Eukaryotic Regulatory Element Conservation Analysis and Identification Using Comparative Genomics

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Abstract
Comparative genomics is a promising approach to the challenging problem of eukaryotic regulatory element identification, because functional noncoding sequences may be conserved across species from evolutionary constraints. We systematically analyzed known human andSaccharomyces cerevisiaeregulatory elements and discovered that human regulatory elements are more conserved between human and mouse than are background sequences. AlthoughS. cerevisiaeregulatory elements do not appear to be more conserved by comparison ofS. cerevisiaetoSchizosaccharomyces pombe, they are more conserved when compared with multiple other yeast genomes (Saccharomyces paradoxus, Saccharomyces mikatae, andSaccharomyces bayanus). Based on these analyses, we developed a sequence-motif-finding algorithm called CompareProspector, which extends Gibbs sampling by biasing the search in regions conserved across species. Using human–mouse comparison, CompareProspector identified known motifs for transcription factors Mef2, Myf, Srf, and Sp1 from a set of human-muscle-specific genes. It also discovered the NFAT motif from genes up-regulated by CD28 stimulation in T-cells, which implies the direct involvement of NFAT in mediating the CD28 stimulatory signal. UsingCaenorhabditis elegans–Caenorhabditis briggsaecomparison, CompareProspector found the PHA-4 motif and the UNC-86 motif. CompareProspector outperformed many other computational motif-finding programs, demonstrating the power of comparative genomics-based biased sampling in eukaryotic regulatory element identification.