Evolution of Molecular Circuitries

“Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.” (Sidney Brenner)

We work on genomic and cellular tools that help leveraging the unique information hidden in molecular variation among primates. We work closely with the computationally oriented Hellmann lab. They contribute their strong experience in comparative genomics, (single-cell) RNA-seq data analysis, network evolution and power simulations.

Research

Cross-species comparisons are essential for understanding human biology, disease, and evolution. They help identify functional elements in the genome, assess the relevance and limitations of model organisms, and reveal changes that emerged during the evolution of a new type of animal—us. Such comparative approaches provide a unique molecular perspective on who we are.

We investigate how human-specific changes in the transcription factor FOXP2 contributed to the evolution of speech and language using mouse models, and we study how and why molecular phenotypes, such as gene expression, change—or remain conserved—during primate development. Addressing these questions requires efficient and scalable measurements of molecular phenotypes, and we therefore devote substantial effort to applying and optimizing bulk and single-cell RNA-seq approaches. It also requires experimental access to relevant cellular systems. Because induced pluripotent stem cells (iPSCs) and their derivatives have transformed such access in humans, we are working to extend this opportunity across species by generating iPSCs from a broad range of primates.

Research Topics

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Methods & Tools

Researcher using a multichannel pipette at a laboratory workbench. — © Carolin Bleese

Prime-seq2 - an efficient, sensitive, and scalable bulk RNA-seq protocol optimized to maximize usable reads.
mcSCRB-seq- a sensitive, UMI-based, plate-based method for single-cell RNA-seq.
10X scRNA-seq and multiome - high-throughput profiling of gene expression and chromatin accessibility at single-cell resolution.
Primate CRISPRi- inducible gene repression in primate iPSCs for comparative functional studies of gene regulation.
TAMED FISH - an image-analysis workflow for cell detection, spatial localization, and quantification of fluorescence in situ hybridization signals.
Primate iPSCs- cross-species stem-cell models for studying the evolution of gene regulation and development.

Teaching

Students at the microscope — © Carolin Bleese

See the teaching of the Enard & Hellmann labs.

Selected Publications

Pförtner, F., Briem, E., Enard, W., & Richter, D. (2026). Increasing usable reads in RNA-seq protocols. iScience, 29(8), 116984. https://doi.org/10.1016/j.isci.2026.116984

Jocher, J., Janssen, P., Vieth, B., Edenhofer, F. C., Dietl, T., Térmeg, A., Spurk, P., Geuder, J., Enard, W., & Hellmann, I. (2026). Identification and comparison of orthologous cell types from primate embryoid bodies shows limits of marker gene transferability. eLife, 14, RP105398. https://doi.org/10.7554/eLife.105398.3

Edenhofer, F. C., Térmeg, A., Ohnuki, M., Jocher, J., Kliesmete, Z., Briem, E., Hellmann, I., & Enard, W. (2024). Generation and characterization of inducible KRAB-dCas9 iPSCs from primates for cross-species CRISPRi. iScience, 27(6), 110090. https://doi.org/10.1016/j.isci.2024.110090

Kliesmete, Z., Wange, L. E., Vieth, B., Esgleas, M., Radmer, J., Hülsmann, M., Geuder, J., Richter, D., Ohnuki, M., Götz, M., Hellmann, I., & Enard, W. (2023). Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals. eLife, 12, e83593. https://doi.org/10.7554/eLife.83593

Janssen, P., Kliesmete, Z., Vieth, B., Adiconis, X., Simmons, S., Marshall, J., McCabe, C., Heyn, H., Levin, J. Z., Enard, W., & Hellmann, I. (2023). The effect of background noise and its removal on the analysis of single-cell expression data. Genome Biology, 24(1), 140. https://doi.org/10.1186/s13059-023-02978-x

Janjic, A., Wange, L. E., Bagnoli, J. W., Geuder, J., Nguyen, P., Richter, D., Vieth, B., Vick, B., Jeremias, I., Ziegenhain, C., Hellmann, I., & Enard, W. (2022). Prime-seq, efficient and powerful bulk RNA sequencing. Genome Biology, 23(1), 88. https://doi.org/10.1186/s13059-022-02660-8

Geuder, J., Wange, L. E., Janjic, A., Radmer, J., Janssen, P., Bagnoli, J. W., Müller, S., Kaul, A., Ohnuki, M., & Enard, W. (2021). A non-invasive method to generate induced pluripotent stem cells from primate urine. Scientific Reports, 11(1), 3516. https://doi.org/10.1038/s41598-021-82883-0

Ziegenhain, C., Vieth, B., Parekh, S., Reinius, B., Guillaumet-Adkins, A., Smets, M., Leonhardt, H., Heyn, H., Hellmann, I., & Enard, W. (2017). Comparative analysis of single-cell RNA sequencing methods. Molecular Cell, 65(4), 631–643.e4. https://doi.org/10.1016/j.molcel.2017.01.023

Schreiweis, C., Bornschein, U., Burguière, E., Kerimoglu, C., Schreiter, S., Dannemann, M., Goyal, S., Rea, E., French, C. A., Puliyadi, R., Groszer, M., Fisher, S. E., Mundry, R., Winter, C., Hevers, W., Pääbo, S., Enard, W., & Graybiel, A. M. (2014). Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance. Proceedings of the National Academy of Sciences, 111(39), 14253–14258. https://doi.org/10.1073/pnas.1414542111

Enard, W., Gehre, S., Hammerschmidt, K., Hölter, S. M., Blass, T., Somel, M., Brückner, M. K., Schreiweis, C., Winter, C., Sohr, R., Becker, L., Wiebe, V., Nickel, B., Giger, T., Müller, U., Groszer, M., Adler, T., Aguilar, A., Bolle, I., Calzada-Wack, J., Dalke, C., Ehrhardt, N., Favor, J., Fuchs, H., Gailus-Durner, V., Hans, W., Hölzlwimmer, G., Javaheri, A., Kalaydjiev, S., Kallnik, M., Kling, E., Kunder, S., Moßbrugger, I., Naton, B., Racz, I., Rathkolb, B., Rozman, J., Schrewe, A., Busch, D. H., Graw, J., Ivandic, B., Klingenspor, M., Klopstock, T., Ollert, M., Quintanilla-Martinez, L., Schulz, H., Wolf, E., Wurst, W., Zimmer, A., Fisher, S. E., Morgenstern, R., Arendt, T., Hrabé de Angelis, M., Fischer, J., Schwarz, J., & Pääbo, S. (2009). A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell, 137(5), 961–971. https://doi.org/10.1016/j.cell.2009.03.041

Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S. L., Wiebe, V., Kitano, T., Monaco, A. P., & Pääbo, S. (2002). Molecular evolution of FOXP2, a gene involved in speech and language. Nature, 418(6900), 869–872. https://doi.org/10.1038/nature01025

Enard, W., Khaitovich, P., Klose, J., Zöllner, S., Heissig, F., Giavalisco, P., Nieselt-Struwe, K., Muchmore, E., Varki, A., Ravid, R., Doxiadis, G. M., Bontrop, R. E., & Pääbo, S. (2002). Intra- and interspecific variation in primate gene expression patterns. Science, 296(5566), 340–343. https://doi.org/10.1126/science.1068996