BioEd Online

Think your genes have evolved to make the perfect proteins for your body? Think again. Researchers have found that a secondary function of some pieces of DNA has held this evolution in check, slowing the associated genes' progress in becoming 'ideal' protein machines.

As a result, "human proteins may well not be as good as they could be" says Laurence Hurst of the University of Bath, UK, who led the study published in PLoS Biology¹.

Genes hog most of the attention when it comes to DNA, because it is these sequences that tell a cell which amino acids to thread together into a protein. It has commonly been assumed that evolution acted on genes over the millennia to favour an amino-acid sequence that is perfectly honed to its protein's task, be it building a cell wall or promoting a chemical reaction.

But DNA is known to harbour other kinds of information, sometimes written on top of protein-coding genes, like an overlapping cipher. The new study shows that these secondary codes partly determine the amino acids of a protein.

Hurst's research focused on short sequences of DNA where such a second code exists and acts as a 'splice enhancer'. After DNA is copied into a molecule of RNA, these enhancers tell a human cell how to snip out unneeded sections and splice together the remainder, so it can be used as the template for protein production.

The team estimated how quickly different segments of DNA in the genome have evolved, by looking at how many changes have occurred between equivalent mouse and human genes. In areas of DNA that have this dual function - as both splice enhancers and protein code — far fewer changes have built up, they report. Sequences near enhancers have evolved at half the rate of other sections of DNA, or even more slowly. And genes containing lots of the enhancers also seem to have evolved more slowly as a whole.

The extent to which splice enhancers constrain protein evolution is "really surprising", says evolutionary biologist Laurent Duret at the University of Lyons, France.

Held back

Researchers already knew of other factors that make some proteins or parts of proteins evolve much faster than others, even though they don't change what a protein does. Proteins that are manufactured abundantly, for example, seem to evolve slowly, perhaps because their codes are less prone to errors during protein production.

The finding raises the intriguing idea that we could tweak DNA in order to make super-proteins that are even more efficient than the natural human version.

In the lab, it is possible to eliminate the need for splicing. So a DNA sequence could have its splicing function removed from it completely, and researchers could introduce genetic changes to produce a faster or stronger protein. Biotechnology researchers could perhaps use this technique to create more efficient enzymes.

Geneticists know that there are other layers of information written on top of the protein code too: one, for example, contains instructions for packaging up DNA into neat little coils. It would be extremely interesting to find out whether this secondary code also holds back the evolution of proteins, Hurst says.