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Construction of Substitution Matrices • BLOSUM: BLOcks SUbstitution Matrix • PAM: Point Accepted Mutations

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Page 1: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Construction of Substitution Matrices

• BLOSUM: BLOcks SUbstitution Matrix

• PAM: Point Accepted Mutations

Page 2: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Substitution Matrices

• Contain values proportional to the probability that amino acid A mutates into amino acid B for all pairs of amino acids through a period of evolution

Page 3: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Substitution Matrices

• Contain values proportional to the probability that amino acid A mutates into amino acid B for all pairs of amino acids through a period of evolution

• Are constructed from a large and diverse sample of sequence alignments

Page 4: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Substitution Matrices

• Contain values proportional to the probability that amino acid A mutates into amino acid B for all pairs of amino acids through a period of evolution

• Are constructed from a large and diverse sample of sequence alignments

• Multiple alignment of well studied gene sequences from different species

Page 5: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Substitution Matrices

• Contain values proportional to the probability that amino acid A mutates into amino acid B for all pairs of amino acids through a period of evolution

• Are constructed from a large and diverse sample of sequence alignments

• Multiple alignment of well studied gene sequences from different species

• Use orthologs - functionally similar

Page 6: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Substitution Matrices

• Contain values proportional to the probability that amino acid A mutates into amino acid B for all pairs of amino acids through a period of evolution

• Are constructed from a large and diverse sample of sequence alignments

• Multiple alignment of well studied gene sequences from different species

• Use orthologs - functionally similar• Observed substitutions tend to preserve

functions

Page 7: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Substitution Matrices

• Contain values proportional to the probability that amino acid A mutates into amino acid B for all pairs of amino acids through a period of evolution

• Are constructed from a large and diverse sample of sequence alignments

• Multiple alignment of well studied gene sequences from different species

• Use orthologs - functionally similar• Observed substitutions tend to preserve functions• Minimal gaps

Page 8: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

How to Construct Substitution Matrices

Tabulate substitutions• A to A: 9867 times

• A to R: 2 times

• A to N: 9 times

• etc….

Page 9: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

How to Construct Substitution Matrices

Page 10: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

How to Construct Substitution Matrices (BLOSUM)

Page 11: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

How to Construct Substitution Matrices (BLOSUM)

Page 12: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

How to Construct Substitution Matrices

Page 13: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Finding the Random Mutation Rate

• Compute overall occurrence of an amino acid in a protein database

Page 14: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Finding the Random Mutation Rate

• Compute overall occurrence of an amino acid in a protein database

http://www.ebi.ac.uk/swissprot/sptr_stats/index.html

Page 15: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Finding the Random Mutation Rate

• Compute overall occurrence of an amino acid in a protein database

http://www.ebi.ac.uk/swissprot/sptr_stats/index.html

Page 16: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Finding the Random Mutation Rate

Example:

Expected random mutation rate is 1 in 10000 and observed mutation rate of W to R is 1 in 10

Score = log (0.1/0.0001) = log (1000) = +3

Page 17: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Page 18: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Page 19: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Page 20: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Page 21: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

PAM Matrices

[1 point mutation per 100 amino acids]• does not take into account different evolutionary

rates between conserved and non-conserved regions

• PAM1 is 1% average change in amino acids

• PAM 250:??

Page 22: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

PAM Matrices

Page 23: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

PAM vs. BLOSUM

Page 24: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Basic Local Alignment Search Tool (BLAST)

• Heuristic method

Page 25: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

BLAST Algorithm

Page 26: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

BLAST Algorithm

Page 27: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

BLAST Algorithm

Page 28: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Page 29: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Page 30: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

What can we search and compare?

DNA vs DNA

Protein vs Protein

DNA vs Protein

Protein vs DNA

Page 31: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

Reading Frames

Page 32: Construction of Substitution Matrices BLOSUM: BLOcks SUbstitution Matrix PAM: Point Accepted Mutations

The best BLAST program

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