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- Changes in DNA that have the potential to be propagated through the DNA replication (SNPs/indels/CNV)
- Mutations in a germline cell of an individual can become polymorphisms in a population.
- Polymorphisms can lead to fixation within a species, resulting in divergence between two species.



Single nucleotide variants/polymorphisms are changes in one base pair in a sequence, eg) A -> G


Insertions and deletions:

Insertions or deletions of a few base pairs.



Copy number variation: the mutation is the duplication event. Segregation within the population results in one type having only one copy and the other type having more than one.



- Every variant site in the DNA of a population.
- In human genetics a polymorphism is something >1% in a population, but this depends on the population size, but SNPs are often used to talk about a high frequency.
- Frequencies are too high to be explained by mutation alone.



This is context dependant.
- A phenotype that segregates
- The nucleotide variant eg) A or C
- A group of variants eg) multiple states of 100 nucleotides.



- What happens when every individual in a population gets the variant.


Neutral Theory of Evolution - Kimua & Otah

- Most variation in gene sequences are due to neutral mutations rather than adaptive variation, ie: mutations arise in organisms and, as long as they are not detrimental, they can remain in the genome.


Neutralists believe..

- Most molecular variation that is fixed is neutral (they are functionally/physiologically equivalent alleles)
- Therefore evolution is governed by drift.
- Does allow for deleterious and advantageous mutations, but these get purged via negative selection
- Treated as the null hypothesis.


Genetic Drift:

- eg) 3 populations with 100 individuals with a starting frequency of 0.02, after 30 generations one of the populations has lost the variant.
- Drift is a stochasitc sampling function (mathematical predictions can be made but they may not be precise).


Selectionists believe..

- Adaptive evolution explains much of the differences between species and much of the variation within species.
- Variants are maintained within the population due to balancing selection.


Balancing selection:

- Natural selection is maintaining variation within populations
eg) sick cell mutations, favourable in heterozygotes.


What is the null hypothesis for molecular evolutionary studies?

"Is the observed data consistent with the neutral model?" If not, we have to find out why.


Probability of fixation =

Probability of fixation = 1/2N
- Looking back in time in the lineages of al contemporary alleles will eventually 'coalesce' to a single ancestor allele.
- Assuming the population has stayed at the same size, only one of these 2N variants has become fixed now.


Mutations arise by..

- Damage of molecular structure by radiation, mutagenic compounds, free radicals
- Repair mechanisms failing to restore the DNA to the original state
- Misincorporation (ie. copy error) during DNA replication
- Transposable element insertion and DNA breaks
- Unqeual crossing over/unequal seggregation


Mutation rate can be calculated by..

- Performing mutation accumulation experiments. eg) Mukai et al. 1964 with 1000 drosophila over 200+ generations, found 5x10(-6) mutations/gene/generation.
- Completing full genome sequences. eg) Arabidopsis mutation accumulation 30 generations. 7x10(-9) base substitutions were found per generation.


Mutation rate can be calculated by..

- Estimating from divergence data
- The Neutral model says: the mutation rate = fixation rate.
Mutation is 2N(mutation).
Fixation rate = 2N(mutations) x 1/(2N) = (mutation rate)
- Look at the divergence of neutral sites between two species


Neutral sites include:

- Junk DNA with no particular function, eg pseudogenes.



Genes that arose with a particular function, but have since lost their function and so it doesn't matter what happens to their sequences now.


Divergence =

- d is the number of changes that have occurred
- n is the number bases we have compared.
- Convert this to a rate of evolution using time
= d/2T


Parallel changes or revertants:

= k
- A change in DNA down one lineage eg) A -> T also occurs in the other species.


Dukes and Kantor Correction formula =

k = -3/4 In(1 - 4/3d) where
- d is the number of mutations observed and
- k is the number of mutations that have actually occurred.
- If all base changes occur at an equal frequency then d approaches 0.75, two random sequence are the same at 1/4 bases.



Purine to purine change or pyrimidine to pyrimidine eg)



Purine to Pyrimidine or vise verse change eg)
A or G C or T


There are more types of transversions, but transitions happen more frequently. Why?

It is easier to change from a purine to purine (A -> G) than a purine to a pyrimidine (A -> C or T) because A and G are both double ringed structures. A double ring structure to a single ring structure is harder!


Kimuras 2-paramter model

- Allows transversions and transitions to happen at different rates.


CG ->T G mutation is more common in mammals! Why?

- Mammalian genomes are deficient in 5'-CpG-3' di-nucleotides, and are enriched for TpG.
- CpG is often methylated AND 5-methy cytosine can be deaminated to get thymidine
- Take into account the sequence context