Transcript Document

Hickory Dickory Dock:
Understanding the Molecular Clock
Felisa Wolfe
[email protected]
ERUPT: Biocomplexity Seminar
28 Feb 2003
Structure of Talk:
I. Making (shakin’) a Tree
1. Basis
2. Assumptions
3. Methods
II. Applying a Clock
1. Types
2. Examples (general)
3. Pros and Cons
Making a Tree: Basis
Allele: alternative form of a gene
N population size
2N  gene copies
What can change allele frequency?
1. Mutation
2. Natural Selection
3. Genetic drift
4. migration
Making a Tree: Basis (con’d)
Mutations: 3 types
1- silent
2- missense (change in AA)
3- nonsense (termination codon)
4- indels- change length of codon
Making a Tree: Assumptions
Natural Selection:
1- Hardy-Weinberg before selection
2- selection = survivorship (diploid)
3- Infinite population size
Making a Tree: Assumptions (con’d)
Neutral Mutation Theory (Kimura and Ohta, 1974)
1- AA substitution rate is ~ constant
2- functionally less important evolves faster
3- deleterious and neutral more common
4- gene duplication precedes new function
5- deleterious and neutral mutation loss more
often than positive beneficial fixation
Making a Tree: Methods
Phylogenetic Trees as NETWORKS
Ancestral species vs. ancestral sequence
Human
Chimp
Gorilla Orangutan
ATGC
Branch Lengths:
Two -methods
Distanceto build trees:
1- Distance
- # changes
2- Character
- Time
TTGC
Making a Tree: Methods (con’d)
n OTUs external nodes
n-2  internal nodes
n
# rooted distinct
topologies
# unrooted
distinct
topologies
2
1
1
3
3
1
4
15
3
5
105
15
6
954
105
10
34,459,425
2,027,025
Making a Tree: Methods (con’d)
Distance:
•Build a matrix requires decision
•Construct tree according to algorithm
Ex. UPGMA, Neighbor Joining
Character:
•Consider data and tree together
•Predict character states of internal nodes
Ex. Max. Parsimony, Max. Likelihood
AlignmentsLine up sequences (AA or DNA),
High similarity strongly suggests homology
Basis for determining tree topologies &
branch lengths
Making a Tree: Methods (con’d)
Maximum Likelihood:
Best tree is most likely under model of the probability of
mutations.
Star Phylogeny
Ex.
1 A
2 A
3 A
4 A
C
C
C
C
T
T
A
A
G
G
G
C
X1
1
X2
X3
X4
2
4
3
Applying a Clock
“The molecular clock hypothesis postulates that for
any given macromolecule (a protein or DNA
sequence) the rate of evolution is approximately
constant over time in all evolutionary lineages”
Li 1997
Can be used similar to dating of geologic time
using radioactive elements.
Applying a Clock: Types
1. No Clock – each branch has an independent
rate; n sequences then (2n-3) parameters
(branch lengths)
2. Global Clock – all braches have same rate; (n-1)
parameters  ( (n-1) internal nodes)
3. Local Clock - default rate for all branches; except
for predefined branches
4. TipDate – depends on when isolated, i.e.
pathogens (virus, etc.)
Applying a Clock: Examples
Applying a Clock: Examples (con’d)
X
A
• 3 taxa
• 1 fossil taxa around
at time of common
ancestor?
• Fossils tend to
come with data
Ex. X @ 106 Y
?
B
C
A
B
(DAC + DBC)/ 2
A
B
C
C
8
21
23
106
DAB
=
?
Applying a Clock: Pros and Cons
Causes of rate variation among lineages
1- efficiency of DNA repair
2- Generation-time effect hypothesis
3- Metabolic-rate hypothesis
Conclusions:
• Natural selection and genetic drift both active;
dependent on N.
• Neutral Mutation Theory widely accepted be
cautious!
• Analyses on “gene” evol.; remember not organism
evolution (i.e. molecule vs. whole phenotype)
• Trees dependent on model. Maybe misleading- ML
most robust.
• After the above 4 points:
clock can be applied in wide variety of situations to
understand the relationships AND timing between
organisms.
Many thanks to:
Ken Miller
Mimi Katz
Paul Falkowski
Oscar Schofield
Costantino Vetriani
John Reinfelder
Jody Hey
Ed Stiefel
Lee Kerkhof
Colomban de Vargas
Yi Sun
Daniel Grzbeyk
Rob Sherrell
Yibu Chen
Antonietta Quigg
Tuo Shi
Augie Trey
Nick DeVito
Nashwa Choudhry
General References:
Hudson, R.R., (1990) “Gene genealogies and the
coalescent process.” in Oxford Surveys on
Evolutionary Biology. D. Futuyma and J.
Antonovics, Eds. Oxford Univ. Press, NY. Pp. 1-44
Kimura, M. and T. Ohta. (1974) “On some principles
governing molecular evolution.” PNAS 71:28482852
Li, W-H. Molecular Evolution 1997
Yang, Z. (1997). “PAML: A program package for
phylogenetic analysis by maximum likelihood.”
CABIOS. 13:555-556
Zuckerkandl, E. and L. Pauling (1965) “Molecules as
documents of evolutionary history.” Journal of
Theoretical Biology. 8(2):357-366
…and many, MANY others.