Previously unknown gene is unique to placental mammals

Domestic pigs develop more muscle and store less fat than their wild ancestor, the wild boar.

"This is a result of the systematic selection that has been ongoing the last 60 years to breed pigs that produce the lean meat the consumers prefer," says Leif Andersson who led the study. "This explains why a pork chop today contains much less fat compared with the pork chops produced a hundred years ago."

Leif Andersson and his colleagues decided already twenty years ago to cross the wild boar with the domestic pig in an attempt to find genetic explanations for this selection response in pigs. Some years ago they discovered a specific mutation in a non-coding DNA sequence that regulates the expression of an important growth factor, IGF2. This mutation contributes very significantly to the difference in muscle growth between pigs and wild boars.

"We have now in collaboration with researchers at the Broad Institute used a sophisticated molecular method to isolate the protein that binds the DNA sequence that is altered in pigs," says Lin Jiang, one of the PhD students associated with the project. "Surprisingly, the protein is previously unknown and we named it ZBED6. The protein is present in all placental mammals including humans."

Barbara McClintock received the Nobel prize 1983 for her important discovery of "jumping genes" in the genome. It is now reported that ZBED6 has evolved from a member of the same family of jumping genes as McClintock studied in maize. The ZBED6 ancestor integrated in the genome of a primitive mammal at least 150 million years before present. It has since then been domesticated and is now stably integrated in the genome at the same position in all placental mammals.

"Our finding that the DNA-binding parts of the protein are 100% identical among all mammals that we have investigated including humans shows that ZBED6 must have evolved an essential function," says Lin Jiang.

The new results show that ZBED6 does not only regulate the expression of the IGF2 growth factor in pig muscle but appears to regulate hundreds if not thousands of other genes in mammals.

"The results indicate that we have discovered a new "orchestra conductor" that controls the activities of many genes in the mammalian cell," says Leif Andersson. "It will be very exciting to further study the biological significance of ZBED6 and find out to which extent the action of this factor influences various diseases in humans."

The study is a beautiful illustration that strong basic research leads to unexpected discoveries, Leif Andersson concludes. They started this project 20 years ago by asking the question: What are the genetic mechanisms explaining the remarkable increase in muscle growth in the domestic pig. This led to the discovery of the IGF2 mutation and a previously unknown mechanism that regulates muscle mass.

"Now we have discovered a previously unknown protein that originates from a jumping gene and this protein appears to have an important regulatory role during development. The discovery provides new basic knowledge concerning the evolution of placental mammals and is of considerable biomedical significance," says Leif Andersson.