides may change the sequence of amino acids in a polypeptide chain. This may change the 3D shape of the protein, affecting the protein function and subsequently affect the characteristics (phenotype) of the organism. Thus, t his could manifest as a disease in the organism as well. Gene mutations can result in inheritable diseases. Q. In which cells must the mutation occur for it to be inheritable? Germline cells, gametes, sex cells, cells of the gonads. Gene mutation may involve a change in one or a few bases. If it involves a change in just a single base, it is called a point mutation. (Note: gene mutation  point mutation). Types of gene mutations: 1) Substitution – occurs when one nucleotide is replaced by another. ATGGCCA  ACGGCCA 2) Insertion/addition – occurs when one or several nucleotides are added/inserted in a sequence. ATGGCCA  ATCTGGCCA 3) Deletion – occurs when one or several nucleotides are removed from a sequence. ATGGCCA  ACCA 4) Inversion – A segment of nucleotide sequences separates from the allele and rejoins at the original position but it is inverted and the sequence is now reversed. ATGGCCA  ATCCGGA Deletion or insertion (of 1 or 2 nucleotides) often results in the production of a non-functional protein as ribosomes begin to read incorrect triplets from the point of insertion or deletion. The original codons downstream of the point of mutation are not read correctly. Such mutations are known as frame-shift mutations, and are more severe in their consequences. Notes to self

4 EJC H2 Biology T3W3 Mutations & Diseases An analogy: Original message (in-frame): THE CAT BIT THE RAT Insertion of one letter (frame shifted): THE CXA TBI TTH ERA T Deletion of one letter (frame shifted): THE CTB ITT HER AT Q. What is the effect of adding 3 consecutive letters to the reading frame here? THE MCA TBI TTH ERA T THE MAC ATB ITT HER AT THE MAD CAT BIT THE RAT Addition of 3 consecutive nucleotides will result in the restoration of the reading frame However, the addition will result in changes to the primary sequence of the polypeptide chain and this could result in a loss or modification of function of the polypeptide. It is usually less severe than a frameshift mutation. Fig. 1: Possible results of frameshift mutations A ‘Meaning’ is lost beyond point of mutation Notes to self

5 EJC H2 Biology T3W3 Mutations & Diseases Substitution is the most common type of gene mutation. This type of mutation is usually not as serious as deletion or addition as the replacement of a nucleotide may not necessarily affect the function of the protein as much. Q. Can you think of two reasons as to why this is the case? Hint 1: The 3rd nucleotide of the codon…. Hint 2: Type of amino acid…. Reason 1: This is because the genetic code is degenerate. i.e. more than 1 codon can code for an amino acid. These codons differ at their 3rd nucleotide e.g. UCU, UCC, UCA and UCG and they all code for the amino acid serine. Therefore, the amino acid sequence is not affected as a result of the mutation at the third base of a codon. Such a mutation is also known as a ‘silent’ mutation as the amino acid being coded for is not changed. Reason 2: Even though the substitution mutation results in a different amino acid being coded for, the ‘new’ amino acid has an R gr oup which has similar chemical properties to the amino acid it had replaced. E.g. the codon TTC codes for lysine whereas TCC codes for arginine. Both lysine and arginine have positively charged R-groups. Thus, a mutation from T  C may not affect the folding of the polypeptide and the function of the protein as both amino acids have R -groups with similar properties. Such mutations are known as conservative mutations. Fig. 2: Types of substitution mutations and their effects Notes to self

6 EJC H2 Biology T3W3 Mutations & Diseases Example of disease: Sickle Cell Anaemia Sickle cell anaemia is an example of a disease caused by a single nucleotide substitution mutation. In a normal adult: o The normal adult haemoglobin (Hb A) is a quaternary protein which is a tetram