Lecture 23 (Part 2) – Base Composition Evolution

Question 1

What do we mean by “base composition”?

Answer 1

The proportions of the four bases (A, C, G, and T/U) present in DNA or RNA.

Question 2

How is base composition usually expressed?

Answer 2

Usually expressed as the percentage of bases that are G and C - the GC content.

Question 3

What would a GC content that is greater than 50% indicate?

Answer 3

Bias or skew in a certain direction.

Question 4

What is the typical range for GC content in vertebrates?

Answer 4

40-45%.

Question 5

What is the approximate GC content in humans?

Answer 5

41% approx.

Question 6

Where do we see the most variation in GC content?

Answer 6

In unicellular organisms.
- Single-celled fungi
- Bacteria
- Archaea

Question 7

What are the two main hypotheses for variation in GC content?

Answer 7

1. Mutationist - GC biases are just a reflection of mutation patterns.
2. Selectionist - GC biases are an adaption to selective pressures.
   - In other words, the GC content can have a fitness impact and thus should be shaped by selection
   - “Optimal GC content”

Question 8

What does the mutationist hypothesis argue?

Answer 8

That GC biases are just a reflection of mutational patterns.
1. Involves the propensity of different bases to spontaneously mutate.
- There is a universal bias towards AT pairs.
- This is related to the inherent chemical properties of the bases (e.g., cytosine prone to deamination which leads to GC to AT mutations)

2. Also involves the fidelity and bias of DNA replication and repair machinery.
   - E.g., biased DNA mismatch repair systems
   - Can differ between species (e.g., GC biased gene conversions in diploids leads to an increase of GC alleles relative to AT)

Question 9

What does the selectionist hypothesis argue?

Answer 9

GC biases are an adaption to selection pressures.
- GC-rich genomes are more thermodynamically stable (due to stacking interactions)
- UV radiation produces thymidine dimers, thus high amounts of T are more susceptible to damage, and GC-rich sequences are more protected
- Lifestyle influences may lead to selection on GC content (e.g., nitrogen-fixing and aerobic bacteria tend to have higher GC content)

Question 10

What is a GC skew?

Answer 10

When the freq(G) is very different to the freq(C) on a single strand.
- GC skew = (G - C)/(G + C)

Question 11

What is an AT skew?

Answer 11

When the freq(T) is very different to the freq(A) on a single strand.
- AT skew = (A - T)/(A + T)

Question 12

Why do we observe an abrupt shift in the frequency of G and C at the origin of replication?

Answer 12

It is related to whether the strand is a leading strand or a lagging strand!
(See lecture 23 @16:30)

Question 13

What bases do leading strands tend to be enriched for?

Answer 13

G and T.

Question 14

What bases do lagging strands tend to be enriched for?

Answer 14

C and A.

Question 15

How would the mutationist hypothesis explain the skew?

Answer 15

Asymmetrical mutation pressures for the leading and lagging strand.
- Difference in patterns of replication error
- E.g., Leading strand is more prone to cytosine deamination during replication because it is left as a single strand for longer (which would change AT to GC skews)

Evidence:
- The boundaries coincide with origin and terminus of replication (suggests a link with the replication process)
- Bias is stronger at third codon positions and in intergenic DNA (characteristic of mutation bias)

Question 16

On which strand is there more genes found?

Answer 16

More genes are found in the leading strand than in the lagging strand.
- The selectionist explanation for this is that it may prevent less “head on collisions” between replication and transcription machinery.

Question 17

What is another reason why asymmetric gene content between the leading and lagging strand may give us GC and AT skews?

Answer 17

Codon usage bias.

Question 18

What is meant by codon usage bias?

Answer 18

The non-random usage of synonymous codons (i.e., one codon being preferentially selected to code for an amino acid, for example CUG codon highly used to code for Leucine in E. coli)

Question 19

Is this preference for a particular codon due to mutation or selection?

Answer 19

1. Mutation bias is a factor
   - AT rich genomes having a preference for codons ending in AT (and vice versa)
   - However, this is not always observed!
2. Most agree that codon bias is due to selection
   - Two most popular selection hypotheses invoke “translational efficiency” and “translational accuracy”
   - Certain codons helping promote better translation?

Question 20

What is the translational efficiency hypothesis (in terms of codon bias)?

Answer 20

Using codons that are recognised by more abundant tRNAs will allow for faster translation and higher protein yield.

Evidence:
- The most highly expressed genes tend to show the highest level of codon bias

Question 21

What is the translational accuracy hypothesis (in terms of codon bias)?

Answer 21

Argues that rarer tRNAs are frequently mistranslated. Thus, using common ones prevents errors.

Evidence:
- Codons for highly conserved amino acids tend to show the most codon bias