Linda Odenthal-Hesse

Regulating factors of “default” recombination in gene promoters

Evolution is shaped by meiotic recombination. Meiotic recombination is an intricate process that reshuffles genetic information before it passed on to the next generation, and thus generating new combinations of alleles that evolution can then act on. Despite being a fundamental process with relevance to biology and medicine, surprisingly little is known on how meiotic recombination is regulated. In humans and most other mammals, meiotic recombination events are clustered in 1-2 kb wide recombination hotspots whose locations are determined in trans by the protein PR-domain containing 9 (PRDM9). Mice lacking PRDM9 direct recombination to promoters and functional elements, resulting in meiotic arrest and infertility. Similarly, the domestic dog Canis familiaris lacks a functional copy of PRDM9, and linkage data showed that historical recombination events cluster in these same functional elements as in sterile PRDM9 knockout mice. Given that dogs are fully fertile, this suggests a default mechanism enabling controlled recombination at these locations, and in the absence of PRDM9, which is active at least in dogs.

We isolated de-novo recombination events at dog recombination hotspots and observed high frequencies of de-novo recombination resolution. This revealed that double-stranded breaks can be efficiently repaired in functional elements in dogs (Jeschke & Odenthal-Hesse, in preparation). However, we also uncovered an intriguing phenomenon of differences in recombination frequencies between individual dogs, which points to previously unknown regulating factors. Since it is assumed that recombination in promoters may be a default mechanism preventing sterility, this regulating factor is likely a default regulation factor active across mammalian systems.

The proposed PhD project aims at uncovering dynamics and regulating factors of default recombination in promoters, and the project will implement a host of techniques, from whole-genome ChIP-Sequencing to fine-scale mapping of meiotic recombination products and third-generation sequencing techniques. Candidates with a background in biology, genetics, biochemistry or related fields with extensive wet-lab experience and interest in computational data analysis would be ideal.