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Lambda = rate of amino acid change.

= substitutions per amino acid site per unit time
= (total substitutions/length of protein)/total time
lambda = k/2T


Observed divergence (D) will underestimate the number of changes that have actually happened if there are multiple hits and parallel changes:

- K = -In(1-D)
- This is the formula to correct for multiple hits


What assumptions do we make in order to correct for multiple hits?

- We assume all amino acid replacements happen with equal likelihood


The likelihood of amino acids changes depends on:

- The pattern of DNA mutation
- The genetic code (four fold degenerate sites etc)
- Functional equivalency of amino acids, size and polarity


Dayhoff matrices:

- The likelihood of each type of amino acid replacements being derived empirically from data of closely related sequences


How do you check that rates are constant over time?
(4 points)

1. Align multiple sequences
2. Calculate D for each pair of sequences
3. Estimate K to correct for multiple substitutions
4. Estimate T from the fossil records


Different proteins have different substitution rates, why?

- Different proteins have different functional constraints


Kimura and Ohta concluded that..

- different proteins evolve at different rates because they have different proportions of deleterious mutations
- each protein keeps to its own clock


If most substitutions in proteins are neutral:

k = 2Nu X (1/2N) = u


If most substitutions in proteins are adaptive:

k = 4Nuas
It is unlikely that the product of population size, advantageous mutation rate and selective co-efficient would be constant over the phylogeny of species


Do all proteins evolve in a clock like way?

- No!
- When they don't this might be telling us something


If the clock holds then we expect Dax = Dbx.

- Look at sites that are different and attribute where they most likely happened (because its the most parsimonious scenario) when two species are compared to an out group species


What values would lead to rejection of the null hypothesis, that there is a clock?

When a chi squared is greater than the threshold:
- Both are greater than the 3.84 threshold and are therefore significant at p<0.05


Drosophila Esterase 6 in D.melanogaster.

- In D.mel the transfer of Est6 induces females to lay rather than re-mate.
- It is a monomer. In other species it is a dimer, and isn't found in the ejaculatory duct.


Relaxation of selective restraint:

- less deleterious mutations
- more neutral mutations
- increase rate of change


Selection for amino acid change in some lineages:

- new amino acids arise that are favourable


The "primate slow down":

- A difference in the molecular level of evolution.


Mutational input can be in the form of:

- DNA damage (exogenous, endogenous)
- Replication errors (base misincorporations, slippage)
- DNA repaire (enzyme efficiency)
- Selection (standing variation, rates of evolution)


Generation time hypothesis:

- More replications per year are expected to lead to more errors per year.


Metabolic rate hypothesis:

- The higher the metabolic rate, the more DNA damaging free radicals


DNA repair hypothesis:

- Large animals have more cells and longer life span, so error checking will be selected to be better (the primate slow down).
- Big species will evolve at a slower rate on the nuclear level than smaller species.


Ohta's nearly neutral model:

- population size is relevant to fixation rate.
- Slightly deleterious alleles will occasionally get fixed.
- They are more likely to become fixed in large population sizes.