Similarity searching for homologs, typically using the BLAST programs, is the most powerful and widely used strategy for characterizing newly sequenced genomes. Similarity searching is both sensitive – homologs that last shared a common ancestor more than 2 billion years ago are readily identified using protein sequences – and reliable – similarity statistics accurately predict the frequency of false positives. Homology inference is asymmetrical. While homology, or common ancestry, can be reliably inferred from statistically significant excess sequence or structural similarity, non-homology cannot be deduced from a lack significant similarity. Because sequences change faster than structures, homologous proteins with very similar structures often lack excess similarity.
