Lecture 6 Flashcards
Mutational distance
Codon table illustrates some amino acids are more prone to non-synonymous substitutions than others by virtue of non-redundancy (Met, Trp), or 2-fold redundancy (Asp, Glu)
Other have 4 or even 6-fold redundancy (Leu, Arg, Ser).
How many mutational steps are required for each amino acid substitution?
Full table would be 20x20 matrix, but:
Step 1: Phe->Leu would be TTT->TTA
Step 2: Tyr->Gln would be TAT -> ??? -> CAA
Tyr -> His -> Gln
Tyr -> Asn -> Lys
Tyr -> Asp -> Glu
Where can we reach from each amino acid in 1 step
Met: Valine, Isoleucine, leucine, Threonine, Lysine, Arginine (6)
Phe: leucine, isoleucine, methionine, valine, serine, tyrosine, cysteine (7)
Gly: Asparagine, glutamic acid, alanine, valine, Arginine, Cys (6)
Ser: Arg, Gly, Cys, Asp, Thr, Ile, Phe, Leu, Tyr Pro, Ala (11)
75 pairs of amino acids requiring 1 step out of 190
Some amino acids have a greater one step substitution range than others (possibly due to number of codons)
Reaching stop codons in 1 step
TAA: Ser, Leu, Lys, Gln, Glu
TAG: Trp, Ser, Leu, Tyr, Gln, Lys, Glu
TGA: Cys, trp, Arg, Gly, Ser, Leu
Serine and leucine always a single step away from stop codons in all three stop codons
Tyrosine, Lysine, Glutamate, glutamine, and Trp are one step away from two stop codons
Nonsense mutations: amino acid -> STOP (10 amino acids) - truncate protein so usually disadvantageous
Missense mutations: amino acid -> another, could be positively selected, neutral, or negatively selected mutations
Nonpolar amino acids
Alanine
Glycine
Leucine
Isoleucine
Methionine
Tryptophan
Phenylalanine
Proline
Valine
Polar amino acids
Cysteine
Serine
Threonine
Tyrosine
Asparagine
Glutamine
Polar basic amino acids
Histidine
Lysine
Arginine
Polar acidic amino acids
Aspartate
Glutamate
Is there much difference in properties of amino acids in missense mutations?
No
Phenylalanine and leucine can reach serine (non-polar to polar) in a single step.
Glutamate and aspartate can reach glycine and alanine (Polar acidic -ve -> non-polar) and K (polar acidic -ve -> polar basic +ve) in one step.
Polar acidic -ve amino acids can’t reach polar amino acids in a single step.
Codon bias
1-letter code - 4 amino acids
2-letter code - 16 amino acids
3-letter code - 64 amino acids (but redundancy as only 20 amino acids)
Redundancy affects mutational distance:
from STOP codons
between amino acids
for property change
Theories of codon bias
Why is one codon favoured over other codons?
- Remove STOP-adjacency problem
- Reduce likelihood of deleterious substitution
- Prevalence for high or low GC content in genome
- Speed translation (or allow for control of speed of translations) via differential levels of tRNAs
- Codon bias can vary gene to gene, or be global phenomenon in genomes
Codon bias - Wright’s Nc
Nc - effective codon number
Ranges from 20-64 (20 = maximum bias)
Transversion and transition bias
4 nucleotides: A, C, G, T
Purines: A, G (R)
Pyrimidines: C, T (Y)
Transition: R->R or Y->Y mutation
Transversion: R->Y or Y->R mutation
Kappa = transition rate/transversion rate
Kappa is almost always >1, sometimes spectacularly so
Transition vs transversion bias 2
An excess of transitions over transversions will reduce the proportion of mutations that are non-synonymous
Transition/transversion bias therefore reduces missense mutation and stabilises protein sequence – Why do this?
Constraint – natural selection acts against substitutional changes in a well-adapted protein
Transition/transversion bias has a tendency to reduce nonsense mutation – see codon table
