Journal club06/27/08

Phylogenetic footprinting

• A technique used to identify TFBS within a non-coding region of DNA of interest by comparing it to the orthologous sequences in different species (1988 by Tagle)

• The function and DNA binding preferences of transcription factors are well-conserved between diverse species

• Important non-coding DNA sequences that are essential for regulating gene expression will show differential selective pressure. (A slower rate of change occurs in TFBS than in other parts of the non-coding genome)

Phylogenetic footprinting

Phylogenetic footprinting

• Not all conserved sequences are under selection pressure

• To eliminate false positives, statistical analysis must be performed that the motifs reported have a mutation rate meaningfully less than that of the surrounding nonfunctional sequence.

Mixture selective pressure

• Maintain the function of the protein encoded by the gene (AA selecvtive pressure)

• Maintain their regulatory role (CRUNCS) – ex: regulatory factors binding sites

Methods

• Sequence conservation:

1. Entropy score

2. Parsimony score

• Conservation p-value (mixture models)

• Posterior distributions of conservation scores

• Conditional p-values

Parsimony V.S. Entropy Score

Fitch’s algorithm

Aligned codons illustrating to what extent the conservation of each column is surprising, given the amino acids encoded

L: CUN, UUA, UUG; W: UUG; V: GUN; A:GCN; G:GGN; D: GAU, GAC

How surprising?1. Conditional model

1. Conditional model

2. Mixture model

Hydrophobic favorGlycine favor

50 functional classes

2. Mixture model

Non-coding model: HKY model

j ( A , j ,C , j ,G, j ,T , j )

j represents the transition/transversion rate ratio for

j

How to compute :