New Insights: PRDM9 and its role in Hybrid Sterility and Meiotic Recombination in Wild Mice

March 12, 2024

Infertility is a widespread health issue affecting both male and female reproductive organs. Fertility, crucial for conception and the development of healthy children, depends on normal eggs and sperm produced through meiotic cell division. Understanding the regulating mechanisms of these processes is critical, to unravel the mystery of infertility and chromosome abnormalities. PRDM9 plays an important role in regulating meiotic recombination but also influences hybrid sterility in wild mice. New research findings from the Meiotic Recombination and Genome Instability Research Group at the Max Planck Institute for Evolutionary Biology in Plön, in collaboration with the Group of Professor Jiří Forejt, at the Institute of Molecular Mouse Genetics of the Czech Academy of Sciences, show that hybrid sterility is oligogenetically controlled by PRDM9 even, in wild mice, and therefore outside the laboratory model.

The latest findings provide crucial insights into the genetic basis of infertility and hybrid sterility in mammals. Particularly highlighted is the role of the PRDM9 protein, which precisely determines the position of meiotic recombination in the genome. By placing specific epigenetic modifications, PRDM9 acts as a signaling molecule for other protein complexes. The highly conserved domain of PRDM9 interacts directly with various enzymes to remodel chromatin, thus making DNA accessible for recombination. This process leads to the targeted initiation of double-stranded DNA breaks and significantly contributes to genetic diversity.

The rapid variability of PRDM9's DNA-binding domain results in remarkable diversity across many different organisms. This variability can can also explain the differences in the positioning of meiotic recombination when comparing different individuals. However, this variability also has a downside: differences in PRDM9 between subspecies make it the only known hybrid sterility gene in vertebrates. When male offspring of two different subspecies of mice from specific laboratory strains with incompatible variants of PRDM9 meet, this leads to the termination of meiosis and thus infertility of the male offspring. This principle has been confirmed in recent years in wild-derived inbred strains of different subspecies.

The principle of hybrid sterility should also apply in the wild. However, in a naturally occurring hybrid zone in the wild, very few infertile offspring of the same two mouse subspecies were found, and the genomes of wild mouse populations are already very different from those of laboratory strains. "Therefore, it was important to investigate which variants of the PRDM9 protein are found in wild mice, to characterize their evolutionary relationships, and to examine the effects of natural PRDM9 variation in the context of hybrid sterility" says Dr. Linda Odenthal-Hesse, Research Group Leader of the Meiotic Recombination and Genome Instability Research Team.

The Role of PRDM9 and Non-Binary Regulation

In five different wild-captured mouse populations belonging to two mouse-subspecies, fourteen Prdm9 alleles were identified eight of which were novel. The examination of the evolution and phylogenetic relationships of this very complex gene was achieved with the help of newly developed computational tools based on mathematical predictions of the complex genic-evolution of the PRDM9 coding minisatellite. Subsequently, the natural Prdm9-allels were examined for their effects on hybrid sterility. "Our findings illustrate that the hybrid sterility of wild mice is also controlled by PRDM9, but that only a few variants of PRDM9 lead to complete sterility," says Dr. Odenthal-Hesse, adding further: "Interestingly, the two known variants that cause sterility in laboratory mice also lead to sterility in wild mice, even though they were not present in the wild mouse populations in which they are nevertheless able to induce sterility."

The latest investigations unequivocally confirm that the widely accepted functional mechanism of PRDM9-mediated hybrid sterility, which induces asymmetry in recombination initiation breaks, can occur in wild mice. On the other hand, the data suggest that the regulation of hybrid sterility is not binary, meaning there are not either completely fertile or completely sterile animals in the wild, but a rather gradual decrease in fertility with increasing divergence of homologues.

The article was recently published in the renowned journal Genetics (Genetics, Volume 226, Issue 3, March 2024) under the title "Natural variation in the zinc-finger-encoding exon of Prdm9 affects hybrid sterility phenotypes in mice."

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