Of mice and men: phylogenetic footprinting aids the discovery of regulatory elements

Abstract

Phylogenetic footprinting is an approach to finding functionally important sequences in the genome that relies on detecting their high degrees of conservation across different species. A new study shows how much it improves the prediction of gene-regulatory elements in the human genome.

Figure 1

An example of a position-specific weight matrix (PWM) adapted from the TRANSFAC database [5]. The sequences that have been shown experimentally to bind to the human transcription factor GATA-1 have 14 positions, among which only positions 6–10 are fully conserved. Abbreviations: R, G or A (purine); N, any; S, G or C (strong); D, G or A or T. Twelve sequences were used to build this matrix.

Figure 2

Using phylogenetic footprinting to detect conserved TFBSs. This schematic diagram shows a hypothetical human gene aligned with its orthologs from three other mammals. Cross-species sequence comparison reveals conserved TFBSs in each sequence. Sequence motifs of the same shape (colored in green) represent binding-sites of the same class of transcription factors. TFBS1 and TFBS4 are conserved in all four mammals; TFBS3 represents a newly acquired, primate-specific binding site. TFBS2 and TFBS2' represent orthologous regulatory sites that have diverged significantly between the primate and rodent lineages. Blue rectangles represent TATA boxes.