Recapitulating evolutionary divergence in a single regulatory element causes expression changes of the lens gene Tdrd7

Roscito, J. G.; Subramanian, K.; Naumann, R.; Sarov, M.; Shevchenko, A.; Bogdanova, A.; Kurth, T.; Forster, L.; Kreysing, M.; Hiller, M.

doi:10.1101/2020.03.22.002535

bioRxiv · 10.1101/2020.03.22.002535

Recapitulating evolutionary divergence in a single regulatory element causes expression changes of the lens gene Tdrd7

Roscito, J. G.·Subramanian, K.·Naumann, R.·Sarov, M.·Shevchenko, A.·Bogdanova, A.·Kurth, T.·Forster, L.·Kreysing, M.·Hiller, M.

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Abstract

Mutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved non-coding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated the evolutionary changes by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR-Cas9. Strikingly, this repressor element has a large effect, causing a more than two-fold up-regulation of Tdrd7 in developing lens. Interestingly, the increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, likely explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.

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Roscito, J. G., Subramanian, K., Naumann, R., Sarov, M., Shevchenko, A., Bogdanova, A., Kurth, T., Forster, L., Kreysing, M., Hiller, M.. 2020-03-25. Recapitulating evolutionary divergence in a single regulatory element causes expression changes of the lens gene Tdrd7. https://doi.org/10.1101/2020.03.22.002535

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