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Patterns, Profiles, and Multiple Alignment. OUTLINE. Profiles and Sequence Logos Profile Hidden Markov Models Aligning Profiles Multiple Sequence Alignments by Gradual Sequence Adition Other Ways of Obtaining Multiple Alignments Sequence Pattern Discovery. OUTLINE.

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Patterns, Profiles, and Multiple Alignment

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Patterns profiles and multiple alignment

Patterns, Profiles, and

Multiple Alignment


Outline
OUTLINE

  • Profiles and Sequence Logos

  • Profile Hidden Markov Models

  • Aligning Profiles

  • Multiple Sequence Alignments by Gradual Sequence Adition

  • Other Ways of Obtaining Multiple Alignments

  • Sequence Pattern Discovery


Outline1
OUTLINE

  • Profiles and Sequence Logos

  • Profile Hidden Markov Models

  • Aligning Profiles

  • Multiple Sequence Alignments by Gradual Sequence Adition

  • Other Ways of Obtaining Multiple Alignments

  • Sequence Pattern Discovery


Profile hidden markov models
Profile Hidden Markov Models

Hidden Markow Models:

A hidden Markov model (HMM) is a statisticsl model,

in which the system being modeled is assumed to be a Markov process (Memoryless process: its future and past are independent),

with hidden states.


Profile hidden markov models1
Profile Hidden Markov Models

  • Hidden Markow Models:

    • Has a set of states each of which has limited number of transitions and emissions,

    • Each transition between states has an assisgned probability,

    • Each model strarts from start state and ends in end state,


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Profile Hidden Markov Models

Hidden Markow Models parameters:

A set of finite number of states, Si,

The transition probability from state Si to Sj, aij,

The emission probability density of a symbol ω

in state Si


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Profile Hidden Markov Models

Hidden Markow Models parameters:

Firstly discuss:

Morkov Models,

Markov Assumption


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Profile Hidden Markov Models

Markow Models and Assumption (cont.):

To understand HMMs:

Talk about weather,

Assume there are three types of weather:

Sunny,

Rainy,

Foggy.

Assume weather does not change during the day (if it is sunny it will sunny all the day)


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Profile Hidden Markov Models

Markow Models and Assumption (cont.): Weather prediction is about the what would be the weather tomorrow,

Based on the observations on the past.


Profile hidden markov models6
Profile Hidden Markov Models

Markow Models and Assumption (cont.): Weather at day n is

qn depends on the known weathers of the past days (qn-1, qn-2,…)


Profile hidden markov models7
Profile Hidden Markov Models

Markow Models and Assumption (cont.): We want to find that:

means given the past weathers what is the probability of any possible weather of today.


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Profile Hidden Markov Models

Markow Models and Assumption (cont.): For example:

if we knew the weather for last three days was:

the probability that tomorrow would be is:

P(q4 = | q3 = , q2 = , q1 = )


Profile hidden markov models9
Profile Hidden Markov Models

Markow Models and Assumption (cont.):

For example:

this probability could be infered from the statistics of past observations

the problem: the larger n is, the more observations we must collect.

for example: if n = 6 we need 3(6-1) = 243 past observations.


Profile hidden markov models10
Profile Hidden Markov Models

Markow Models and Assumption (cont.):

Therefore, make a simplifying assumption Markov assumption:

For sequence:

the weather of tomorrow only depends on today (first order Markov model)


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Profile Hidden Markov Models

Markow Models and Assumption (cont.): Examples:

The probabilities table:


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Profile Hidden Markov Models

Markow Models and Assumption (cont.): Examples:

HMM:


Profile hidden markov models13
Profile Hidden Markov Models

Markow Models and Assumption (cont.): Examples:

Given that day the weather is sunny, what is the probability that tomorrow is sunny and the next day is rainy ?

Markov assumption


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Profile Hidden Markov Models

Markow Models and Assumption (cont.): Examples:

If the weather yesterday was rainy and today is foggy what is the probability that tomorrow it will be sunny?


Profile hidden markov models15
Profile Hidden Markov Models

Markow Models and Assumption (cont.):

Examples:

If the weather yesterday was rainy and today is foggy what is the probability that tomorrow it will be sunny?

Markov assumption


Profile hidden markov models16
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

What is HMM:

Suppose that you are locked in a room for several days,

you try to predict the weather outside,

The only piece of evidence you have is whether the person who comes into the room bringing your daily meal is carrying an umbrella or not.


Profile hidden markov models17
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

What is HMM (cont.):

assume probabilities as seen in the table:


Profile hidden markov models18
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

What is HMM (cont.):

Now the actual weather is hidden from you.

You can not directly see what is the weather.


Profile hidden markov models19
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

What is HMM (cont.):

Finding the probability of a certain weather

is based on the observations xi:


Profile hidden markov models20
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

What is HMM (cont.):

Using Bayes rule:

For n days:


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Profile Hidden Markov Models

Hidden Markov Models (HMMs):

What is HMM (cont.):

We can omit So:

With Markov assumptions:


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Profile Hidden Markov Models

Hidden Markov Models (HMMs):

Examples:

Suppose the day you were locked in it was sunny. The next day, the caretaker carried an umbrella into the room.

You would like to know, what the weather was like on this second day.


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Profile Hidden Markov Models

Hidden Markov Models (HMMs):

Examples:

Calculate 3 probabilities:


Profile hidden markov models24
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

Examples:

Consider the event with highest value. It is most likely to happen.


Profile hidden markov models25
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

Another Examples:

Suppose you do not know how the weather was when your were locked in. The following three daysthe caretaker always comes without an umbrella. Calculate the likelihood for the weather on thesethree days to have been


Profile hidden markov models26
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

Another Examples:

As you do not know how the weather is on thefirst day, you assume the 3 weather situations are equi-probable on this dayand the prior probability for sun on day one is therefore


Profile hidden markov models27
Profile Hidden Markov Models

Hidden Markov Models (HMMs):

Another Examples:

Assumption:


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Profile Hidden Markov Models

Hidden Markov Models:

Another Examples:


Profile hidden markov models29
Profile Hidden Markov Models

HMMs to represent a family of sequences

Given a multiple alignment of sequences, wecan use an HMM to model the sequences.

Each column of the alignment may be represented by a hidden state that produced represented by a hidden state that produced that column.

Insertions and deletions can be represented by other states


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Profile Hidden Markov Models

HMMs to represent a family of sequences


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Profile Hidden Markov Models

HMMs to represent a family of sequences

http://www.ifm.liu.se/bioinfo/assignments/hmm-profile.png


Profile hidden markov models32
Profile Hidden Markov Models

HMMs to represent a family of sequences

http://www.ifm.liu.se/bioinfo/assignments


Profile hidden markov models33
Profile Hidden Markov Models

Determining the states of the HMM

The structure is usually fixedand only the number of “match” states is to be determined


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Profile Hidden Markov Models

Determining the states of the HMM

An alignment column with no gaps can be considered as a “match” state considered as a match state.

An alignment column with a majority of gapscan be considered an “insert” state can be considered an insert state.


Profile hidden markov models35
Profile Hidden Markov Models

  • Determining the transition probabilities

    • From a stateuthetransitiontoanotherstate v is representedbyt(u.v).

    • Thesummationoverallstates w thatareconnectedtostate u bytransitiongivesone:

    • The transition probabilities from a state (excepttheendstate) always add up to 1.


Profile hidden markov models36
Profile Hidden Markov Models

  • Determining the transition probabilities


Profile hidden markov models37
Profile Hidden Markov Models

  • Determining the transition probabilities

    • mu,v: number of transitionsfromstateutostate v

    • Transitionprobabilities t(u,v) can be estimated:


Profile hidden markov models38
Profile Hidden Markov Models

  • Determining the emission probabilities

    • Emission probabilities in a match or insertstate also adds up to 1.


Profile hidden markov models39
Profile Hidden Markov Models

  • Determining the emission probabilities

    • eMu: emissionprobabilityfor a residuefromthe u thmatchstate,


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Profile Hidden Markov Models

  • Determining the emission probabilities

    • eIu: emissionprobabilityfor a residuefromthe u thinsertstate,

    • Theprobabilitiesareusuallytakenfromtheoveralaminoacidcomparison of a selected data set.




Profile hidden markov models43
Profile Hidden Markov Models

HMMs examples:

  • 5 transitions in gap region:

    • C  out,

    • G out

    • AC,

    • CT,

    • T out

    • Out transition 3/5

    • Stay transition 2/5

gap region


Profile hidden markov models44
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Given a profile HMM, any given path through the model will emit a sequence with an associated probability,

The path probability is the product of all transition and emission probabilities along thepath.


Profile hidden markov models45
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

Given a query sequence we can compute the most probable path that will emit that query sequence.


Profile hidden markov models46
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

Another interesting question: What is the probability that a given sequence can be generated by the hidden Markov model

Solution:Calculated by summing over all possible path giving rise to a given sequence


Profile hidden markov models47
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

Will be applied to profiles HMM similar to:


Profile hidden markov models48
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

At a profile position u:

Mu : Match state,

Iu : Insertion state,

Du : Delete state,

t(Mu, Mu+1) : transition probability from state Mu to Mu+1


Profile hidden markov models49
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

During the algorithm:

A record must be kept of the highest probability up to that point in the model and for a given amount of emited sequences.


Profile hidden markov models50
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

During the algorithm:

When the sequence up to and including residue xi has been emited, the highest probability will be written as VDu(xi)


Profile hidden markov models51
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

Dynamic Programming:

COLUMNS:

NUMBER OF STATES IN HMM

ROWS:

LENGTH OF THE QUERY OR EMITTED SEQUENCE


Profile hidden markov models52
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

Recurrence relations:


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Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm:

Recurrence relations (log):


Profile hidden markov models54
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm (EXAMPLE):


Profile hidden markov models55
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm (EXAMPLE):

Start Probabilities:

Emission Probabilities:


Profile hidden markov models56
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm (EXAMPLE):


Profile hidden markov models57
Profile Hidden Markov Models

Scoring a sequence against a profile HMM

Viterbi algorithm (EXAMPLE):

GGCTGATT


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Profile Hidden Markov Models

  • Scoring a sequence against a profile HMM

    • Viterbialgorithm (EXAMPLE):

G  G  C T GA T T

BeginM1M2I3I3I3I3I3M3End


References
References

  • M. Zvelebil, J. O. Baum, “Understanding Bioinformatics”, 2008, Garland Science

  • Andreas D. Baxevanis, B.F. Francis Ouellette, “Bioinformatics: A practical guide to the analysis of genes and proteins”, 2001, Wiley.

  • Barbara Resch, “Hidden Markov Models - A Tutorial for the Course Computational Intelligence”, 2010.


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