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Evidence for the Evolutionary Organization of Gene Clusters

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Introduction & Summary: Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus

The expression of neighboring genes is often regulated by shared cis-Regulatory Modules (CRMs). However, little is known about how neighboring genes evolved to be near each other, how (in some cases) these genes evolved to be regulated by a common CRM, or about how the encoded proteins interact.

In this paper, the authors examined two adjacent genes encoding the transmembrane (TMEM) proteins TMEM138 and TMEM216. Although the genes TMEM138 and TMEM216 share no sequence homology and appear to have evolved from different gene families, certian mutations in either gene result in an indistinguishable ciliopathy phenotype known as Joubert Syndrome (JBTS). The authors demonstrate that the genes' adjacency resulted from amphibian-to-reptile evolution (Figure 1), that they are co-expressed in mammals but not fish, suggesting that is their adjacency that allows for co-expression (Figure 2), and that their co-expression is regulated by a common CRM. They go on to demonstrate the encoded proteins' interaction with each other (Figure 3) and that knocked-down expression of each protein in zebrafish results in slightly different morphological phenotypes (Figure 4). From these data, the authors argue that genes can be evolutionarily rearranged to form functional clusters regulated by common CRMs, and that the chromosomal rearrangement that occurred with TMEM138 and TMEM216 led to congruent functions and indistinguishable mutant phenotypes in humans.

In the pages linked below, I present their data, describing the conclusiosn the authors drew from it and, briefly, the methods used to obtain it. On the last page, I summarize and evaluate the authors' conslusions.


Proceed to Figure 1


Figure 2

Figure 3

Figure 4

Conclusions & Evaluation





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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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