# L5 The Molecular Clock Flashcards

1
Q

The Molecular Clock

A
• Depends on the aa/nucleotide rate of change
• The alpha globin protein seem to be changing at a steady rate
• provides a useful null model, can be used to screen for interesting genes
2
Q

lambda

A

See OneNote

• rate of aa change = substitutions per aa site per unit time = (total substitutions/length of protein)/total time

lambda = K/2T (2 species)

3
Q

Hartl and Clark Equation

A

See OneNote
K = -ln(1-D)
D = number of apparent changes, will underestimate changes if there are multiple hits and parallel changes

Assumptions: all mutations occur at equal rates?

4
Q

The likelihood of aa changes depends on

A
1. Protein abundance bias

2. aa have different biophysical properties

5
Q

Dayhoff Matrices

A

the likelihood of each type of aa replaces are derived empirically from data of closely related sequences

6
Q

Is the replacement rate (K) constant over time?

A
• Align multiple sequences
• Calculate D for each pair of sequences (perhaps using substitution matrix to correct for types)
• Estimate k to correct for multiple substitutions
• Estimate T from the fossil record
• Plot T vs K, is it linear?
7
Q

Protein substitution rate

A
• different proteins have different substitution rate BUT rate is constant within proteins

Each data set conforms to a line, evolving in their own clock-like fashion - why? Different proteins have different constraints acting on them (functional constraint)

8
Q

Kimura and Ohta - protein evolution rates

A

See OneNote
- if most substitutions in proteins are neutral, fixation rate = mutation rate

• if most substituions in proteins are adaptive,
f = 4NmuaS (see oneNote for eqn.) =

Kimura argued that it is unlikely that the product of population size, advantageous mutation rate and selective co-efficient would be constant over the phylogeny of species

9
Q

Do all proteins evolve in a clock-like way? Is the observed rate different significant?

A

Relative rate tests

10
Q

Relative rate tests

A

See OneNote diagram

• if the clock holds then we expect Dax = Dbx
• Tajimas 1D test, p<0.05 is significant
11
Q

Drosophila Esterase 6

A

See OneNote

In most lineages of the subgenus Sophophora esterase-6 is a homodimeric haemolymph protein. In the melanogaster subgroup of species it has become a monomer which is mainly expressed in the male sperm ejaculatory duct. Our analyses of esterase-6 sequences from three melanogaster subgroup species and two close relatives reveal a brief period of accelerated amino acid sequence change during the transition between the ancestral and derived states.

12
Q

Deviations from the clock at the level of the gene

A
1. relaxation of functional constraint?

2. selection for aa change in some lineages?

13
Q

Causes of rate variation

A
1. gene effects e.g. functional constraint, mutation rate heterogeneity
2. genome level/lineage effects
3. combination of things that aren’t explicitly modelled (residual effects)
14
Q

Deviations from the clock at the level of the taxon

A
1. metabolic rate hypothesis
2. DNA repair hypothesis
3. Generation time hypothesis
15
Q

Metabolic rate hypothesis

A

Higher metabolic rate => the more DNA damaging free radicals

Shark have a very low metabolic rate, less free radical => less DNA damage?

correlation between metabolic rate and DNA change doesn’t hold

16
Q

DNA repair hypothesis

A

Large animals have more cells (and longer life span) so error checking selected to be better (“primate slow down”)

Humans have a much more efficient DNA glycosylase enzyme than rodents

correlation holds

17
Q

Generation time hypothesis

A

More replications per year expected to lead to more errors per year

Different number of germ line divisions per year between the different organisms - many more cell division in some species in comparison to others

correlation holds

18
Q

A problem with the clock

A

Shouldn’t the molecular clock be measured in generations rather than years?
- it depends on what causes mutations, irradiation? Errors in DNA synthesis and repair?

19
Q

Ohta’s nearly neutral model

A

See OneNote

• population size is relevant to fixation rate

Big population sizes seem to have small generation times

If deleterious mutations are being fixed then mutation rate doesn’t equal fixation rate

In small populations, deleterious mutations can become fixed, hence, population size would be relevant to fixation rate

In large mutations, deleterious mutations do not become fixed

20
Q

Deviations from the clock because the model is wrong

A

Variants to the rate of the clock “ticking”

So…
Allow a greater variance, the data would conform better => over-dispersed clock/relaxed clock

Use a relaxed clock to account for all the noise