8. Gene mutations

What is gene mutation?

A change in sequence of nucleotides in DNA

What are the 2 causes of gene mutation

Spontaneous or induced

What are causes of spontaneous mutation

Errors in DNA replication + spontaneous damage in DNA

Outcome of gene mutation (step by step)

1. Change in sequence of nucleotides in DNA

2. Change in sequence of codons in RNA

3. Change in sequence of AA in polypeptide chains

4. Change in 3D conformation of proteins

5. Function and characteristics

6. Gene mutation manifest as disease in organism

What is point mutation

Gene mutation that involves change in SINGLE base

What are the 4 types of gene mutations (SID)

Substitution, Insertion/addition, deletion, inversion

When does substitution mutation not affect protein function as much?

1. genetic code is degenerate, same AA can be coded for by more than 1 codon. Some Codon differ at 3rd base all code for same AA, thus AA sequence not affected as it is SILENT MUTATION

2. Diff AA coded for has similar chemical properties to AA it had replaced. (E.g. both positively charged) CONSERVATIVE MISSENSE MUTATION

3. Base substitution occur in introns (non coding), → transcribed to form introns in mRNA → removed in mRNA → not affected

What does DEGENERATE code mean

Same AA can be coded for by more than 1 codon

*What is silent mutation (shh sneaky no one noticed)

No change in AA coded for despite changing base sequence. Does not affect protein structure and function. Usually change in 3rd base as genetic code is DEGENERATE

*What is nonsense mutation (NO STOP)

Introduction of stop codon (AUG) in the mRNA strand due to change in base sequence. Translation terminated prematurely → ppc truncated → non functional

*What is missense mutation (miss)

Change in base sequence with gene results in change in AA coded for. Usually change in 1 or 2 base.

What are the 2 types of missense mutation

1. Conservative

2. Non conservative

What is conservative missense mutation

New aa has similar chemical properties → chemical properties of resulting pp observed (same)

What is non conservative missense mutation

New AA different chemical properties of resulting→ affect protein function

Insertion and deletion mutations are…

Frameshift mutations

Why are insertion & deletion mutations more severe?

Frameshift mutation. Diff sequence of AA encoded, produce non functional protein as ribosomes read incorrect triplets from the point of intersection or deletion.

Which direction does reading frame shift in insertion

Downstream from point of insertion

Which direction does reading frame shift in deletion

Downwards from point of deletion

Why does frameshift mutations occur

Genetic code is non overlapping and continuous, thus Ravi some just reads the sequence of bases as they are

When does frameshift not occur

1. Add/delete 3 nucleotides, codons still read correctly after point of mutation → extra or less AA

2. Inverted 3 nucleotides as no change in reading frame

Structure of adult haemoglobin

• globular protein, roughly spherical

• Quaternary structure, 4 ppc, 2 alpha globin & 2 beta globin

• 1 prosthetic haem group attaches to each globin chain

What mutation is sickle cell anaemia caused by?

Single nucleotide substitution mutation in gene that codes for beta globin chain

What type of disorder is sickle cell anaemia

Homozygous recessive disorder. Need 2 copies of mutant gene form, heterozygous are carriers

Impact of DNA substitution mutation on sickle cell anaemia

1. Change in aa in ppc(6th codon GAG → GUG, glutamate to valine. Forms sickle cell haemoglobin HbS)

2. *Change in HbS properties (R groups of valine is non polar and hydrophobic) → change in 3D conformation when oxygen is unloaded at low oxygen concentrations → formation of exposed hydrophobic patch/region on surface of beta globin chain

3. Change shape of the RBC. Hydrophobic region stick to hydrophobic region of adjacent HbS molecule via hydrophobic interactions STICK TGT→ Polymerisation of HbS into **normal rigid rod-like fibres** that DISTORT normal biconcave shape of rbc into sickle shape at low oxygen levels

Effects of sickle cell anaemia

1. RBC more fragile, break easily, shorter lifespan. Actively destroyed in spleen → shortage of rbc and poor oxygen transport (anaemia, breathlessness, weakness, heart failure)

2. Rbc less flexible, get lodged in small blood vessels/capillaries → reduce blood circulation (depriving organs, damage to organs