Tame affairs: domesticated transposase and domestic pigs.

Our opinion on transposable elements has evolved considerably during the past decade. First considered as genome parasites and selfish elements, mobile sequences have been rehabilitated by the demonstration of their crucial role in gene and genome evolution. Notably, transposable elements have repeatedly contributed regulatory and coding sequences to host genes during evolution. A fascinating facet of the evolutionary impact of transposable elements is their ability to act as a source of new genes with novel functions. In eukaryotes, genes from both retrotransposable elements—which transpose through the reverse transcription of an RNA intermediate—and DNA transposons have been domesticated or exapted to fulfil functions that are useful to the host (Volff, 2006). Proteins encoded by transposons are of obvious interest for the host cell, as they can bind to, replicate or degrade nucleic acids, cut and rearrange DNA, and interact with or process proteins. Genome sequencing has uncovered many protein-coding genes that seem to be derived from domesticated transposable elements in phyla as diverse as fungi, plants and animals—including humans. These sequences have lost their ability to transpose and are thus single-copy elements located at the same position in the genome of divergent species. The proteins they encode are also conserved, indicating that they are useful to the host, although their functions remain largely unknown. However, two recent papers—one in this issue of EMBO reports— show that a domesticated hAT transposase functions as an important transcription factor involved in development, cell proliferation and growth in placental mammals (Butter, 2010; Markjlung, 2009). The domesticated transposase was identified though a search for genomic sequences that have been involved in domestication and selection in the pig. An evolutionarily conserved, paternally expressed quantitative trait locus that controls muscle mass and back-fat thickness in European pigs had previously been found in intron 3 of the insulinlike growth factor 2 gene (IGF2; van Laere et al, 2003). In domestic pigs selected for lean growth, a G to A nucleotide substitution was shown to be associated with threefold increase in IGF2 mRNA expression in postnatal muscle, as well as with higher muscle content, increased heart size and reduced subcutaneous fat deposition. This mutation was thought to abrogate the binding of a putative transcriptional repressor of IGF2, which both studies identify by using DNA–protein interaction screens based on quantitative mass spectrometry. The repressor —a 110 kDa protein known as MGR or ZBED6—is related to transposases encoded by DNA transposons from the hAT superfamily. It has a typical hAT dimerization domain and BED zinc fingers necessary for DNA binding, which suggest it is a domesticated transposase. ZBED6 is encoded by an intronless gene located in the first intron of an unrelated gene and is a member of a family that includes at least five other genes in placental mammals. Several lines of evidence are presented in both studies to demonstrate that ZBED6 is the genuine repressor of IGF2: the protein can bind to the wild-type but not to the mutated regulatory sequence in vitro and binds to the IGF2 locus in vivo; its knockdown in a mouse myoblast cell line increases IGF2 expression and promotes cell proliferation, wound healing and myotube formation; and its ectopic expression represses the activity of a reporter gene under the control of the wild-type IGF2 regulatory sequence. Together, the results show that the transcriptional repressor ZBED6 is a domesticated transposase with an important role in muscle growth regulation (Fig 1). The mutation of its binding site in IGF2 abrogates repression and leads to increased muscle mass and reduced fat deposition in many commercially bred pigs. In addition, the identification of more than 1,000 ZBED6 binding sites in the mouse genome suggests that many other target genes—and possibly biological pro cesses— are regulated by this transcription factor, which is consistent with the fact that ZBED6 is expressed broadly in mammals. ZBED6 putative target genes are involved in development, transcriptional regulation, cell differentiation, morphogenesis, neurogenesis, cell –cell signalling and muscle development. Notably, the human orthologues of ZBED6 target genes seem to be particularly associated with developmental disorders, cancer, cardiovascular diseases or neuro logical diseases (Markjlung et al, 2009). There is increasing evidence that transposases from the hAT superfamily function as novel transcription factors in various phyla. For example, an Arabidopsis hAT-like transposase encodes a global gene regulator that is essential for normal plant growth (Bundock & Hooykaas, 2005) and other domesticated hAT transposases have been identified in vertebrates, insects, nematodes and plants (Feschotte & Pritham, 2007). In addition, other superfamilies of DNA transposons have evolved into new genes in various organisms, such as the recombinationactivating gene Rag1, which is derived from a Transib transposon (Kapitonov & Jurka, 2005) and catalyses the somatic recombination responsible for immunoglobulin and T-cell receptor diversity in humans and other jawed vertebrates. Retrotransposable elements are also a source of new genes, such as those derived from retrotransposon gag and from endogenous retrovirus envelope that are necessary for placenta formation in mammals (Volff, 2006). The precise evolutionary origin of ZBED6 remains to be elucidated. At least five other Tame affairs: domesticated transposase and domestic pigs