Phylogenetics:
Bayesian Phylogenetic Analysis
COMP 571 - Spring 2016
Luay Nakhleh, Rice University
Bayes Rule
P(X = x|Y = y) =
P(X = x, Y = y)
P(X = x)P(Y = y|X = x)
= P
0
0
P(Y = y)
x0 P(X = x )P(Y = y|X = x )
Bayes Rule
Example (from “Machine Learning: A
Probabilistic Perspective”)
Consider a woman in her 40s who decides to
have a mammogram.
Question: If the test is positive, what is the
probability that she has cancer?
The answer depends on how reliable the test
is!
Bayes Rule
Suppose the test has a sensitivity of
80%; that is, if a person has cancer, the
test will be positive with probability
0.8.
If we denote by x=1 the event that the
mammogram is positive, and by y=1 the
event that the person has breast
cancer, then P(x=1|y=1)=0.8.
Bayes Rule
Does the probability that the woman in
our example (who tested positive) has
cancer equal 0.8?
Bayes Rule
No!
That ignores the prior probability of
having breast cancer, which,
fortunately, is quite low: p(y=1)=0.004
Bayes Rule
Further, we need to take into account
the fact that the test may be a false
positive.
Mammograms have a false positive
probability of p(x=1|y=0)=0.1.
Bayes Rule
Combining all these facts using Bayes
rule, we get (using p(y=0)=1-p(y=1)):
p(y = 1|x = 1)
=
=
=
p(x=1|y=1)p(y=1)
p(x=1|y=1)p(y=1)+p(x=1|y=0)p(y=0)
0.8⇥0.004
0.8⇥0.004+0.1⇥0.996
0.031
How does Bayesian reasoning apply to
phylogenetic inference?
Assume we are interested in the
relationships bet ween human, gorilla,
and chimpanzee (with orangutan as an
outgroup).
There are clearly three possible
relationships.
How does Bayesian reasoning apply to phylogenetic inference? Assume we are
interested in the relationships between man, gorilla, and chimpanzee. In the standard case, we need an additional species to root the tree, and the orangutan would
be appropriate here. There are three possible ways of arranging these species in a
phylogenetic tree: the chimpanzee is our closest relative, the gorilla is our closest
relative, or the chimpanzee and the gorilla are each other’s closest relatives (Fig. 7.1).
A
B
C
Probability
1.0
Prior distribution
0.5
0.0
Before the analysis, we need to specify
our prior beliefs about the relationships.
For example, in the absence of
background data, a simple solution
would be to assign equal probability to
the possible trees.
be appropriate here. There are three possible ways of arranging these species in
phylogenetic tree: the chimpanzee is our closest relative, the gorilla is our closes
relative, or the chimpanzee and the gorilla are each other’s closest relatives (Fig. 7.1)
A
B
C
Probability
1.0
Prior distribution
0.5
0.0
[This is an uninformative prior]
Data (observations)
To update the prior, we need some data,
typically in the form of a molecular
sequence alignment, and a stochastic
model of the process generating the
data on the tree.
In principle, Bayes rule is then used to
obtain the posterior probability
distribution, which is the result of the
analysis.
The posterior specifies the probability of
each tree given the model, the prior, and
the data.
When the data are informative, most
of the posterior probability is typically
concentrated on one tree (or, a small
subset of trees in a large tree space).
be appropriate here. There are three possible ways of arranging these species in a
phylogenetic tree: the chimpanzee is our closest relative, the gorilla is our closest
relative, or the chimpanzee and the gorilla are each other’s closest relatives (Fig. 7.1).
A
B
C
Probability
1.0
Prior distribution
0.5
0.0
Data (observations)
Probability
1.0
0.5
0.0
Posterior distribution
To describe the analysis mathematically,
consider:
the matrix of aligned sequences X
the tree topology parameter τ
the branch lengths of the tree ν
(typically, substitution model
parameters are also included)
Let θ=(τ,ν)
model (see below), which does not have any free parame
θ = (τ, v).
Bayes’ theorem allows us to derive the posterior distrib
f (θ) f (X|θ)
f (θ|X) =
f (X) us
Bayes theorem allows
posterior distribution as
to derive the
The denominator is an integral over the parameter va
f (✓)f (X|✓)
f (✓|X)
=
a summation
over discrete
topologies and a multidimen
f (X)
possible branch length values:
where
f (X) =
!
f (θ) f (X|θ) dθ
"!
f (v) f (X|τ, v) dv
=
τ
v
Fig. 7.2
Fredrik Ronquist, Paul van der Mark, and John P. Huelsenbeck
Posterior Probability
218
48%
32%
20%
topology A
topology B
topology C
Posterior probability distribution for our phylogenetic analysis. The x-axis is an imag
one-dimensional representation of the parameter space. It falls into three different re
corresponding to the three different topologies. Within each region, a point along th
The marginal probability distribution on topologies
Why
they called
marginal
Bayesianare
phylogenetic
analysis using
M R B AYES : theory
probabilities?
Topologies
Joint probabilities
τ
τ
τ
ν
A
0.10
0.07
0.12
0.29
ν
B
0.05
0.22
0.06
0.33
ν
C
0.05
0.19
0.14
0.38
0.20
0.48
0.32
A
Branch length vectors
219
B
Marginal probabilities
C
Markov chain Monte Carlo
Sampling
In most cases, it is impossible to derive
the posterior probability distribution
analytically.
Even worse, we can’t even estimate it by
drawing random samples from it.
The reason is that most of the posterior
probability is likely to be concentrated
in a small part of a vast parameter
space.
The solution is to estimate the posterior
probability distribution using Markov
chain Monte Carlo sampling, or MCMC
for short.
Monte Carlo = random simulation
Markov chain = the state of the
simulator depends only on the current
state
Irreducible Markov chains (their
topology is strongly connected) have
the property that they converge
towards an equilibrium state regardless
of starting point.
We just need to set up a Markov chain
that converges onto our posterior
probability distribution!
(step i + 1) given its current state (in step i). These
ition rates if we are working with continuous-time
A Markov chain can be defined by describing the full set of probability
rules for the state of the chain in the next step (step i + 1) given its curr
transition
probabilities are analogous to transition rates if we are wor
one with
two states
Markov
processes.
e figure
to the
right
babilities are shown
ties next
to thethe
line.
Consider
simplest possible Markov chain: one with two states
0.6 time. The figure to the right
d to (0,
the and
graph
1) are:
that operates in discrete
shows the states in
are shown
0.4circles.
0 The transition
1 probabilities
0.1
as arcs connecting the states with the probabilities next to the line.
The full probability statements0.9
that correspond to the graph are:
Stationary Distribution
of a Markov Chain
P(xi+1 = 0|xi = 0) = 0.4
0.
P(xi+1 = 1|xi = 0) = 0.6
e of them must sum Figure
1: =A0|x
graphical
depicP(xi+1
0.9
i = 1) =
r state at step i we tion of a two-state Markov
P(xi+1 = 1|xi = 1) = 0.1
t have some state so process.
Note that, because these are probabilities, some of them must sum Fig
to one. In particular, if we are in a particular state at step i we tio
on the
canstate
call at
thestep
state xi . In the next step, we must have some state so
(step i + 1) given its current state (in step i). These
ition rates if we are working with continuous-time
A Markov chain can be defined by describing the full set of probability
rules for the state of the chain in the next step (step i + 1) given its curr
transition
probabilities are analogous to transition rates if we are wor
one with
two states
Markov
processes.
e figure
to the
right
babilities are shown
ties next
to thethe
line.
Consider
simplest possible Markov chain: one with two states
0.6 time. The figure to the right
d to (0,
the and
graph
1) are:
that operates in discrete
shows the states in
are shown
0.4circles.
0 The transition
1 probabilities
0.1
as arcs connecting the states with the probabilities next to the line.
The full probability statements0.9
that correspond to the graph are:
Stationary Distribution
of a Markov Chain
P(xi+1 = 0|xi = 0) = 0.4
0.
P(xi+1 = 1|xi = 0) = 0.6
e of them must sum Figure
1: =A0|x
graphical
depicP(xi+1
0.9
i = 1) =
r state at step i we tion of a two-state Markov
P(xi+1 = 1|xi = 1) = 0.1
t have some state so process.
Note
that, are
because
areP(xprobabilities,
some of them must sum Fig
P(xi =these
0|x0 = 0)
i = 1|x0 = 0) P(xi = 0|x0 = 1) P(xi = 1|x0 = 1) ?
What
to one. In particular, if we are in a particular state at step i we tio
on the
canstate
call at
thestep
state xi . In the next step, we must have some state so
(step i + 1) given its current state (in step i). These
ition rates if we are working with continuous-time
Stationary Distribution
of a Markov Chain
one with two states
e figure to the right
babilities are shown
ties next to the line.
d to the graph are:
0.6
0.4
0
1
0.1
0.9
P(xi = k|x0 = `) = P(xi = k|xi 1 = 0)P(xi 1 = 0|x0 = `)
e of them must sum Figure 1:+P(x
= 1)P(xi 1 = 1|x0 = `)
i = k|xi 1depicA graphical
r state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
(step i + 1) given its current state (in step i). These
ition rates if we are working with continuous-time
Stationary Distribution
of a Markov Chain
one with two states
e figure to the right
babilities are shown
ties next to the line.
d to the graph are:
0.6
0.4
0
1
0.1
0.9
P(xi = k|x0 = `) = P(xi = k|xi 1 = 0)P(xi 1 = 0|x0 = `)
e of them must sum Figure 1:+P(x
= 1)P(xi 1 = 1|x0 = `)
i = k|xi 1depicA graphical
r state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
transition probabilities
(step i + 1) given its current state (in step i). These
ition rates if we are working with continuous-time
Stationary Distribution
of a Markov Chain
one with two states
Note that:
e figure to the right
P(x
= 1|x = 0) = P(x
= 1|x
= 1)P(x
= 1|x = 0) + P(x
= 1|x
= 0)P(x
= 0|x = 0)
= 0.1 ⇤ 0.6 + 0.6 ⇤ 0.4
babilities are shown
= 0.3
ties next to the line.
So, if we sum over all possible states at i + 2, the relevant probability statements sum to one.
0.6
d to the graph are:
i+2
i
i+2
i+1
i+1
i
i+2
i+1
i+1
It gets tedious to continue this for a large number of steps into the future. But we can ask a
computer to calculate the probability of being in state 0 for a large number of steps into the future
by repeating the calculations (see the Appendix A for code). Figure (2) shows the probabilities of
the Markov process being in state 0 as a function of the step number for the two possible starting
states.
0.4
0
1
0.1
1.0
0.8
0.6
0.6
0.8
1.0
0.9
0.0
0.2
0.4
Pr(x_i=0)
0.0
0.2
0.4
Pr(x_i=0)
e of them must sum Figure 1: A graphical depicr state at step i we tion of a two-state Markov
t have some state so process.
0
5
10
i
15
0
5
10
i
15
on the state at step
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
P(xi = 0|x0 = 0)
P(xi = 0|x0 = 1)
i
(step i + 1) given its current state (in step i). These
ition rates if we are working with continuous-time
Stationary Distribution
of a Markov Chain
one with two states
Note that:
e figure to the right
P(x
= 1|x = 0) = P(x
= 1|x
= 1)P(x
= 1|x = 0) + P(x
= 1|x
= 0)P(x
= 0|x = 0)
= 0.1 ⇤ 0.6 + 0.6 ⇤ 0.4
babilities are shown
= 0.3
ties next to the line.
So, if we sum over all possible states at i + 2, the relevant probability statements sum to one.
0.6
same probability
d to the graph are:
i+2
i
i+2
i+1
i+1
i
i+2
i+1
i+1
It gets tedious to continue this for a large number of steps into the future. But we can ask a
computer to calculate the probability of being in state 0 for a large number of steps into the future
by repeating the calculations (see the Appendix A for code). Figure (2) shows the probabilities of
the Markov process being in state 0 as a function of the step number for the two possible starting
states.
0.4
0
1
regardless of
starting state!
0.1
1.0
0.8
0.6
0.6
0.8
1.0
0.9
0.0
0.2
0.4
Pr(x_i=0)
0.0
0.2
0.4
Pr(x_i=0)
e of them must sum Figure 1: A graphical depicr state at step i we tion of a two-state Markov
t have some state so process.
0
5
10
i
15
0
5
10
i
15
on the state at step
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
P(xi = 0|x0 = 0)
i
P(xi = 0|x0 = 1)
re working with continuous-time
Stationary Distribution
of a Markov Chain
P(xi+2 = 1|xi = 0) = P(xi+2 = 1|xi+1 = 1)P(xi+1 = 1|xi = 0) + P(xi+2 = 1|xi+1 = 0)P(xi+1 = 0|xi =
= 0.1 ⇤ 0.6 + 0.6 ⇤ 0.4
= 0.3
So, if we sum over all possible states at i + 2, the relevant probability statements sum to one.
s
t
n
e.
1.0
0.6
Pr(x_i=0)
0.4
0.2
0.9
0.0
0.1
0.4
1
0.2
0
0.0
0.4
Pr(x_i=0)
0.6
0.8
0.6
0.8
1.0
It gets tedious to continue this for a large number of steps into the future. But we can ask a
computer to calculate the probability of being in state 0 for a large number of steps into the future
by repeating the calculations (see the Appendix A for code). Figure (2) shows the probabilities of
the Markov process being in state 0 as a function of the step number for the two possible starting
states.
m Figure 1: A graphical depice tion of a two-state Markov
o process.
p
Note that:
0
5
10
15
0
5
i
10
15
i
P(xi = 0|x0 = 0)
P(xi = 0|x0 = 1)
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
starting states (0 and 1) for the Markov process depicted in Figure (1).
Note that the probability stabilizes to a steady state distribution. Knowing whether the chain
started in state 0 or 1 tells you very little about the state of the chain in step 15. Technically, x15
and x0 are not independent of each other. If you work through the math the probability of the
state at step 15 does depend on the starting state:
P(x15 = 0|x0 = 0) = 0.599987792969
P(x15 = 0|x0 = 1) = 0.600018310547
But clearly these two probabilities are very close to being equal.
If we consider an even larger number of iterations (e.g. the state at step 100), then the probabilities
are so close that they are indistinguishable.
3
re working with continuous-time
Stationary Distribution
of a Markov Chain
P(xi+2 = 1|xi = 0) = P(xi+2 = 1|xi+1 = 1)P(xi+1 = 1|xi = 0) + P(xi+2 = 1|xi+1 = 0)P(xi+1 = 0|xi =
= 0.1 ⇤ 0.6 + 0.6 ⇤ 0.4
= 0.3
So, if we sum over all possible states at i + 2, the relevant probability statements sum to one.
s
t
n
e.
1.0
0.6
Pr(x_i=0)
0.4
0.2
0.9
0.0
0.1
0.4
1
0.2
0
0.0
0.4
Pr(x_i=0)
0.6
0.8
0.6
0.8
1.0
It gets tedious to continue this for a large number of steps into the future. But we can ask a
computer to calculate the probability of being in state 0 for a large number of steps into the future
by repeating the calculations (see the Appendix A for code). Figure (2) shows the probabilities of
the Markov process being in state 0 as a function of the step number for the two possible starting
states.
m Figure 1: A graphical depice tion of a two-state Markov
o process.
p
Note that:
0
5
10
15
0
5
i
10
15
i
P(xi = 0|x0 = 0)
P(xi = 0|x0 = 1)
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
starting states (0 and 1) for the Markov process depicted in Figure (1).
where does the 0.6
come from?
Note that the probability stabilizes to a steady state distribution. Knowing whether the chain
started in state 0 or 1 tells you very little about the state of the chain in step 15. Technically, x15
and x0 are not independent of each other. If you work through the math the probability of the
state at step 15 does depend on the starting state:
P(x15 = 0|x0 = 0) = 0.599987792969
P(x15 = 0|x0 = 1) = 0.600018310547
But clearly these two probabilities are very close to being equal.
If we consider an even larger number of iterations (e.g. the state at step 100), then the probabilities
are so close that they are indistinguishable.
3
re working with continuous-time
Stationary Distribution
of a Markov Chain
P(xi+2 = 1|xi = 0) = P(xi+2 = 1|xi+1 = 1)P(xi+1 = 1|xi = 0) + P(xi+2 = 1|xi+1 = 0)P(xi+1 = 0|xi =
= 0.1 ⇤ 0.6 + 0.6 ⇤ 0.4
= 0.3
So, if we sum over all possible states at i + 2, the relevant probability statements sum to one.
s
t
n
e.
1.0
0.6
Pr(x_i=0)
0.4
0.2
0.9
0.0
0.1
0.4
1
0.2
0
0.0
0.4
Pr(x_i=0)
0.6
0.8
0.6
0.8
1.0
It gets tedious to continue this for a large number of steps into the future. But we can ask a
computer to calculate the probability of being in state 0 for a large number of steps into the future
by repeating the calculations (see the Appendix A for code). Figure (2) shows the probabilities of
the Markov process being in state 0 as a function of the step number for the two possible starting
states.
0
5
10
15
0
5
i
10
15
i
P(xi = 0|x0 = 0)
P(xi = 0|x0 = 1)
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
starting states (0 and 1) for the Markov process depicted in Figure (1).
m Figure 1: A graphical depice tion of a two-state Markov
o process.
p
Note that:
where does the 0.6
come from?
Note that the probability stabilizes to a steady state distribution. Knowing whether the chain
started in state 0 or 1 tells you very little about the state of the chain in step 15. Technically, x15
and x0 are not independent of each other. If you work through the math the probability of the
state at step 15 does depend on the starting state:
P(x15 = 0|x0 = 0) = 0.599987792969
P(x15 = 0|x0 = 1) = 0.600018310547
But clearly these two probabilities are very close to being equal.
stationary distribution: π0=0.6 π1=0.4
If we consider an even larger number of iterations (e.g. the state at step 100), then the probabilities
are so close that they are indistinguishable.
3
Stationary Distribution
of a Markov Chain
one with two states
e figure to the right
babilities are shown
ties next to the line.
d to the graph are:
0.6
0.4
0
1
0.1
0.9
e of them must sum Figure 1: A graphical depicr state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
we could state it as:
Stationary Distribution
of a Markov Chain
one with two states
e figure to the right
babilities are shown
ties next to the line.
d to the graph are:
0.6
0.4
0
1
0.1
0.9
Imagine infinitely many chains. At equilibrium (steady-state),
the “flux out” of each state must be equal to the “flux into”
that state.
e of them must sum Figure 1: A graphical depicr state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
we could state it as:
ut running infinitely many chains. If we have an equilibrium probability d
characterize the probability of a chain leaving state 0 in at one particular
s is with
the joint
probability of being in state 0 at step i and the probability o
one
two states
e point
figurei.toThus,
the right
Stationary Distribution
of a Markov Chain
babilities are shown
P(0 ! 1 at i) = P(xi = 0)P(xi+1 = 1|xi = 0)
ties next to the line.
0.6
d to the graph are:
ibrium P(xi = 0) = ⇡0 , so the flux out of 0 at step i is ⇡0 P(xi+1 = 1|xi =
0 0 can only 1come0.1
state) system the flux 0.4
into state
from state 1, so:
0.9
P(1 ! 0 at i) = P(xi = 1)P(xi+1 = 0|xi = 1)
Imagine infinitely many
chains. At equilibrium (steady-state),
= ⇡1 P(xi+1 = 0|xi = 1)
the “flux out” of each state must be equal to the “flux into”
he “flux out” and “flux in” to bethat
identical:
state.
e of them must sum Figure 1: A graphical depicr state at step
we tion
⇡0iP(x
= ⇡1 P(x
ofi =
a 0)
two-state
Markov
i+1 = 1|x
i+1 = 0|xi = 1)
t have some state so process.
⇡0
P(xi+1 = 0|xi = 1)
=
⇡1
P(xi+1 = 1|xi = 0)
on
the isstate
at step A reducible chain has some states that are disconnected from o
jargon
“irreducible.”
roken
up (reduced)
into two or more chains that operate on a subset of the states.
we could
state it as:
ut running infinitely many chains. If we have an equilibrium probability d
characterize the probability of a chain leaving state 0 in at one particular
s is with
the joint
probability of being in state 0 at step i and the probability o
one
two states
e point
figurei.toThus,
the right
Stationary Distribution
of a Markov Chain
babilities are shown
P(0 ! 1 at i) = P(xi = 0)P(xi+1 = 1|xi = 0)
ties next to the line.
0.6
d to the graph are:
ibrium P(xi = 0) = ⇡0 , so the flux out of 0 at step i is ⇡0 P(xi+1 = 1|xi =
0 0 can only 1come0.1
state) system the flux 0.4
into state
from state 1, so:
0.9
P(1 ! 0 at i) = P(xi = 1)P(xi+1 = 0|xi = 1)
Imagine infinitely many
chains. At equilibrium (steady-state),
= ⇡1 P(xi+1 = 0|xi = 1)
the “flux out” of each state must be equal to the “flux into”
he “flux out” and “flux in” to bethat
identical:
state.
e of them must sum Figure 1: A graphical depicr state at step
we tion
⇡0iP(x
= ⇡1 P(x
ofi =
a 0)
two-state
Markov
i+1 = 1|x
i+1 = 0|xi = 1)
t have some state so process.
⇡0
P(xi+1 = 0|xi = 1)
=
⇡1
P(xi+1 = 1|xi = 0)
on
the isstate
at step⇡ A =
jargon
“irreducible.”
reducible
chain
states that are disconnected from o
P(xi =
0) has ⇡some
0
1 = P(xi = 1)
roken
up (reduced)
into two or more chains that operate on a subset of the states.
we could
state it as:
Stationary Distribution
of a Markov Chain
one with two states
e figure to the right
babilities are shown
ties next to the line.
d to the graph are:
0.6
0.4
0
1
0.1
0.9
e of them must sum Figure 1: A graphical depicr state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
we could state it as:
his is the joint probability of being in state 0 at step i and the probability of an 0 ! 1
at point i. Thus,
Stationary Distribution
of a Markov Chain
P(0 ! 1 at i) = P(xi = 0)P(xi+1 = 1|xi = 0)
one with two states
uilibrium
= 0)right
= ⇡0 , so the flux out of 0 at step i is ⇡0 P(xi+1 = 1|xi = 0). In our
e figure P(x
to ithe
o-state) system the flux into state 0 can only come from state 1, so:
babilities
are shown
ties next to the
P(1 line.
! 0 at i) = P(xi = 1)P(xi+1 = 0|xi = 1)
0.6
d to the graph are:
= ⇡1 P(xi+1 = 0|xi = 1)
0.4to be identical:
0
the “flux out” and “flux in”
1
0.1
⇡0 P(xi+1 = 1|xi = 0) = ⇡10.9
P(xi+1 = 0|xi = 1)
⇡0
P(xi+1 = 0|xi = 1)
=
⇡1
P(xi+1 = 1|xi = 0)
cy jargon is “irreducible.” A reducible chain has some states that are disconnected from others, so the
up (reduced)
ebroken
of them
must into
sumtwo or more chains that operate on a subset of the states.
Figure 1: A graphical depicr state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
we could state it as:
4
his is the joint probability of being in state 0 at step i and the probability of an 0 ! 1
at point i. Thus,
Stationary Distribution
of a Markov Chain
P(0 ! 1 at i) = P(xi = 0)P(xi+1 = 1|xi = 0)
one with two states
uilibrium
= 0)right
= ⇡0 , so the flux out of 0 at step i is ⇡0 P(xi+1 = 1|xi = 0). In our
e figure P(x
to ithe
o-state) system the flux into state 0 can only come from state 1, so:
babilities
are shown
ties next to the
P(1 line.
! 0 at i) = P(xi = 1)P(xi+1 = 0|xi = 1)
0.6
d to the graph are:
= ⇡1 P(xi+1 = 0|xi = 1)
0.4to be identical:
0
the “flux out” and “flux in”
1
0.1
⇡0 P(xi+1 = 1|xi = 0) = ⇡10.9
P(xi+1 = 0|xi = 1)
⇡0
P(xi+1 = 0|xi = 1)
=
⇡1
P(xi+1 = 1|xi = 0)
cy jargon is “irreducible.” A reducible chain has some states that are disconnected from others, so the
up (reduced)
operate
on 1
a subset of the states.
⇡ +
⇡ =
ebroken
of them
must into
sumtwo or more chains that
1
Figure 1: A0 graphical
depicr state at step i we tion of a two-state Markov
t have some state so process.
on the state at step
we could state it as:
4
his is the joint probability of being in state 0 at step i and the probability of an 0 ! 1
at point i. Thus,
Stationary Distribution
of a Markov Chain
P(0 ! 1 at i) = P(xi = 0)P(xi+1 = 1|xi = 0)
one with two states
uilibrium
= 0)right
= ⇡0 , so the flux out of 0 at step i is ⇡0 P(xi+1 = 1|xi = 0). In our
e figure P(x
to ithe
o-state) system the flux into state 0 can only come from state 1, so:
babilities
are shown
ties next to the
P(1 line.
! 0 at i) = P(xi = 1)P(xi+1 = 0|xi = 1)
0.6
d to the graph are:
= ⇡1 P(xi+1 = 0|xi = 1)
0.4to be identical:
0
the “flux out” and “flux in”
1
0.1
⇡0 P(xi+1 = 1|xi = 0) = ⇡10.9
P(xi+1 = 0|xi = 1)
⇡0
P(x
= 0|xi =that
1) ⇡ is a probability distribution:
We can then solve for the actual frequencies
by i+1
recognizing
=
⇡1
P(xi+1 = 1|xi = 0)
X
⇡k = 1
cy jargon is “irreducible.” A reducible chain has some states that are disconnected from others, so the
k
broken
up
(reduced)
into
two
or
more
chains
that
operate
on 1
a subset of the states.
⇡ +
⇡ =
e of them must sum
1:
For the system that we areFigure
considering:
1
A0 graphical
depicr state at step i we tion of a two-state Markov
⇡0
0.9
t have some state so process.
=
= 1.5
⇡1
0.6
on the state at step
we could state it as:
4
⇡0 = 1.5⇡1
1.5⇡1 + ⇡1 = 1.0
⇡1 = 0.4
⇡0 = 0.6
Stationary Distribution
of a Markov Chain
If we can choose the transition probabilities of the
Markov chain, then we can construct a sampler
that will converge to any distribution that we desire!
Thus,the
the transition
probabilities
determine the stationary
distribution.
e can choose
transition
probabilities
then we
can construct a sampler that
hen weto
have
a state set S withthat
morewe
than
2 states,
we can express a general statement about
verge
any
would
like.
If wedistribution
can choose the transition
probabilities
then we can construct a sampler that will
ationary distribution:
converge to any distribution that
Xwe would like.
⇡j =than ⇡
P(xi+1 we
= j|x
k)
i =
kstates,
n we have aWhen
state
set
S
with
more
2
can
express
a general statement abou
we have a state set S with more than 2 states, we can express a general statement about the
k2S
onary distribution:
stationary distribution:
X X
⇡ = in”
⇡kargument
P(xi+1 =
= j|x
==
k) k)
he connection to the “flux out”⇡and
“flux
not seem obvious, but(1)
note that
j|xi may
j = j ⇡k P(x
i+1
i
k2S
ux out” can be quantified in terms k2S
of the
1 - the “self-transition.” Let S6=j be the set of st
The connection to the “flux out” and “flux in” argument may not seem obvious, but note that the
at excludes stateout”
j, can
so be
thequantified
“flux out”
is: the 1 - the “self-transition.” Let S be the set of states
terms ofin”
6=j obvious, but note tha
connection “flux
to the “flux
out” andin “flux
argument may not seem
that excludes state j, so the “flux out” is:
out” can be quantifiedflux
in terms
thei+1
“self-transition.”
out ofof
j the
= 1⇡-j P(x
2 S6=j |xi = j) Let S6=j be the set of s
flux outis:
of j = ⇡j P(xi+1 2 S6=j |xi = j)
excludes state j, so the “flux out”
= =⇡j⇡[1
P(x
2 ij|x
i+1
i = j)]
P(xi+1
2 j|x
= j)]
j [1
Stationary Distribution
of a Markov Chain
For the general case of more than 2
states:
The flux in is:
he flux in is:
flux in is:
flux out of j = ⇡j P(xi+1 2 S6=j |xi = j)
= ⇡j [1
P(xi+1 2 j|xi = j)]
X
flux into j = X ⇡k P(xi+1 = j|xi = k)
flux into j =
Forcing the fluxes to be equal gives us:
⇡k P(xi+1 = j|xi = k)
k2S6=j
k2S6=j
X
X
⇡j [1 P(x
j|xi =j j)] ==
⇡k⇡P(x
j|xi=
= j|x
k) i = k)
i+1 =
i+1 =
flux
into
i+1
k P(x
rcing the fluxes to be equal gives us:
k2S6=j
k2S6=j
X
X
⇡j = ⇡j P(xi+1 = j|xi = j) +
⇡k P(xi+1 = j|xi = k)
(2)
⇡j [1 P(xi+1 = j|xi = j)] =
⇡k P(xi+1 = j|xk2S
i =
6=j k)
X
= 6=j ⇡k P(xi+1 = j|xi = k)
ng the fluxes to be equal gives us: k2S
X
k2S
⇡j = X
⇡j P(xi+1 = j|xi = j) +
⇡k P(xi+1 = j|xi = k)
⇡j [1 P(xi+1 = j|xi = j)] =
⇡k P(xi+1 = j|xi =k2S
k) 6=j
Mixing
While setting the transition
probabilities to specific values affects
the stationary distribution, the
transition probabilities cannot be
determined uniquely from the
stationary distribution.
1.0
1.0
states.
0.8
0.6
We just saw how changing transition probabilities will a↵ect the stationary distribution. Perhaps,
there is a one-to-one mapping between transition probabilities and a stationary distribution. In the
form of a question: if we were given the stationary distribution could we decide what the transition
rates must be to achieve that distribution?
0.4
Pr(x_i=0)
0.2
It turns out that the answer is “No.” Which can be seen if we examine equation (2). Imagine
dropping the “flux out” of each state by a factor of 10. Because the “self-transition” rate would
increase by the appropriate amount, we can still end up in the same stationary distribution.
0.0
0.0
0.2
0.4
Pr(x_i=0)
0.6
0.8
Mixing
How would such a chain behave? The primary di↵erence is that it would “mix” more slowly.
0
5
10
15
0
5
10
15
Adjacent steps would be more likely to be in the same state, and it would take a larger number
i
i
of iterationsP(x
before
“forgets” its starting state. FigureP(x
(3)i =
depicts
0)
0|x0 = the
1) same probability
i = 0|xthe
0 = chain
statements as Figure (2) but for a process in which P(xi+1 = 1|xi = 0) = 0.06 and P(xi+1 = 0|xi =
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
1) = 0.09.
starting states (0 and 1) for the Markov process depicted in Figure (1).
0.8
1.0
Note that the probability stabilizes to a steady state distribution. Knowing whether the chain
started in state 0 or 1 tells you very little about the state of the chain in step 15. Technically, x15
and x0 are not independent of each other. If you work through the math the probability of the
state at step 15 does depend on the starting state:
But clearly these two probabilities are very close to being equal.
If we consider an even larger number of iterations (e.g. the state at step 100), then the probabilities
are so close that they are indistinguishable.
0.0
0.0
0.2
0.4
0.4
Pr(x_i=0)
P(x15 = 0|x0 = 1) = 0.600018310547
0.2
Pr(x_i=0)
0.6
P(x15 = 0|x0 = 0) = 0.599987792969
0.6
0.8
1.0
P(xi+1 = 1|xi = 0) = 0.6 P(xi+1 = 0|xi = 1) = 0.9
0
10
20
i
P(xi = 0|x0 = 0)
30
40
3
0
10
20
30
40
i
P(xi = 0|x0 = 1)
Figure 3: The probability of being in state 0 as a function of the step number, i, for two di↵erent
P(xi+1 =
1|x
0.06
=(1) 0|x
1) = 0.09
i (0=
i the=state-changing
starting
states
and 0)
1) for =
the Markov
processP(x
depictedi+1
in Figure
but with
transition probabilities scaled down by a factor of 10. Compare this to Figure (2).
1.0
1.0
states.
0.8
0.6
We just saw how changing transition probabilities will a↵ect the stationary distribution. Perhaps,
there is a one-to-one mapping between transition probabilities and a stationary distribution. In the
form of a question: if we were given the stationary distribution could we decide what the transition
rates must be to achieve that distribution?
0.4
Pr(x_i=0)
0.2
It turns out that the answer is “No.” Which can be seen if we examine equation (2). Imagine
dropping the “flux out” of each state by a factor of 10. Because the “self-transition” rate would
increase by the appropriate amount, we can still end up in the same stationary distribution.
0.0
0.0
0.2
0.4
Pr(x_i=0)
0.6
0.8
Mixing
How would such a chain behave? The primary di↵erence is that it would “mix” more slowly.
0
5
10
15
0
5
10
15
Adjacent steps would be more likely to be in the same state, and it would take a larger number
i
i
of iterationsP(x
before
“forgets” its starting state. FigureP(x
(3)i =
depicts
0)
0|x0 = the
1) same probability
i = 0|xthe
0 = chain
statements as Figure (2) but for a process in which P(xi+1 = 1|xi = 0) = 0.06 and P(xi+1 = 0|xi =
Figure 2: The probability of being in state 0 as a function of the step number, i, for two di↵erent
1) = 0.09.
starting states (0 and 1) for the Markov process depicted in Figure (1).
0.8
1.0
Note that the probability stabilizes to a steady state distribution. Knowing whether the chain
started in state 0 or 1 tells you very little about the state of the chain in step 15. Technically, x15
and x0 are not independent of each other. If you work through the math the probability of the
state at step 15 does depend on the starting state:
But clearly these two probabilities are very close to being equal.
If we consider an even larger number of iterations (e.g. the state at step 100), then the probabilities
are so close that they are indistinguishable.
0.0
0.0
0.2
0.4
0.4
Pr(x_i=0)
P(x15 = 0|x0 = 1) = 0.600018310547
0.2
Pr(x_i=0)
0.6
P(x15 = 0|x0 = 0) = 0.599987792969
0.6
0.8
1.0
P(xi+1 = 1|xi = 0) = 0.6 P(xi+1 = 0|xi = 1) = 0.9
0
10
20
i
P(xi = 0|x0 = 0)
30
40
3
0
10
20
30
40
i
P(xi = 0|x0 = 1)
Figure 3: The probability of being in state 0 as a function of the step number, i, for two di↵erent
P(xi+1 =
1|x
0.06
=(1) 0|x
1) = 0.09
i (0=
i the=state-changing
starting
states
and 0)
1) for =
the Markov
processP(x
depictedi+1
in Figure
but with
transition probabilities scaled down by a factor of 10. Compare this to Figure (2).
Mixing
Setting the transition probabilities to
lower values resulted in a chain that
“mixed” more slowly: Adjacent steps
would be more likely to be in the same
state and, thus, would require a larger
number of iterations before the chain
“forgets” its starting state.
Mixing
The rate of convergence of a chain to its
stationary distribution is an aspect of
a Markov chain that is separate from
what the stationary distribution is.
Mixing
In MCMC, we will design a Markov
chain whose stationary distribution is
identical to the posterior probability
distribution over the space of
parameters.
We try to design chains that have high
transition probabilities to achieve
faster convergence.
Detailed Balance
In practice, the number of states is very
large.
Setting the transition probabilities so
that we have equal flux into and out of
any state is tricky.
What we use instead is detailed
balance.
Detailed Balance
We restrict ourselves to Markov chains
that satisfy detailed balance for all
pairs of states j and k:
⇡j P(xi+1 = k|xi = j) = ⇡k P(xi+1 = j|xi = k)
(equivalently:
⇡j
P(xi+1 = j|xi = k)
=
⇡k
P(xi+1 = k|xi = j)
)
This can be achieved using several
different methods, the most flexible of
which is known as the Metropolis
algorithm and its extension, the
Metropolis-Hastings method.
In the Metropolis-Hastings algorithm,
we choose rules for constructing a
random walk through the parameter
space.
We adopt transition probabilities such
that the stationary distribution of our
Markov chain is equal to the posterior
probability distribution:
⇡✓j = P(✓j |Data)
t`,k
⇡k
=
=
tk,`
⇡`
✓
P(D|✓j = k)P(✓j = k)
P(D)
◆,✓
P(D|✓j = `)P(✓j = `)
P(D)
◆
desired property
t`,k
⇡k
=
=
tk,`
⇡`
✓
P(D|✓j = k)P(✓j = k)
P(D)
◆,✓
P(D|✓j = `)P(✓j = `)
P(D)
◆
desired property
t`,k
⇡k
=
=
tk,`
⇡`
✓
P(D|✓j = k)P(✓j = k)
P(D)
detailed balance
◆,✓
P(D|✓j = `)P(✓j = `)
P(D)
◆
desired property
t`,k
⇡k
=
=
tk,`
⇡`
✓
P(D|✓j = k)P(✓j = k)
P(D)
detailed balance
◆,✓
P(D|✓j = `)P(✓j = `)
P(D)
P(D) cancels out, so
doesn’t need to be
computed!
◆
Therefore, we need to set the transition
probabilities so that
t`,k
P(D|✓j = k)P(✓j = k)
=
tk,`
P(D|✓j = `)P(✓j = `)
However, an important problem arises
when doing this, which can be illustrated
as follows:
when dealing with states k,l, it could be
that we need to set tk,l=1 and tl,k=0.5
when dealing with states k,m, it could be
that we need to set tk,m=0.3 and tm,k=0.1
Then, we have tk,m+tk,l=1.3, which violates
the fundamental rules of probability!
from 1 ! 0. For instance, we could set m0,1 = 1 and m1,0 = 1/3.
1/2 and m1,0 = 1/6. Which should we use? We’d like an MCMC simula
so we should set the transition probabilities as high as possible. So,
1/3 sounds best.
Solution:
arguments lead us to the conclusion that m1,2 = 1 and m2,1 = 3/8. Ho
view
the
transition
probability
as
a
m: setting these four transition probabilities in this way means that P(xi+
the move
is proposed
xi+1 = 2|xi = 1)joint
= 1. event:
But this (1)
violates
fundamental
rules of probability
q, and
moveprobabiliti
is
ually-exclusive with
events probability
must sum to 1.0.
With(2)
ourthe
transition
accepted with probability α.
ution is to view a transition probability as a joint event: the move is pro
pted. We can denote the probability of proposing a move from j to k
If
we
denote
by
x’
i+1 the state
the acceptance probability of a move from j to k (given that the mov
proposed
at step
then
If we were to use
x0i+1 to denote
thei+1,
state
proposed at step i + 1 then
q(j, k) = P(x0i+1 = k|xi = j)
↵(j, k) = P(xi+1 = k|x0i = j, x0i+1 = k)
We can choose proposal probabilities that
sum to one for all the state-changing
transitions.
Then, we can multiply them by the
appropriate acceptance probabilities
(keeping them as high as possible, but ≤1).
We get
t`,k
q(`, k)↵(`, k)
P(D|✓j = k)P(✓j = k)
=
=
tk,`
q(k, `)↵(k, `)
P(D|✓j = `)P(✓j = `)
t`,k
q(`, k)↵(`, k)
P(D|✓j = k)P(✓j = k)
=
=
tk,`
q(k, `)↵(k, `)
P(D|✓j = `)P(✓j = `)
We have flexibility in selecting how we
perform proposals on new states in MCMC.
We have to ensure that q(l,k)>0 whenever
q(k,l)>0 (it is fine if both are 0, but we can’t
have one being 0 and the other greater than
0).
t`,k
q(`, k)↵(`, k)
P(D|✓j = k)P(✓j = k)
=
=
tk,`
q(k, `)↵(k, `)
P(D|✓j = `)P(✓j = `)
However, once we have chosen a proposal
scheme, we do not have much flexibility in
choosing whether or not to accept a
proposal.
t`,k
q(`, k)↵(`, k)
P(D|✓j = k)P(✓j = k)
=
=
tk,`
q(k, `)↵(k, `)
P(D|✓j = `)P(✓j = `)
t`,k
q(`, k)↵(`, k)
P(D|✓j = k)P(✓j = k)
=
=
tk,`
q(k, `)↵(k, `)
P(D|✓j = `)P(✓j = `)
↵(`, k)
P(D|✓j = k)P(✓j = k)q(k, `)
=
↵(k, `)
P(D|✓j = `)P(✓j = `)q(`, k)
t`,k
q(`, k)↵(`, k)
P(D|✓j = k)P(✓j = k)
=
=
tk,`
q(k, `)↵(k, `)
P(D|✓j = `)P(✓j = `)
↵(`, k)
P(D|✓j = k)P(✓j = k)q(k, `)
=
↵(k, `)
P(D|✓j = `)P(✓j = `)q(`, k)
acceptance
=
ratio
(
)(
likelihood
ratio
prior
ratio
)(
Hastings
ratio
)
The central idea is to make small
random changes to some current
parameter values, and then accept or
reject the changes according to the
appropriate probabilities
4
if new state rejected, stay in old state
4. Go to step 2
Posterior probability
q *a
Always accept
q
48%
q*b
32%
20%
Topology A
Accept sometimes
Topology B
Topology C
The Markov chain Monte Carlo (MCMC) procedure is used to gen
from the posterior. One first sets up a Markov chain that has the pos
distribution. The chain is then started at a random point and run until
distribution. In each step (generation) of the chain, a small change i
Bayesian phylogenetic analysis using M R B AYES : theory
Markov chain Monte Carlo steps
1. Start at an arbitrary point (q)
2. Make a small random move (to q*)
3. Calculate height ratio (r ) of new state (to q*) to old state (q)
(a) r > 1: new state accepted
(b) r < 1: new state accepted with probability r
if new state rejected, stay in old state
4. Go to step 2
ability
q *a
Always accept
q
or reject the proposed value with the probability
!
∗
∗ "
f (θ |X)
f (θ|θ )
r = min 1,
×
f (θ|X)
f (θ ∗ |θ)
!
∗
∗
∗ "
f (θ|θ )
f (θ ) f (X|θ )/ f (X)
×
= min 1,
f (θ) f (X|θ)/ f (X)
f (θ ∗ |θ)
!
∗)
∗
∗ "
f (θ
f (X|θ )
f (θ|θ )
= min 1,
×
×
f (θ)
f (X|θ)
f (θ ∗ |θ)
The three ratios in the last equation are referred to as the prior r
prior
likelihood
proposal
ratio, and theratio
proposal ratio (or
Hastings
ratio),
respectively.
T
ratio
ratio
correspond to the ratio of the numerators in Bayes’ theorem; not
2σ
x
An example
ofsliding
a proposal
mechanism
is when the
Both the
window and normal
proposals can be problematic
likelihood varies over the parameter range. For instance, changing a bran
the betathe
proposal:
from 0.01 to 0.03 is likely to have a dramatic effect on the posterior but ch
from 0.51 to 0.53 will hardly be noticeable. In such situations, the multiplier
is appropriate. It is equivalent to a sliding window with width λ on the log sc
parameter. A random number u is drawn from a uniform distribution on th
(−0.5, 0.5) and the proposed value is x ∗ = mx, where m = e λu . If the value o
the form 2 ln a, one will pick multipliers m in the interval (1/a, a).
The beta and Dirichlet proposals are used for simplex parameters. They
values from a beta or Dirichlet distribution centered on the current values of the
Assume that the current values are (x1 , x2 ). We then multiply them with a value
is a tuning parameter, and pick new values from the distribution Beta(αx1 , α
higher the value of α, the closer the proposed values will be to the current valu
Assume the current values are (x1,x2);
Multiply them with a value α;
Pick new values from Beta(αx1,αx2)
10
Beta(70,30)
(α = 100)
Beta(7,3)
(α = 10)
0
0
x = (0.7,0.3)
1
Box 7.2 Proposal mechanisms
A simpler proposal mechanism is to
types of proposal
mechanisms
are commonly used to
defineFour
a continuous
uniform
distribution
The simplest is the sliding window proposal. A continuous u
of width w, centered on the current
w is centered on the current value x, and the new value x ∗ is
valueThe
x, and
the width
newwvalue
x* parameter.
is drawnA larger valu
“window”
is a tuning
fromproposals
this distribution.
and lower acceptance rates, while a smaller value l
and higher acceptance rates.
w
x
The normal proposal is similar to the sliding window
More complex moves are needed to
change tree topology.
A common type uses operations such as
SPR, TBR, and NNI.
Burn-in, mixing, and
convergence
If the chain is started from a random
tree and arbitrarily chosen branch
lengths, chances are that the initial
likelihood is low.
The early phase of the run in which the
likelihood increases very rapidly
towards regions in the posterior with
high probability mass is known as the
burn-in.
224
Fredrik Ronquist, Paul van der Mark, and John P. Huelsenbeck
Trace plot
−26880
Putative stationary phase
ln L
−26920
−26960
−27000
Burn-in
0
100000
200000
300000
400000
500000
Generation
Fig. 7.5
The likelihood values typically increase very rapidly during the initial pha
because the starting point is far away from the regions in parameter spa
posterior probability. This initial phase of the Markov chain is known as the
224
Fredrik Ronquist, Paul van der Mark, and John P. Huelsenbeck
Trace plot
−26880
Putative stationary phase
ln L
−26920
−26960
−27000
Burn-in
0
100000
200000
300000
400000
500000
Generation
Fig. 7.5
The likelihood values typically increase very rapidly during the initial pha
because the starting point is far away from the regions in parameter spa
samples
in this region are discarded!
posterior probability. This initial phase of the Markov chain is known as the
As the chain approaches its stationary
distribution, the likelihood values tend
to reach a plateau.
This is the first sign that the chain may
have converged onto the target
distribution.
However, it is not sufficient for the chain to
reach the region of high probability in the
posterior; it must also cover this region
adequately.
The speed with which the chain covers the
interesting regions of the posterior is
known as its mixing behavior.
The better the mixing, the faster the chain
will generate an adequate sample of the
posterior.
(a)
Target distribution
Sampled value
25
20
Too modest proposals
Acceptance rate too high
Poor mixing
15
10
5
0
100
200
300
400
500
Generation
(b)
Sampled value
25
20
Too bold proposals
Acceptance rate too low
Poor mixing
15
10
5
0
100
200
300
400
500
Generation
(c)
Sampled value
25
20
Moderately bold proposals
Acceptance rate intermediate
Good mixing
15
10
5
0
100
200
300
400
500
Generation
Fig. 7.6
The time it takes for a Markov chain to obtain an adequate sample of the posterior depends
critically on its mixing behavior, which can be controlled to some extent by the proposal
tuning parameters. If the proposed values are very close to the current ones, all proposed
In Bayesian MCMC sampling of
phylogenetic problems, the tree topology
is typically the most difficult parameter
to sample from.
Therefore, it makes sense to focus on
this parameter when monitoring
convergence.
Summarizing the results
The stationary phase of the chain is
typically sampled with some thinning,
for instance every 50th or 100th
generation.
Once an adequate sample is obtained, it
is usually trivial to compute an
estimate of the marginal posterior
distribution for the parameter(s) of
interest.
For example, this can take the form of a
frequency histogram of the sampled
values.
When it is difficult to visualize this
distribution or when space does not
permit it, various summary statistics
are used instead.
The most common approach to
summarizing topology posteriors is to
give the frequencies of the most
common splits, since there are much
fewer splits than topologies.
pairwise distances (see REF. 10 for some suggestions), so
there is considerable debate on which correction to use
(see BOX 2 for a discussion of model selection).
Furthermore, these corrections have substantial variance
when the distances are large.
tion (ME), like NJ, requires that the data be compressed
into a distance matrix; therefore, like NJ, its success is
dependent on the sequence divergences being adequately corrected for multiple hits (or the tree being so
easy to infer that poor distance estimates are sufficient).
Summary
Source: Nat Rev Genet, 4:275, 2003
Box 2 | The phylogenetic inference process
The flowchart puts phylogenetic estimation (shown in the green box) into the context of an
Collect data
entire study. After new sequence data are collected, the first step is usually downloading other
CTTACATCGTAGCCTAGATC
relevant sequences. Typically, a few outgroup sequences are included in a study to root the
tree (that is, to indicate which nodes in the tree are the oldest), provide clues about the early
Retrieve homologous
ancestral sequences and improve the estimates of parameters in the model of evolution.
sequences
Insertions and deletions obscure which of the sites are homologous. Multiple-sequence
CTACTGTAGCAGTCCGTAGA
GCTTAATCGTAGCTAGATCA
alignment is the process of adding gaps to a matrix of data so that the nucleotides (or amino
CTTACATCGTAGCCTAGATC
acids) in one column of the matrix are related to each other by descent from a common ancestral
residue (a gap in a sequence indicates that the site has been lost in that species, or that a base was
Multiple sequence
inserted at that position in some of the other species). Although models of sequence evolution
alignment
55–58
, most phylogenetic methods
that incorporate insertions and deletions have been proposed
C-TAC-T-GTAG-C-AG-TC
CTTA-ATCGTAG-CTAGATC
proceed using an aligned matrix as the input (see REF. 59 for a review of the interplay between
CTTACATCGTAGCCTAGATC
alignment and tree inference).
In addition to the data, the scientist must choose a model of
Model selection
sequence evolution (even if this means just choosing a family of
models and letting software infer the parameters of these models).
Traditional
Bayesian
Increasing model complexity improves the fit to the data but also
approaches
approaches
Input for phylogenetic
increases variance in estimated parameters. Model selection60–63
estimation
strategies attempt to find the appropriate level of complexity on the
begin characters;
dimensions nchar=898;
basis of the available data. Model complexity can often lead to
format missing=? gap=Estimate
matchchar=.
computational intractability, so pragmatic concerns sometimes
interleave
datatype=dna;
'best' tree
options gapmode=missing;
matrix
outweigh statistical ones (for example, NJ and parsimony are mainly
Lemur_catta
AAGCTTCATAGGAGCAACCAT
Homo_sapiens AAGCTTCACCGGCGCAGTCAT
justifiable by their speed).
MCMC
Pan
AAGCTTCACCGGCGCAATTAT
Gorilla
AAGCTTCACCGGCGCAGTTGT
As discussed in BOX 3, data and a model can be used to create a sample
Pongo
AAGCTTCACCGGCGCAACCAC
Assess
of trees through either Markov chain Monte Carlo (MCMC) or multiple
confidence
tree searches on bootstrapped data (the ‘traditional’ approach). This
collection of trees is often summarized using consensus-tree techniques,
which show the parts of the tree that are found in most, or all, of the
'Best' tree with measures of support
trees in a set. Although useful, CONSENSUS METHODS are just one way of
summarizing the information in a group of trees. AGREEMENT SUBTREES are
Homo sapiens
89
more resistant to ‘rogue sequences’ (one or a few sequences that are
Pan
100
difficult to place on the tree); the presence of such sequences can make a
Gorilla
consensus tree relatively unresolved, even when there is considerable
Pongo
agreement on the relationships between the other sequences.
Hylobates
Sometimes, the bootstrap or MCMC sample might show substantial
support for multiple trees that are not topologically similar. In such
cases, presenting more than one tree (or more than one consensus of
Hypothesis testing
trees) might be the only way to appropriately summarize the data.
duct of
d the
Summary
Source: Nat Rev Genet, 4:275, 2003
at
r
es. The
distantly related sequences to diverge from each other
more slowly than is expected, or even become more
similar to each other at some residues. Many of the sites
in a DNA sequence are not helpful for phylogenetic
the algorithm is converting the DNA or protein
sequences into a distance matrix that represents an estimate of the evolutionary distance between sequences
(the evolutionary distance is the number of changes that
have occurred along the branches between two
ny refers
ees on the
ires the
ns to
Table 1 | Comparison of methods
Method
Advantages
Disadvantages
Software
Neighbour
joining
Fast
Information is lost in compressing
sequences into distances; reliable estimates
of pairwise distances can be hard to obtain
for divergent sequences
PAUP*
MEGA
PHYLIP
Parsimony
Fast enough for the analysis of hundreds
of sequences; robust if branches are
short (closely related sequences or
dense sampling)
Can perform poorly if there is
substantial variation in branch lengths
PAUP*
NONA
MEGA
PHYLIP
Minimum
evolution
Uses models to correct for unseen
changes
Distance corrections can break down when
distances are large
PAUP*
MEGA
PHYLIP
Maximum
likelihood
The likelihood fully captures what the
data tell us about the phylogeny under
a given model
Can be prohibitively slow (depending on
the thoroughness of the search and access to
computational resources)
PAUP*
PAML
PHYLIP
Bayesian
Has a strong connection to the maximum
likelihood method; might be a faster way
to assess support for treesthan
maximum likelihood bootstrapping
The prior distributions for parameters must be
specified; it can be difficult to determine
whether the Markov chain Monte Carlo (MCMC)
approximation has run for long enough
MrBayes
BAMBE
For a more complete list of software implementations, see online link to Phylogeny Programs. For software URLs, see online links box.
| VOLUME 4
www.nature.com/reviews/genetics
© 2003 Nature Publishing Group
Acknowledgment
Material in these slides are based on
Chapter 7 in “The Phylogenetic
Handbook”, Lemey, Salemi, Vandamme
(Eds.)
Some of the material is based on MCMC
notes by Prof. Mark Holder
Questions?