The report by van der Aa et al
] describes two subsets of the 240 zebrafish TRIMs, which the authors named the fintrim
) and the bloodthirsty-related
) genes. The 84 ftr
genes and 33 btr genes encode class IV TRIMs (RING finger-B-box-coiled-coil-B30.2 proteins) [4
]. The ftr
genes stem from an unknown ancestor and make up a teleost-specific family encoding proteins induced by viral infection. Ftrs evolved through positive selection of residues in the B30.2 domain homologous to those involved in viral recognition of the mammalian anti-retroviral protein TRIM5α; they are therefore likely to form a family of immune receptors since, in a changing viral environment, diversity of recognition of determinants is a selective advantage for an immune system [6
]. The family illustrates a recurrent observation: during evolution, families of genes with non-immune functions in other organisms may become diversified in some species to fulfill functions in immune recognition and defense. Another example of such evolution is shown by members of the immunoglobulin superfamily in invertebrates and vertebrates [8
]. In the case of Ftr proteins, the pressure to diversify must have been intense because different species of phylogenetically distant teleosts have generated ftr
families through different mechanisms: tandem duplications in zebrafish and retrotranspositions in medaka. This convergence suggests again that Ftr diversity has adaptive value. One possibility is that this great diversity compensates for deficiencies in adaptive immunity to viruses.
The other subset of zebrafish TRIMs, the Btrs, stems from an ortholog of mammalian Trim-39. Members of this subset are not documented to have any involvement in immunity, but the fact that the genes are highly amplified whereas trim-39 is not raises some interesting questions, and studying the origin and diversification of both subsets may prove useful.
Can any possible evolutionary scheme be derived from the position of ftr and btr genes on the chromosomes? Their presence on 16 of the 25 chromosomes suggests they are very mobile and can diversify independently of each other. However, their multiplicity may partly be due to the fact that, in addition to the two rounds of polyploidization common to gnathostomes, teleosts have had an extra round, which resulted in eight potential paralogous sets of chromosomes instead of the four found in other vertebrates. So do the numerous ftr and btr clusters match as many paralogous regions? Indeed, it seems that they are all located on chromosomes that also contain major histocompatibility complex (MHC) genes or their paralogs (Figure ). This pattern fits with the hypothesis that, during the generation of the zebrafish genome, a region containing MHC and TRIM-B30.2 genes duplicated several times, in agreement with the above hypothesis of several genome duplications. If validated by statistical tests, this observation would suggest two things: first, that the ftr genes, which are present in a smaller number of clusters than the other TRIM-B30.2 genes, diversified later and specifically in teleosts from one of those early MHC-linked genes; and second, that the MHC-TRIM-B30.2 linkage is ancient and preceded the two rounds of genome duplication common to gnathostomes. Therefore, it is likely that relatives of TRIM-B30.2 existed in invertebrates.
Figure 1 Position of MHC and TRIM-B30.2 genes in the zebrafish genome. Green asterisks denote chromosomes with clusters of btr and ftr genes, and the number of these genes on the respective chromosome is shown below in green. MHC and MHC-paralogous genes are in (more ...)
The linkage to MHC and its three paralogous regions [9
] is not only ancient, it is also conserved, as several genes encoding proteins with TRIM and B30.2 domains and with antiviral activity are also MHC-linked in various vertebrate lineages, such as birds and mammals [10
] (Figure ), and some are also moderately amplified (such as TRIM5
genes, with five contiguous members) in a way that is reminiscent of the ftr
]. Was the immunological antiviral function of such receptors a reason to be selected for co-segregation with the region of the MHC containing genes encoding proteins that are associated with inflammatory responses, such as tumor necrosis factor and components of the antigen-presentation machinery? It may have contributed to the creation of a massive assembly of immunity-related genes, which would have had the advantage of being inheritable as a single unit. This linkage may no longer have any selective value in some species, given that it is not apparent in the stickleback, a species of teleosts that has diverged more recently than the zebrafish. In zebrafish, it may simply be a 'fossil' of an ancient, once useful architecture.
Figure 2 Comparison of sequences and chromosomal positions of TRIM and MHC genes between species. (a) Human MHC-paralogous regions. The 1pq, 6p21 and 9q segments are the classical MHC-paralogous regions . For simplicity only selected markers are shown, particularly (more ...)