MUTATIONS

• A   Mutation   occurs when a DNA gene is damaged or changed in such a way as to alter the genetic message carried by that gene.
  
  
• A  Mutagen  is an agent of substance that can bring about a permanent alteration to the physical composition of a DNA gene such that the genetic message is changed.
  
  
• Once the gene has been damaged or changed the mRNA transcribed from that gene will now carry an altered message.
  
  
• The polypeptide made by translating the altered mRNA will now contain a different sequence of amino acids. The function of the protein made by folding this polypeptide will probably be changed or lost.

Chemical Mutagens  – They change the sequence of bases in a gene in a number of ways:

• Mimic the correct nucleotide bases in a DNA molecule, but fail to base pair correctly during DNA replication.
  
  
• Remove parts of the nucleotide (such as the amino group on adenine), again causing improper base pairing during DNA replication.
  
  
• Add hydrocarbon groups to various nucleotides, also causing incorrect base pairing during DNA replication.

Radiation -  High energy radiation from a radioactive material or from X-rays is absorbed by the atoms in water molecules surrounding the DNA. This energy is transferred to the electrons which then fly away from the atom. Left behind is a  free radical, which is a highly dangerous and highly reactive molecule that attacks the DNA molecule and alters it in many ways.


Radiation can also cause double strand breaks in the DNA molecule, which the cell's repair mechanisms cannot put right.

Sunlight-  It contains ultraviolet radiation (the component that causes a suntan) which, when absorbed by the DNA causes a cross link to form between certain adjacent bases. In most normal cases the cells can repair this damage, but unrepaired  dimers  of this sort cause the replicating system to skip over the mistake leaving a gap, which is supposed to be filled in later.


Unprotected exposure to UV radiation by the human skin can cause serious damage and may lead to skin cancer and extensive skin tumors.

Spontaneous -  Mutations occur without exposure to any obvious mutagenic agent. Sometimes DNA nucleotides shift without warning to a different chemical form (know as an  isomer ) which in turn will form a different series of hydrogen bonds with it's partner. This leads to mistakes at the time of DNA replication.

• EXAMPLES :
1. Nitrous Acid:
• Nitrous Acid affects DNA complementation.
• The acid randomly modifies the base adenine so that it will pair with cytosine instead of thymine.
• This change is made evident during DNA replication when a new base pair appears in daughter cells in a later generation.
2. A Base Analog:
• A base analog is a compound sufficiently similar to one of the four DNA bases but have different pairing properties.
• For example, 5-bromouracil is the analog of thymine but sometimes pairs with guanine and 2-aminopurine is the analog of adanine but sometimes pairs with cytosine.
• The incorporation of a base analog will result in base pair substitution .
3. UV Light:
• Exposure to direct UV light induces covalent linking between adjacent thymine nucleotides on a DNA strand forming a thymine dimer.
• These dimers cause the strand to buckle, disrupting normal base pairing. This prevents proper replication and transcription.
• Bacteria have enzymes to fix the damage created by UV light.
• An enzyme cuts the DNA at two point and removes the damaged portion.
• DNA polymerase synthesizes a new DNA segment using the healthly strand as a template.
• DNA ligase joins the new fragment to the old strand.

Types of Mutations :
NOTE: For all others examples cited below, the below given DNA sequence shall be considered as wild type:

•  ATG  CCG  TGT   CAG  ATG  TTC     ---------------- DNA
•  AUG CCG UGU  CAG AUG UUC    ------------  mRNA

              Met    Pro   Cys   Gln    met    phe  ------  Amino acid sequence    

1. Synonymous / Silent Mutations

1. No alteration in polypeptide product of the gene
2. Single base pair substitution
3. Occur in the third position of a codon
4. Codes for the same amino acid
5. No alteration of the protein

Example: Samesense Mutation:
a codon is changed to a different codon that specifies the same amino acid.

    ATG CCG TGC CAG ATG TTC        -----MUTATED DNA (compare with wild type)
    AUG CCG UGC CAG AUG UUC   -----    mRNA
    Met     Pro   Cys    Gln    Met   Phe  --------  amino acid sequence

2. Non-Synonymous Mutations

1. Occur less frequently than synonymous mutations
2. Leads to alteration in the encoded polypeptide
3. Result in abnormal function® disease

Occur in one of three main ways:

1. Missense
2. Nonsense
3. Frameshift

Missence mutation: a codon is changed to a different codon that specifies a different amino acid.
ATG CCG TGG CAG ATG TTC        -----MUTATED  DNA
AUG CCG UGG CAG AUG UUC       -----    mRNA
Met    Pro   Trp    Gln    Met   Phe  --------  amino acid sequence

Nonsense Mutation: A codon that specifies an amino acid is changed to a stop codon. (termination codon), this mutation usually destroys the function of the gene product.
ATG CCG TGA CAG ATG TTC        ----- MUTATED DNA
AUG CCG UGA CAG AUG UUC       -----    mRNA
Met   Pro   STOP                          --------  amino acid sequence