So, what were those approaches, and what did they uncover? In essence, the logic runs as follows. Sequences that are functionally important are likely to be conserved during evolutionary history. So if a sequence is present in many different species, it is probably functionally significant. The more distantly related the species, and the more closely conserved the sequences, the more fundamentally important the sequence is liable to be.

In the yeast paper, the scientists looked at the sequence for four different species of yeast. They asked where each of more than 200 known regulatory elements, which control the transcription of genes from the DNA, bound to the genome. They further looked for short DNA sequences, known as motifs, that were conserved across the four different species. And they knew something of the structure of some regulators, which further helped to identify the binding sites and the motifs that identified them. The result, which emerged after considerable computational effort, was a set of motifs that all the evidence indicated were sites at which DNA would be regulated. Many of the sites discovered in this way had already been identified as regulatory elements in other individual studies. The good news was that this comparative technique identified several more motifs that had not previously come to light.

The mammalian study goes further. The researchers looked for conserved sequences across human, rat, mouse, and dog genomes, and they looked in two different kinds of places. One was the promoter region, the sequence in front of the gene itself that has long been known to be part of the control mechanism. The other was in the sequences known as 3’UTRs, which code for an untranslated region—that is, a sequence not converted into protein—at the end of messenger RNA, again long known to be involved in gene regulation. In both regions, the researchers aligned the sequences across the four genomes and looked for highly conserved motifs. In the promoters they found 175 candidate motifs, which included most of the previously known regulatory sites and 105 entirely new sites. In the 3’UTRs there were 106 motifs likely to be involved in regulation.

The new motifs in the promoters shed some light on regulation. Several were even more strongly conserved than known regulatory elements, and almost all were expressed in particular tissues. The most highly conserved new motifs were associated with the development of cells of the blood system, while others were linked to trachea and lung and brain tissues. The regulators also tended to occupy the same physical location relative to the start of the gene, within 100 base-pairs of the transcription start site (TSS), the formal beginning of the gene. Some of the motifs were even more constrained, being found in all four species a set distance from the TSS.

Regulatory elements in the 3’UTRs are not nearly as well understood, having been discovered much more recently. Nevertheless, the team led by Lander and Kellis was able to show that these sequences are closely linked to microRNA (miRNA) sequences, which play a crucial role in controlling the conversion of genes into proteins after the gene promoter has been activated and the gene has been transcribed into messenger RNA. They say that previous estimates for the number of miRNA genes are low, and that around one in five human genes are probably under this form of control.