Whole-genome Comparative Annotation and Regulatory Motif Discovery in Multiple Yeast Species

摘要

In [13] we reported the genome sequences of S. paradoxus, S. mikatae and S. bayanus and compared these three yeast species to their close relative, S. cerevisiae. Genome-wide comparative analysis allowed the identification of functionally important sequences, both coding and non-coding. In this companion paper we describe the mathematical and algorithmic results underpinning the analysis of these genomes. We developed methods for the automatic comparative annotation of the four species and the determination of orthologous genes and intergenic regions. The algorithms enabled the automatic identification of orthologs for more than 90% of genes despite the large number of duplicated genes in the yeast genome, and the discovery of recent gene family expansions and genome rearrangements. We also developed a test to validate computationally predicted protein-coding genes based on their patterns of nucleotide conservation. The method has high specificity and sensitivity, and enabled us to revisit the current annotation of S.cerevisiae with important biological implications. We developed statistical methods for the systematic de-novo identification of regulatory motifs. Without making use of co-regulated gene sets, we discovered virtually all previously known DNA regulatory motifs as well as several noteworthy novel motifs. With the additional use of gene ontology information, expression clusters and transcription factor binding profiles, we assigned candidate functions to the novel motifs discovered. Our results demonstrate that entirely automatic genome-wide annotation, gene validation, and discovery of regulatory motifs is possible. Our findings are validated by the extensive experimental knowledge in yeast, confirming their applicability to other genomes.