Our research investigates the evolutionary origin and consequences of functional genetic diversity in the context of health and disease. A particular focus of the group lies on the dynamics and trade-offs that govern successful antigen presentation and recognition in the adaptive immune system of vertebrates. We are exploring the complex interactions between the functional variability of antigen-presenting MHC molecules, the dynamics of the interacting T cell repertoire, and the antigen evolution in pathogens in order to improve our understanding of immune-mediated diseases in particular and the evolution of the adaptive immune system in general.
Current projects address specific questions in the following research themes:
Evolution of an optimal immune response
The vertebrate immune system combines a plethora of specific and unspecific mechanisms to defend the body against invading (and coevolving) pathogens. The more diverse the immune response, the broader the spectrum of recognized pathogens. However, a too diverse immune response may also increase the risk of self-reactivity, in humans known as autoimmune diseases. Hints for such a trade-off can be observed at multiple levels in the immune system, but is most apparent at the Major Histocompatibility Complex (MHC). The MHC encodes highly polymorphic molecules that each recognize specific pathogens, but every individual carries only a very limited number of these genes. We are interested in the processes and constraints that increase or limit and thus shape the individual genetic diversity at the MHC. A current focus is the link between MHC diversity and both infection and autoimmunity in human populations, but ultimately we are also interested in a broader perspective and are exploring in which ways diversity at the MHC interacts with other immune genes and the genetic background. For this work we are mostly using computational tools and approaches.
Dynamics of antigen presentation and recognition
The initiation and success of an antigen-specific adaptive immune response depends on both the presentation of the antigen by an MHC molecule and the recognition of the antigen:MHC complex by an appropriate T cell receptor. A comprehensive understanding of adaptive immunity thus requires studying both antigen presentation by the MHC and the development of the individual T cell repertoire. In this context, we are exploring the diversity and composition of naïve and mature T cell repertoires within and among individuals, and in response to MHC variability and antigen exposure. For this work we mainly use our experimental model organism, the three-spined stickleback, and next generation sequencing technology.
Evolutionary Genomics of the Major Histocompatibility Complex (MHC)
The MHC is characterized by exceptional genetic and genomic properties, including a vast number of protein-coding alleles, gene copy number variation, and both extensive linkage disequilibrium but also recombination hot spots. It is assumed that these properties are to a large extent the result of natural selection, but very little is known about the processes ultimately responsible for the observed patterns. We are exploring the structural organization and patterns of diversity in the MHC region within and between natural populations (mainly sticklebacks and humans), with the ultimate goal to identify genetic, genomic, and environmental factors that contribute to the genomic organization of the MHC. This work includes computational approaches as well as genetic and genomic techniques, including next generation sequencing.
Human population genetics and genomics
Pathogen-mediated selection has repeatedly been suggested as one of the major drivers for human evolution, with immune genes frequently showing the strongest signatures of selection and dominating any outlier test for genetic divergence between populations. The increasing genomic resources from human populations and the availability of epidemiological data provides unparalleled opportunities to explore local immunogenetic adaptation in humans. However, contemporary data limits our ability to infer selection processes in the past. We are therefore also investigating immunogenetic evolution in historical populations, focusing on drastic epidemiological events in modern human history.