Hickory Dickory Dock: Understanding the Molecular Clock

Felisa Wolfewolfe@imcs.rutgers.edu

ERUPT: Biocomplexity Seminar28 Feb 2003

Structure of Talk:

I. Making (shakin’) a Tree1. Basis2. Assumptions3. Methods

II. Applying a Clock1. Types2. Examples (general)3. Pros and Cons

N population size2N gene copies

Making a Tree: Basis

What can change allele frequency?1. Mutation2. Natural Selection3. Genetic drift4. migration

Allele: alternative form of a gene

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

Natural Selection:

1- Hardy-Weinberg before selection

2- selection = survivorship (diploid)

3- Infinite population size

Making a Tree: Assumptions

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: Assumptions (con’d)

Making a Tree: Methods

Phylogenetic Trees as NETWORKSAncestral species vs. ancestral sequence

Two methods to build trees: 1- Distance2- Character

Branch Lengths:- Distance- # changes- Time

ATGC TTGCHuman Chimp Gorilla Orangutan

n OTUs external nodesn-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)

Alignments-Line up sequences (AA or DNA),High similarity strongly suggests homologyBasis for determining tree topologies & branch lengths

Making a Tree: Methods (con’d)Distance:•Build a matrix requires decision

•Construct tree according to algorithmEx. UPGMA, Neighbor Joining

Character:•Consider data and tree together

•Predict character states of internal nodes

Ex. Max. Parsimony, Max. Likelihood

Making a Tree: Methods (con’d)

Maximum Likelihood: Best tree is most likely under model of the probability of mutations.

Ex.1 A C T G2 A C T G3 A C A G4 A C A C

1

2

3

4

X1 X4X2 X3

Star Phylogeny

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

X A

B

C

? • 3 taxa• 1 fossil taxa around

at time of common ancestor?

• Fossils tend to come with data

Ex. X @ 106 Y

Applying a Clock: Examples (con’d)

A

A

B

B C

C

8

21 23

(DAC + DBC)/ 2

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 MillerMimi KatzPaul FalkowskiOscar SchofieldCostantino Vetriani John ReinfelderJody HeyEd StiefelLee KerkhofColomban de VargasYi SunDaniel GrzbeykRob Sherrell Yibu ChenAntonietta QuiggTuo ShiAugie TreyNick DeVitoNashwa 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. 1-44Kimura, M. and T. Ohta. (1974) “On some principles governing molecular evolution.” PNAS 71:2848-2852Li, W-H. Molecular Evolution 1997Yang, Z. (1997). “PAML: A program package for phylogenetic analysis by maximum likelihood.” CABIOS. 13:555-556Zuckerkandl, E. and L. Pauling (1965) “Molecules as documents of evolutionary history.” Journal of Theoretical Biology. 8(2):357-366

…and many, MANY others.