Improving animal models to understand gene regulation in human diseases

The role of animal models in understanding biological processes and their dysregulations in humans is imperative and established in the research community. While extensive resources and knowledge on the genetic information of popular organisms such as human and mouse exist, such resources are lacking for other strong popular organisms like zebrafish and dogs.

In this thesis, we aimed at improving the genome annotation of zebrafish and dogs as well as further showing their importance in understanding human disease. We have been part of an international consortium called DANIO-CODE that aims for systematically annotating the zebrafish genome. We initiated similar effort for canine models, The Dog Genome Annotation Project (DoGA). Through these efforts, we aim to strengthen zebrafish and dogs as model organisms for studying human health.

In Paper I, we presented a platform that allows the efficient and comprehensive sequencing data collection for large-scale genome annotation projects. We further showed an implementation of DANIO-CODE Data Coordination Center and its comparison to established platform. In Paper II, we reported the systematic annotation of the zebrafish genome together with a collection of resources to facilitate the research community using zebrafish as a model organism. We addressed the gap in understanding the genomic elements in the zebrafish genome and further describe an improvement in genomics elements of zebrafish. We built the most comprehensive dog tissue biobank and further characterized the gene promoter regions of dogs in Paper III. We improved the promoter definition in various dog tissues together with gene expression levels associated with those promoters.

Finally, we showcased the use of animal model in understanding disease in Paper IV through an example of an eye disease known as progressive retinal atrophy, which shares similar phenotypes with retinitis pigmentosa in humans.

List of scientific papers

I. Hörtenhuber, M., Mukarram, A. K., Stoiber, M. H., Brown, J. B., & Daub, C. O. (2020). *-DCC: A platform to collect, annotate, and explore a large variety of sequencing experiments. GigaScience. 9(3), giaa024.
https://doi.org/10.1093/gigascience/giaa024

II. Baranasic, D.*, Hörtenhuber, M.*, Balwierz, P.*, Zehnder, T.*, Mukarram, A. K.*, Nepal, C., Varnai, C., Hadziev, Y., Jimenez-Gonzalez, A., Li, N., Wragg, J., D’Orazio, F., Díaz, N., Hernández-Rodríguez, B., Chen, Z., Stoiber, M. H., Dong, M., Stevens, I., Ross, S. E., Eagle, A., Martin, R., Obasaju, P., Rastegar, S., McGarvey, A. C., Kopp, W., Chambers, E., Wang, D., Kim, H. R., Acemel, R. D., Naranjo, S., Lapinski, M., Chong, V., Mathavan, S., Peers, B., Sauka-Spengler, T., Vingron, M., Carninci, P., Ohler, U., Lacadie, S. A., Burgess, S., Winata, C., van Eeden, F., Vaquerizas, J.M., Gómez-Skarmeta, J. L., Onichtchouk, D., Brown, J.B., Bogdanovic, O., Westerfield, M., Wardle, F. C., Daub, C. O.#, Lenhard, B.#, & Müller, F.# (2021). Integrated annotation and analysis of genomic features reveal new types of functional elements and large-scale epigenetic phenomena in the developing zebrafish. bioRxiv. *These authors contributed equally. #Co-corresponding authors. [Manuscript]
https://doi.org/10.1101/2021.08.09.454869

III. Mukarram, A. K.*, Arumili, M.*, Hytönen, M. K.*, Araujo, C., Quintero, I. B., Syrjä, P., Airas, N., Kaukonen, M., Kyöstilä, K, Pääkkönen, T., Hörtenhuber, M., Stevens, I., Iivanainen, A., Yoshihara, M., Gusev, O., Bannasch, D., DoGA Consortium, Ezer, S., Sukura, A., Katayama, S., Kere, J.#, Daub, C. O.#, & Lohi, H.# (2021). Dog Gene Promoterome and Tissue Expression Atlas. *These authors contributed equally. #Co-corresponding authors. [Manuscript]

IV. Kaukonen, M., Quintero, I. B., Mukarram, A. K., Hytönen, M. K., Holopainen, S., Wickström, K., Kyöstilä, K, Arumili, M., Jalomäki, S., Daub, C. O., Kere, J., Lohi, H., & DoGA Consortium. (2020). A putative silencer variant in a spontaneous canine model of retinitis pigmentosa. PLoS Genetics. 16(3), e1008659.
https://doi.org/10.1371/journal.pgen.1008659