Molecular Evolution

Lecture 3. Origins of variation: mutation

Different molecular regions, different rates

• DNA distant from genes evolves very quickly (at about one substitution per 108 years),

• Flanking regions upstream and downstream from a gene evolve less quickly than that,

• Introns evolve less quickly than those, though not much less,

• Third positions of codons evolve less quickly than introns,

• First and second positions of codons evolve less quickly than that,

Within a protein:– active sites evolve very slowly,– sites that bind heme, or interact with other proteins evolve a bit faster but

also very slowly,– interior sites evolve less quickly than exterior sites,– substitutions that involve less radical changes of the amino acid (i.e. that

change to a rather similar amino acid) happen more readily.

Of base changes, transitions (A -> G or C -> T) happen several times more readily than transversions (all other changes).

Between protein-coding loci, some (fibrinopeptide, for example) evolve rapidly, some less so (hemoglobins, cytochromes), and some (histones, for example) change very slowly.

Different molecular regions, different rates

Rates and causes of molecular evolution

• Different parts of the genome are useful for answering different problems. Fast evolving sequences are useful for recent events, but become saturated and unrecognizable when comparing more distant relatives. Slow evolving sequences are useful around the base of the tree, but don’t have any variability at all among close relatives.

Effects of replication timing...

• Genes near replication origins are duplicated early and hence experience greater copy number than those replicated last

• Copy # correlates with expression• Expression inversely correlates with

evolutionary rate• So: genes replicated first evolve more slowly

Kinds of mutations:

1. Point mutations (Base substitutions)

2. Reading frame shifts

3. Large scale insertions (Bacteriophage; Transposons)

4. Large scale deletions

5. Thymine (pyrimidine) dimers

6. Gross damage - X-rays, gamma rays, etc.

(Some mutations are caused by improper [template-free]DNA repair - i.e. SOS repair)

1. Point Mutations(Base substitutions)

Substitutions (base-pair substitutions)

Two Types1. Transitions - purine for a purine

G A- pyrimidine for a pyrimidine

C T2. Transversions - purine for

pyrimidineG CG T- pyrimidine for purine

SILENTSILENT = bp change does not affect the amino acid that is encoded. e.g. UGC -> UGU is silent because both are codons for cysteine.

AUGCCCGGGUACUGCUGCCGAGUG

MetProGlyTyrCysArgVal

AUGCCCGGGUACUGUUGUCGAGUG

MetProGlyTyrCysArgVal

C T transition in DNA sequence resulted in C U change in mRNA

**

MISSENSE (replacement)MISSENSE (replacement) = bp change alters the amino acid that is encoded. The severity of the mutation depends on the nature of the change. e.g. the change GAA -> GAU will change glutamic acid to aspartic acid.

AUGCCCGGGUACGAAGAACGAGUG

MetProGlyTyrGluArgVal

AUGCCCGGGUACGAUGAUCGAGUG

MetProGlyTyrAspArgVal

However, the change GAA -> AAA would be significant since it replaces glutamic acid with lysine which is very different.

AUGCCCGGGUACGAAGAACGAGUG

MetProGlyTyrGluArgVal

AUGCCCGGGUACAAAAAACGAGUG

MetProGlyTyrLysArgVal

**

**

NONSENSENONSENSE = bp change results in the creation of a stop codon. Proteins will be truncated as a result of this type of mutation.

e.g. the change UAC -> UAG.

AUGCCCGGGUACUACGAACGAGUG

MetProGlyTyrGluArgVal

AUGCCCGGGUAGUAGGAACGAGUG

MetProGlySTOPSTOP

Truncated proteins usually have no function and can be detrimental to the cell

**

Nonsense Mutations

mRNA

mRNA

Wildtype gene

Nonsense Mutation

Inactive peptide fragment

Start Stop

StopStart

2. Reading frame shifts:

3’3’

5’5’

Transcription

Translation

gene Bgene Bgene Agene A gene Cgene C

5’

3’3’

5’5’

Transcription

Translation

gene Bgene Bgene Agene A gene Cgene C

5’

Stop codon

Transcription and Translation are coupled in bacteria, so nonsense substitutions have *polar* effects (polarity)

Slipped strand mispairing

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.figgrp.1097

Holliday junction / crossing over

• http://engels.genetics.wisc.edu/Holliday/holliday3D.html

3. Transposition; transposon mutagenesis; “jumping genes”

Mutations (insertions) caused by IS elements and Transposons:

Antibiotic resistance gene(s)

Transposase gene

Rates of MutationA. Spontaneous mutation

• result from errors in replication • frequency of 10-7 to 10-10 per bp per

generation

B. Induced mutation

• result from application of chemical and physical agents (mutagens)

• increase the frequency of a mutation

Is the mutation rate optimal or minimal?

A comparison of mutation rates