Laboratory of Regulatory Evolution

Research group of Patrick Tschopp

Understanding the origins of phenotypic diversity in nature is a key question in biology. While selective forces drive this process at the population level, enriching for adaptive alleles, translating these genetic variants into beneficial phenotypes is intrinsically linked to an individual’s embryonic and post-embryonic development. Changes in developmental patterning and cell fate specification processes, which can result in varying morphological and cellular features of an organism, thus provide the phenotypic substrate for natural selection to act upon.

The extent to which such modifications are possible can be quite flexible, and dependent on interactions with the environment (‘phenotypic plasticity’), but also constrained by the internal architecture of the underlying developmental programs (‘developmental constraint’). We are interested in the molecular and cellular determinants of this balance, i.e. between ‘phenotypic plasticity’ and ‘developmental constraint’, and how it manifests itself in the context of gene regulation. “Regulatory evolution”, i.e. changes in when and where a particular gene is activated, provides for a flexible and modular approach to generate phenotypic diversity, while avoiding pleiotropic effects usually associated with coding mutations.

Thanks to advances in sequencing and genome engineering technologies, the molecular and cellular mechanisms of regulatory evolution can now be investigated across many species and tissue types, at the appropriate cellular resolution and in unprecedented detail. We are taking advantage of functional bulk and single-cell genomics, in combination with experimental perturbations and in silico modeling, to address fundamental questions in gene regulation evolution, cell fate specification and patterning during vertebrate embryogenesis. Our efforts focus on the following four questions:

  1. What are the developmental and evolutionary constraints on gene regulation?
  2. How are cell specification and embryonic patterning intertwined?
  3. How does patterning of different tissue types constrain limb morphological evolution?
  4. To what extent can ‘phenotypic plasticity’ drive adaptive changes in developmental programs?

As a model systems, we study the development of the vertebrate skeleton with its associated neuromuscular system and dietary adaptions in the gastrointestinal tract.

Regulatory evolution of vertebrate skeletogenesis -
what are the developmental and evolutionary constraints on gene regulation?

Skeletogenesis occurs through the initial condensation of mesenchymal progenitors, followed by differentiation into various skeletal cell types. Depending on anatomical location, three distinct mesenchymal progenitor pools contribute to the different parts of the vertebrate skeleton: the somitic mesoderm forms the axial skeleton, whereas the lateral plate mesoderm and the neural crest give rise to the appendicular skeleton and parts of the cranial skeleton, respectively.
We are studying the gene regulatory mechanisms underlying this convergent specification of skeletal cells, originating from distinct embryonic sources, across multiple vertebrate species.

Cell fate decisions during digit development -
how are cell specification and embryonic patterning intertwined?

Individual digit patterns in tetrapod hands and feet are determined by the number and size of their bony elements, the phalanges, and how they are connected to each other via synovial joints. Understanding the developmental dynamics of digit progenitor proliferation, and their specification into phalanx or joint cell fates, would thus allow us to decipher the underlying molecular and cellular mechanisms of digit morphological diversification.
We are using experimental embryology, functional genomics and imaging to outline the underlying developmental logic of this process. In collaboration with Dagmar Iber’s group (D-BSSE ETH Zürich) we are developing in silico models, to better understand its evolutionary flexibility.

Adapting the limb neuromuscular system to skeletal changes -
how does patterning of different tissue types constrain limb morphological evolution?

During limb musculoskeletal development diverse tissue types with distinct embryonic origins need to be functionally integrated. How is their patterning coordinated, in order to give rise to a fully functional limb? Moreover, what are the potential developmental constraints originating from such patterning interdependency between different tissue types?
We address this question in the context of the autopod, hands and feet, where the appendicular skeleton shows the highest degree of morphological diversity and functional specialization. We are using experimental embryology and genetic mouse models (in collaboration with Rolf Zeller’s group, Department of Biomedicine, Uni Basel), coupled to lightsheet microscopy and single-cell genomics.

Environmentally induced ‘phenotypic plasticity’ in the gastrointestinal tract -
how plastic are developmental programs in response to novel dietary niches?

Dietary adaptations play a key role in generating and maintaining organismal diversity on Earth, and are known to function as important drivers of morphological, cellular and molecular diversifications in the gastrointestinal tract of vertebrates. The relative importance and ontogenetic timing of these three processes, as well as their phylogenetic distribution, however, can vary substantially.
Together with the Salzburger (Uni Basel), Kaessmann (Uni Heidelberg) and Clauss (Uni Zürich) labs, we are investigating the potential for ‘phenotypic plasticity’ during the development of the gastrointestinal tract in the context of two adaptive radiations in vertebrates, mammals and cichlids, using imaging, functional genomics and cross-trophic type feeding experiments.