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Flashcards in 4. Molecular Evolution Deck (20):

Requirement for a scientific theory

- Must make testable predictions
- Must stand or fall according to whether the predictions are confirmed or refuted


What is natural selection from today's view point

- Is not simply a hypothesis based on a finite set of data
- But a logical deduction from our knowledge of molecular genetics and ecology.


What causes variation?

• Mutation, due to changes in DNA sequence
• Mostly mistakes during DNA synthesis (occasionally due to radiation)
• Rare because DNA synthesis is exceedingly accurate - accurate due to the proof reading activity in DNA polymerase.
• Most mutations are neutral or deleterious, a minority are beneficial


What does ecology tell us about selection?

• Individuals are in competition with predators, prey and members of their own species.

• New alleles may increase or decrease reproductive success


What is relative fitness?

• Relative fitness (w) is the average number of surviving progeny of a genotype (compared with competing genotypes) after one generation.

• If w<1, the frequency of the allele:
- will decrease with each generation
- until the allele disappears (negative selection)

• If w>1 the frequency of the allele
- will increase with each generation
- until the allele reaches fixation (positive selection)
~ (fixation is when all the other alleles have been displaced and this is the only allele.
• Sometimes you can end up with a balance where more than one allele are in balance in the population


Give examples of some small and large mutations.

- Base substitutions
- Small insertions
- Small deletions

- Large DNA duplications
- Large deletions
- Insertions of transposable elements ~ RNA and DNA bits cut themselves and insert in another place
- Viral insertions ~ especially retro viruses, insert into the genome and stably inherited
- Chromosome rearrangements


Number of mutations and molecular phylogeny

The mutations accumulate over time, so species that share a recent common ancestor will have fewer differences than species that are more distantly related.
- RNA pol very highly conserved in evolution.
- Sequence data can be used to generate evolutionary family trees.


Main points of medical case study - HIV.

• Suggested that HIV introduced to human population through a contaminated batch of polio vaccine. - early vaccines produced by growing polio virus on cultured monkey cells, which could've been contaminated by SIV (Simian immunodeficiency virus).

• Phylogenetic tree was made and it showed that HIV is related to the SIV strands in west Africa – not the ones from east where the monkey cells were used.


What are the patterns seen when comparing sequences for two species?

• Consistently more differences (per unit length of DNA) in intron sequences than in exon sequences.
• There are more differences looking at every third nucleotide, compared to the first two. ~ changes in the first 2 nucleotide, (unless it is neutral or advantageous), it will be removed by natural selection. Whereas, many of the changes in the 3rd nucleotide will not be removed by natural selection.


Mutations that effect the reading frame.

Insertion or deletions - These mutations are almost always negative, and so will be removed by negative selection


What are the different types of mutations?

• Synonymous substitution - doesn't change the AA

• Non-synonymous substitution - change in the AA


Examples of high, moderate and low degree of conservation structures.

• Active sites of enzymes
• Structural regions of proteins

• Signal regions in 5’ and 3’UTRs
• Promoters

• Enhancers (in introns and intergenic DNA)
• Other intronic and intergenic DNA


Gene duplication in evolution

• It is the major driving force for evolution.
• Once a gene has been duplicated:
- one copy can continue to maintain the original function
- while the other can evolve new functions.
- there are likely to be changes both in the coding sequence (i.e. in amino acid sequence) and in control sequences.


Main points for the case study of the beta globin gene locus and mygoglobin and haemoglobin

• Duplication of an ancestral Hb gene gave rise to myoglobin and haemoglobin

- In skeletal muscle
- Monomeric protein
- Hyperbolic O2 dissociation curve
- Oxygen storage

- RBCs
- Tetrameric protein
- SigmoidalO2 dissociation curve
- Oxygen transport


Main points for the case study of the globin gene and alpha and beta globin and gamma gene. And how does expression in these change in a lifetime?

• Ancestral globin gene has undergone multiple duplications and modifications to give the beta and alpha globin complexes on human chromosome 16.

• The γ gene control sequences have evolved so that γ-genes are expressed during foetal life and the β-gene is expressed during postnatal life.
• The above happened by promoter duplication along with coding sequence ~ promoter sequence has evolved so β and γ promoters now bind different transcription factors
• They interact differently with gene enhancers
• Differential control of beta and gamma genes


Different Hb composition for the different types

• Adult Hb (HbA) ~ alpha2beta2
• Minor adult Hb ~ alpha2delta2
• Fetal Hb (HbF) ~ alpha2gamma
• Embryonic Hb (Hb Gower 2) ~ alpha2epsilon2
• Embryonic Hb (Hb Gower 1) ~ zeta2epsilon2


How has HbF evolved to have higher O2 affinity than HbA?

• Changes to the amino acid sequence of the gamma globin protein
• There are actually 2 γ genes (a gamma and b gamma)
- Coding for protine that differ by one AA residue
• Some adults still have HbF ~ doesn’t function too badly, only problems with their foetus as the baby may find it hard to take the oxygen.


What is the pseudogene?

• Ψβ
• Non-functional gene - they cannot make a functional protein
• They are made from a duplicated gene - but lose all the function
• Clear sequence homology to the beta-globin gene
• These are common in the genome
• Most mutations are pseudogenes


What is Fanconi's anaemia?

• Recessive lethal genetic disorder
• Most affected patients die of bone marrow failure during childhood
• Gene arises by random mutation
• Eliminated by natural selection
• Very low allele frequency


Sickle cell anaemia (SCA)

• Point mutation in the β globin gene
• Single amino acid substitution ~ a hydrophilic a.a. (glutamic acid) is replaced by a hydrophobic a.a. (valine) at position 6
• Mutant Hb molecules
aggregate and form crystals when deoxygenated ~ Force red cells into characteristic “sickle” shape
• The crystals damage the red cell membrane resulting in: cell lysis causing anaemia, and cell adhesion
- causing blockage of small blood vessels, followed by tissue infarction
• Not eliminated by natural selection - some homozygous survive
• More common than Fanconi's as heterozygous provides benefit that the people are less likely to die of both SCA and malaria (they can still catch malaria though).