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Conclusions & Evaluation

From the data presented in the previous figures, the authors conclude that TMEM138 and TMEM216 became co-regulated as a result of the amphibian-to-reptile evolutionary transition (Figures 1 and 2). They go on to argue that impairments in TMEM138 and TMEM216 expression result in indistinguishable phenotypes in organisms with co-regulation of the genes and distinguishable phenotypes in organisms without this genetic co-regulation, and that the proteins serve congruent functions in higher-level vertebrates as a result of this co-regulation and non-congruent functions in lower-level vertebrates (Figures 3 and 4). In their own words, the authors say, "Together, the data indicate that before their adjacent genomics localization, the proteins’ organismal functions were not completely congruent and were associated with distinguishable phenotypes, unlike JBTS2-linked Joubert patients" (Lee et al., 2012).

I agree with their conclusion that TMEM138 and TMEM216 are co-regulated as a result of their adjacency, and thus are not co-regulated in zebrafish and lower vertebrates (Figures 1 and 2). I also agree that TMEM138 and TMEM216 perform closely related functions (Figure 3). However, I think the authors overstate their conclusions (drawn primarily from Figure 4) regarding the effects of co-regulation. First, it is inappropriate to say that mutations in both genes result in indistinguishable phenotypes in humans. The gross morphological phenotypes may be indistinguishable, but, as they demonstrated in Figure 3, the phenotypes are distinguishable at a cellular level (TMEM138 mutations result in shorter cilia and TMEM216 mutations result in fewer ciliated cells). Additionally, it is inappropriate to call the functions of the proteins completely congruous in humans - Figure 3 also demonstrates that they are localized in adjacent, but not the same, vesicle pools, and that the function of one protein is dependent on the function of the other. Thus, their own data (Figure 3) refute their claims regarding the genes' functional similarities.

These claims regarding the functional similarity of the genes in humans and mice are premises for their argument regarding the importance of co-regulation. To claim that the evolution of their genomic adjacency and co-regulation caused functional similarity, the authors must demonstrate both functional similarity in organisms with genomic adjacency and co-regulation of these genes and a lack of functional similarity in organisms without genomic adjacency and co-regulation of these genes. The proteins' functions may have been more similar in organisms with co-regulation than in organisms without co-regulation, but the difference is one of degree. Their language (quoted above) suggests that the genomic adjacency and co-regulation resulted in a more substantial difference.

They could have strengthened their arguments by using models with greater similarity. For instance, the morphological defects observed in zebrafish with antisense morpholino-induced knockdown of the TMEM138 and/or TMEM216 is not an appropriate model for comparison to human Joubert Syndrome patients in which one of those genes is expressed but mutated. Transgenic TMEM138/TMEM216 knockout mice and/or transgenic mice containing mutated TMEM138/TMEM216 genes would have helped bridge the disparity between modeling human mutations with zebrafish knockdowns.

On the whole, I find their data very interesting. It suggests that genomic rearrangments and co-regulation can slightly alter the functional relationship between genes. Although that is not necessarily surprising, I did not know it to be the case until this paper demonstrated it. However, as discussed above, I feel their conclusions are slightly overstated given their data.


Introduction & Summary

Figure 1

Figure 2

Figure 3

Figure 4


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Lee, J.H., Silhavy, J.L., Lee, J.E., Al-Gazali, L., Thomas, S., Davis, E.E., Bielas, S.L., Hill, K.J., Iannicelli, M., Brancati, F., Gabriel, S.B., Russ, C., Logan, C.V., Sharif, S.M., Bennett, C.P., Abe, M., Hildebrandt, F., Diplas, B.H., Attie-Bitach, T., Katsanis, N., Rajab, A., Koul, R., Sztriha, L., Waters, E.R., Ferro-Novick, S., Woods, C.G., Johnson, C.A., Valente, E.M., Zaki, M.S., Gleeson, J.G. 2012. Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus. Science. 335: 966-969.


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