Background: To meet the needs of gene annotation for newly sequenced organisms, optimized spaced seeds can be implemented into cross-species sequence alignment programs to accurately align gene sequences to the genome of a related species. So far, seed performance has been tested for comparisons between closely related species, such as human and mouse, or on simulated data. As the number and variety of genomes increases, it becomes desirable to identify a small set of universal seeds that perform optimally or near-optimally on a large range of comparisons. Results: Using statistical regression methods, we investigate the sensitivity of seeds, in particular good seeds, between four cDNA-to-genome comparisons at different evolutionary distances (human-dog, human-mouse, human-chicken and human-zebrafish), and identify classes of comparisons that show similar seed behavior and therefore can employ the same seed. In addition, we find that with high confidence good seeds for more distant co...