Research

The ‘Meiotic Recombination and Genomic Instability’ research group investigates how meiotic recombination is controlled, how germ cells recognise and eliminate erroneous recombination events, and how these mechanisms change over the course of evolution. Our research combines molecular genetics, evolutionary biology, cell biology and bioinformatics to understand the regulation of recombination landscapes, meiotic quality control and genome stability in various vertebrate species. The aim of our work is to decipher the molecular and evolutionary mechanisms that ensure fertility and successful meiosis across evolutionary time scales.

Our research group combines molecular genetics, evolutionary biology, reproductive biology, cytology and bioinformatics to investigate how meiotic recombination is initiated, repaired, regulated and evolutionarily adapted. We also use biochemical analyses of recombination proteins, as well as high-resolution STED microscopy of meiotic chromosomes.

 

Current Research Projects

 

Molecular and Evolutionary Cell Biology of Reproduction

Our research addresses one of the central questions in biology: how do organisms maintain their fertility whilst not only genomes but also the molecular mechanisms controlling recombination change over the course of evolution?

Meiotic recombination is essential for the correct distribution of chromosomes and for the generation of genetic diversity. Errors during this process are among the most common causes of infertility, miscarriages and chromosomal abnormalities. Despite decades of research, many molecular and evolutionary mechanisms of recombination control and meiotic quality control are still only partially understood.

 

The Evolution of Recombination Control

A key focus of our research is the evolution of recombination landscapes and the molecular mechanisms that regulate the positioning of meiotic DNA double-strand breaks.

Our work has made a significant contribution to understanding how rapidly evolving recombination regulators influence the activity of recombination hotspots, genome evolution and reproductive isolation. We have characterised the natural diversity of recombination regulators in mouse populations worldwide and shown that only certain allele combinations cause hybrid sterility in wild mice. These findings provide direct mechanistic insights into the role that recombination systems play in the formation of reproductive barriers. Furthermore, we have developed novel phylogenetic and bioinformatic approaches capable of analysing hundreds of allelic variants across thousands of samples. These methods are currently being further developed into widely accessible computer-based tools for evolutionary and clinical applications.

Furthermore, our research investigates how recombination systems change following the evolutionary loss of key recombination regulators. Several vertebrate lineages — including canids and birds — have lost such regulators independently of one another and yet remain fertile. We are investigating how these organisms maintain successful meiosis despite profound changes in recombination initiation.

To this end, we use computer-aided population genetic approaches to analyse historical recombination patterns (backwards in time) as well as de novo recombination events in specific genomic regions, known as hotspots, directly in germ cells (de novo events), alongside simulations of the detected germline instability (e.g. transmission ratio distortion (forward in time)).

To this end, we combine sperm typing, meiotic cytology, population genomic analyses and comparative evolutionary biology to uncover alternative recombination and DNA repair pathways in vertebrates with different evolutionary recombination systems.

 

Meiotic DNA repair and genome stability

A second research focus concerns the molecular mechanisms that ensure successful meiotic DNA repair and genome stability.

Previous work by our group identified a novel mechanism of meiotic drive via non-crossover recombination, demonstrating that recombination can directly skew the inheritance of certain alleles and thereby influence genome evolution in the long term.

Current projects are investigating how meiotic DNA repair pathways differ between vertebrates with different recombination systems, and whether evolutionarily conserved ‘backup’ mechanisms exist to safeguard fertility when classical recombination pathways are disrupted.

Particularly fascinating is the observation that species lacking classical hotspot regulation frequently redirect recombination events to promoter-associated chromatin structures. We are currently investigating how transcriptional activity, chromatin organisation and the recombination machinery interact at these sites, and how these mechanisms have evolved independently of one another in different vertebrate lineages.

Our work combines high-resolution mapping of de novo recombination events in germ cells with immunofluorescence-based analysis of meiotic chromosomes and population-genetic reconstruction analyses of historical recombination.

 

microRNA-mediated regulation of the meiotic pachytene checkpoint

Our most recent work has revealed a fundamentally new level of meiotic regulation: the active control of meiotic progression by X-chromosomal microRNAs.

Whilst investigating hybrid sterility in mice, we first identified extensive copy number variation within a rapidly evolving cluster of X-chromosomal microRNAs. We subsequently demonstrated that this cluster constitutes the functional pachytene checkpoint of meiosis in mice and actively regulates whether defective germ cells proceed with meiosis or are arrested.

It is particularly noteworthy that the removal of this microRNA cluster can restore fertility in otherwise sterile hybrids. These results demonstrate that meiotic checkpoints are not purely passive monitoring systems, but rather constitute evolutionarily dynamic regulatory networks.

Our ongoing work is investigating how this checkpoint system interacts with recombination control, DNA repair, chromosome synapsis and hybrid sterility. In this context, we have already identified target genes involved in the organisation of meiotic chromosomes and DNA repair, and are currently analysing the underlying molecular signalling pathways.

In parallel, we are extending this work to human datasets and investigating whether comparable microRNA-mediated mechanisms contribute to human infertility and susceptibility to aneuploidy.

Using unique transgenic mouse models, modern meiotic cytology, transcriptomics and computer-assisted target gene analyses, our long-term aim is to establish a new conceptual understanding of the post-transcriptional control of meiosis and fertility.

 

Perspective

Our research combines evolutionary biology with reproductive medicine. By understanding the evolution of recombination and quality control systems, we aim to elucidate fundamental principles of fertility, genome stability and reproductive isolation.