Here is a molecular biology discovery that we can chalk up to our increasing love of lean bacon:

"ZBED6, a Novel Transcription Factor Derived from a Domesticated DNA Transposon Regulates IGF2 Expression and Muscle Growth", in PLoS Biology.

If you're a bacon lover, you may not realize how much your culinary satisfaction is intertwined with genetics. The drive to breed leaner pigs has led to the search for genetic variants that affect muscle mass and fat deposition in pigs. Some years back, in order to find such genetic variants, a Swedish research group crossed European Wild Boars and Large White domestic pigs.

This research led the scientists to a variant within the vicinity of the amazing multipurpose gene IGF2 (Insulin-like Growth Factor 2). IGF2 encodes a protein that regulates all sorts of growth processes, and crops up over and over again in studies of cancer, fertility, genetic imprinting, wound healing, metabolic disorders, and much more.

In this case, a genetic variant, a single DNA nucleotide change, inside of an intron of the IGF2 gene, causes major differences in the level of IGF2 gene expression. The variant, an 'A' in domestic pigs (compared to a 'G' in wild boars), causes extremely high IGF2 levels in these domestic pigs. The result is more muscle mass, less fat deposition.

What's happened here is that over the last few decades, breeders have selected for leaner pigs and basically pushed the 'A' version of this variant to high frequency in the domestic pig population, since having the 'A' is apparently a good way to make a lean pig.

So far, I've been describing old research. But in a new paper, the story gets really interesting. The group of Swedish researchers figured out how the 'A' variant works its effects, and in the process have discovered yet one more example of a genetic parasite (a DNA transposon in this case) getting recruited to play a key functional role in the cell. What's more, this recruitment took place a long time back, and this drafted transposon plays a regulatory role in all placental mammals.

Here's how it works: The expression level (i.e., the amount of RNA produced) of the IGF2 gene is regulated in part by its intron sequence. In wild boars, the intron is bound by a regulatory protein, transcriptional repressor that inhibits RNA production. But in domestic pigs, the DNA binding site for the repressor has been destroyed by the 'A' mutation, thus leading to jacked-up expression of the IGF2 gene - which leads to more IGF2 protein, which leads to more muscle and less fat (among other things).

One outstanding mystery was the identity of the transcriptional repressor. IGF2, like I said, is a critical player in human development and health, and so, even if lean bacon was the original motivation for the pig genetics research, scientists are interested in how IGF2 is regulated.

Solving a mystery like the identity of the repressor would have been daunting 10-15 years ago, but it's almost a cakewalk with today's technology. The researchers basically went fishing, using the intron DNA sequence as a lure. They mixed the DNA sequence (they tried both versions - the 'G' and the 'A' variant) with the contents of mouse cells (mice, pigs - it doesn't matter here when we're talking about a regulatory process common to all placental mammals), and pulled out what bound the DNA lure.

The researchers then used mass spectrometry to identify their catch - a protein that bound the 'G' variant but not the 'A' variant. This protein turns out to be among a set of previously identified genes that were derived from transposable elements - basically genome parasites that resemble viruses.

The scientists did all of the appropriate follow-up research to show that this transcriptional repressor, called ZBED6 is indeed a key regulator of IGF2. They also found that it regulates a number of other genes that are known to be linked to various human diseases. Basically, the desire to understand why we're getting leaner bacon has led to a regulatory protein that may play a critical role in human disease.

The evolution of this protein, from a DNA transposon is also interesting. I'll quote from the authors:

The difference between less complex eukaryotes like Caenorhabditis elegans and more complex eukaryotes, such as human, is related not to the number of protein-coding genes, but rather to the complexity of the gene regulatory networks. A large proportion of vertebrate genomes is composed of transposable elements, and their integration in the genome has contributed to the evolution of regulatory networks. The majority of these transposable elements are retrotransposons, but 5%–10% are derived from DNA transposons... A bioinformatic analysis of other vertebrate genomes did not reveal the presence of a functional ZBED6 gene outside the placental mammals. We found evidence for a nonfunctional ZBED6 sequence at the orthologous positions in the Platypus and opossum genomes, but these genomes did not contain an extended open reading frame for ZBED6 (unpublished data). This implies that the integration of ZBED6 happened before the divergence of the monotremes from the other mammals, but that the gene has been inactivated or lost in monotremes and marsupials. Thus, ZBED6 must have evolved its essential function in the time span after the split between marsupial and placental mammals, but before the radiation of different orders of placental mammals. An interesting topic for future research will be to reveal what advantage the development of ZBED6 as a new regulatory protein has provided to the placental mammals.


ZBED6 is an apparent example of a domesticated transposon that has lost its ability to transpose, because it occurs as a single copy gene at the same location in intron 1 of ZC3H11A in all placental mammals for which at least a partial genome sequence is available. ZBED6 has evolved an essential function in this group as implicated by the observation that the two DNA-binding BED domains (about 100 amino acids together) show near 100% amino acid identity across 26 placental mammals (Figure S2). The two BED domains in ZBED6 have apparently evolved by internal duplication because the two copies are more similar to each other than to any other mammalian BED sequence.

Science doesn't get much better than this: genetics, evolution, transposons, and bacon.

(Image courtesy Wikipedia Commons)

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