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Lecture 8 Dayhoff Algorithm

The Dayhoff Algorithm, developed by Margaret Dayhoff in 1978, utilizes a base dataset of 34 protein superfamilies to analyze accepted point mutations and amino acid changes through a series of steps involving mutation probability matrices. The algorithm defines PAM (Percent Accepted Mutation) as a unit of evolutionary divergence, with PAM matrices used to assess the likelihood of amino acid substitutions over different evolutionary distances. The document emphasizes the importance of selecting the appropriate PAM matrix for sequence alignment, particularly in cases of high amino acid identity versus more divergent sequences.

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9 views23 pages

Lecture 8 Dayhoff Algorithm

The Dayhoff Algorithm, developed by Margaret Dayhoff in 1978, utilizes a base dataset of 34 protein superfamilies to analyze accepted point mutations and amino acid changes through a series of steps involving mutation probability matrices. The algorithm defines PAM (Percent Accepted Mutation) as a unit of evolutionary divergence, with PAM matrices used to assess the likelihood of amino acid substitutions over different evolutionary distances. The document emphasizes the importance of selecting the appropriate PAM matrix for sequence alignment, particularly in cases of high amino acid identity versus more divergent sequences.

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aditya23045
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Practical Bioinformatics

Lecture 8
Dayhoff Algorithm
Dayhoff’s Algorithm - Foundation

● Dayhoff (1978) created a "base dataset" to learn from


● 34 protein “superfamilies” grouped into 71 phylogenetic trees.
● Range of conservation (e.g., histones and glutamate dehydrogenase to
immunoglobulin (Ig) chains and kappa casein

● Protein families were aligned, then counted how often any one amino acid in
the alignment was replaced by another.
Accepted Point Mutations
Dayhoff Model (Step 1)
An amino acid change that is accepted by natural selection occurs when:

(1) a gene undergoes a DNA mutation such that it encodes a different amino
acid; and

(2) the entire species adopts that change as the predominant form of the
protein.
PAM rate of proteins used by Dayhoff et. al.
Dayhoff Model (Step 2): Frequency of AA
Dayhoff Model (Step 3): Mutability
Dayhoff Model (Step 4): Mutation Prob over 1 PAM
One PAM:- defined as the unit of evolutionary divergence in which 1% of the
amino acids have been changed between the two protein sequences
PAM1 Mutation Probability Matrix: e.g. 98.7 of Ala in the sequence stay same over 1 PAM
PAM 10

Notice the switches!

Notice higher penalties, e.g. D to R in PAM 10; E to N switches


How can that happen?

Computational Intuition: Matrix Exponentiation is not a Linear Process

Biological Intuition: There may be a multiple step change and indirect paths

For example, if direct A→G is rare, but:

A→S→G is more probable over multiple steps,

is more probable over multiple steps, then raising PAM1 to PAM10 can suddenly
make A→G much more frequent.
Dayhoff Model (Step 5): PAM 250

Simply PAM1 ˆ 250

This matrix applies to an evolutionary distance where proteins share about 20%
amino acid identity.
RECALL:

● Mutability
● NOT Symmetric

PAM250 mutation probability matrix. At this evolutionary distance only one in


five amino acid residues remain unchanged from the original AA sequence.
What do the PAM matrices mean?
Which PAM matrix to use?
Human beta globin (NP_000509.1)
and Chimp beta globin
(XP_508242.1)- 100% amino acid
identity.

Human beta globin and alpha globin


-Divergent. Mismatches are
assigned large negative scores.

Most broadly useful scoring matrix


such as BLOSUM62
Twilight Zone
Dayhoff Model (Step 6):Mutation Probability to Odds

1: substitution occurs as often as can be expected by chance.

> 1: Alignment of two residues occurs more often than expected by chance (e.g., a
conservative substitution of serine for threonine)

<1: Alignment is not favored


Dayhoff Model (Step 7): log Odds as the score
Relatedness

IS symmetric
Using scores to align sequences
Using PAM 250

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