Transcript Slide 1
Journal club 06/27/08 Phylogenetic footprinting • A technique used to identify TFBS within a noncoding 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 • 1. 2. • • • Sequence conservation: Entropy score Parsimony score Conservation p-value (mixture models) Posterior distributions of conservation scores Conditional p-values Parsimony V.S. Entropy Score Fitch’s algorithm 1. Conditional model How surprising? 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 1. Conditional model 2. Mixture model 50 functional classes Hydrophobic favor Glycine favor 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 :