L5 The Molecular Clock Flashcards
The Molecular Clock
- 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
lambda
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)
Hartl and Clark Equation
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?
The likelihood of aa changes depends on
- Protein abundance bias
2. aa have different biophysical properties
Dayhoff Matrices
the likelihood of each type of aa replaces are derived empirically from data of closely related sequences
Is the replacement rate (K) constant over time?
- 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?
Protein substitution rate
- 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)
Kimura and Ohta - protein evolution rates
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
Do all proteins evolve in a clock-like way? Is the observed rate different significant?
Relative rate tests
Relative rate tests
See OneNote diagram
- if the clock holds then we expect Dax = Dbx
- Tajimas 1D test, p<0.05 is significant
Drosophila Esterase 6
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.
Deviations from the clock at the level of the gene
- relaxation of functional constraint?
2. selection for aa change in some lineages?
Causes of rate variation
- gene effects e.g. functional constraint, mutation rate heterogeneity
- genome level/lineage effects
- combination of things that aren’t explicitly modelled (residual effects)
Deviations from the clock at the level of the taxon
- metabolic rate hypothesis
- DNA repair hypothesis
- Generation time hypothesis
Metabolic rate hypothesis
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
DNA repair hypothesis
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
Generation time hypothesis
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
A problem with the clock
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?
Ohta’s nearly neutral model
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
Deviations from the clock because the model is wrong
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
