Molecular Evolution

Question 1

What is Natural Selection and Fitness?

Answer 1

Natural Selection - the effects of a wide range of factors on the frequency of heritable changes in a species.

Fitness - how well a species is able to reproduce in its environment.

Anything that increases fitness is selected for, anything decreasing fitness is selected against and other neutral changes will vary randomly.

Question 2

What is the modern synthesis?

Answer 2

It was realised that evolution could be unified with genetics to explain the molecular process underlying evolution.

Genetic variation is the main source of heritable changes in a species.

Question 3

What are the frequencies of genetic variants affected by?

Answer 3

• Selection
• Mutation
• Migration
• Genetic Drift

Question 4

What is selection?

Answer 4

Genetic variants that confer a positive advantage will be selected for (and vice versa).

Examples might confer resistance to disease, an ability to metabolise a new food source, antibiotic resistance or a change in appearance that enhances mate choice.

Some parts of the genome are resistant to change as they contain vital sequences – they are conserved.

Question 5

What are mutations?

Answer 5

The name for the process by which variation in the genome arises is mutation.

We all carry large numbers of genomic variants and their frequency will depend on selection and when they first arose.

A rare variant may have arisen very recently or be deleterious and being selected against or both.

Question 6

What is migration?

Answer 6

The physical movement of people from a different population results in new pools of variants being introduced to an existing population. This is called admixture.

Population frequencies of specific variants can change purely due to admixture and not be disease-related.

Question 7

What is genetic drift?

Answer 7

This is how the frequency of a variant changes in a population due to chance

Not all organisms in a population will pass on their genetic variants

Mechanisms such as recombination will also result in not all variants being passed on

All variants are subject to genetic drift

Question 8

What is sequence conservation?

Answer 8

DNA sequence that is vital to the survival of an organism does not normally show much evidence of variation

Most variants in these regions will be selected against as they are likely to have a strongly deleterious effect

There is some flexibility for variation in the third base of codons as some amino acids are encoded by multiple codons

Question 9

What are the 3 types of sequence conservation in genes?

Answer 9

High conservation – coding regions (not exons as these contain non-coding regions)

Intermediate conservation – Promoter, 5’ untranslated region (UTR), 3’ UTR, terminator

Low conservation – introns, 3rd base of codons, terminator

Question 10

What can we use sequence conservation for?

Answer 10

Cross-species comparison can be used to generate an evolutionary profile for a gene or gene family.

Cross-species conservation allows us to identify the important regions of a gene (and its protein).

This allows us to concentrate on areas that appear to be important in novel genes.

Question 11

What is phylogenetics?

Answer 11

Phylogeny pertains to the evolutionary history of a taxonomic group of organisms. Thus, phylogenetics is mainly concerned with the relationships of an organism to other organisms according to evolutionary similarities and differences.

Observe sequences –> Reconstruct evolutionary history –> Learn more about evolutionary process –> Develop better evolutionary models.

Taxonomy is the science of naming, describing and classifying organisms and includes all plants, animals and microorganisms of the world.

Question 12

What are phylogenetic trees?

Answer 12

There are many different types of diagrams but the main aim is to illustrate the relatedness of different species /strains/sequences.

Distance between 2 entities on a tree is usually related to how similar they are.

Distance is normally related to both evolutionary pressures and to time.

Time is estimated by measuring mutation rates.

Question 13

How can phylogenetics be useful against infectious disease?

Answer 13

It had been theorised that HIV had been introduced to some of the human population via a contaminated polio vaccine in Africa. Some polio vaccines used to be produced using cultured chimpanzee cells, which could have been infected with SIV.

Phylogenetics were used to determine that SIV genome in chimpanzees was completely distinct from the HIV genomes. Other SIV strains were likely to be the source as they are closely related to HIV.

Question 14

What is gene duplication?

Answer 14

Gene duplication is the duplication of a DNA sequence containing a gene.

The typical mechanism is unequal crossing over during meiosis.

After duplication:

• One copy can continue the original function
• The other copy can evolve new function(s) through changes in the coding sequence and/or control sequences –> through mutation.

Question 15

What is unequal crossing over?

Answer 15

• Recombination between sequences that are not the correct sequence but are very similar
• Often low copy number repeat sequences.

Question 16

What are the 2 globin genes?

Answer 16

• Two clusters
• Alpha-like are on chromosome 16 – 3 genes and 3 pseudogenes
• Beta-like are on chromosome 11 – 5 genes and 1 pseudogene
• The genes are arranged in order of expression during development.

Question 17

Evolution of the globin gene clusters.

Answer 17

Very clear that globin genes have evolved though duplication and accumulation of mutations (divergence)

Some are functioning genes and some are not (pseudogenes)

Divergence of promoters has occurred so they bind different transcription factors and allow expression of genes at different stages of development (Embryo->Foetus->Postnatal)

Question 18

What are pseudogenes?

Answer 18

After gene duplication, one gene can maintain the original function and the other can diverge.

Pseudogenes typically have many mutations and are non-functional.

There are many of them in the genome.

They complicate PCR/sequencing/etc!

Question 19

What is Sickle Cell Disease?

Answer 19

Symptoms typically start at 5-6 months of age.

The main symptoms of SCD are:

• Anaemia – fatigue, restlessness, jaundice
• Acute pain episodes – “crises” – due to oxygen deprivation of tissues
• Increased frequency of infections – spleen damage
• Also stroke, pulmonary hypertension, gallstones, liver and kidney problems, joint problems, delayed puberty.

All this occurs due to ‘sickling’ of red blood cells. They can block blood vessels.

Question 20

What are the genetics of Sickle Cell Disease? Part 1

Answer 20

• A single base change in the beta-globin gene of Haemoglobin A = Haemoglobin S (HbS)
• Codon change is a GAG to GTG
• This is a Glu->Val at position 7 of the protein
• It is an autosomal recessive genetic disease
• The original mutation occurred ~7300 years ago

Question 21

What are the genetics of Sickle Cell Disease? Part 2

Answer 21

If both parents have one copy of HbS then each child has a 1 in 4 chance of having sickle cell anaemia (two copies of HbS)

Sickle trait is common in African, Middle Eastern, Mediterranean and Indian populations and very rare in Northern Europe.

This is due to natural selection and the HbS gene.

Question 22

How does Natural Selection affect the HbS (Haemoglobin S) gene?

Answer 22

Two copies of the HbS variant has significant negative effects on reproductive ability - SCD

However, one copy of the HbS variant confers resistance to severe malaria

This “heterozygote advantage” means that the HbS variant is maintained in the population when otherwise it would have been selected against and lost.

Question 23

Summary

Answer 23

• Mutational processes can lead to genes being duplicated.
• They can also lead to new functions.
• Evolutionary pressure can be very strong and lead to maintenance of apparently damaging variants.
• Malaria and HbS is a good example of this.