The human genome contains a complex array of genes, each with a specific cellular role. Among these, PRDM9 stands out as a gene involved in genetic events. Its actions are relevant to how genetic information is shuffled and passed down through generations. Understanding PRDM9 provides insight into the mechanisms that underpin genetic diversity in many species.
The PRDM9 Protein and Its Function
PRDM9, or PR/SET Domain 9, is a protein-coding gene located on chromosome 5 in humans. It produces a protein with a distinctive structure that interacts with DNA and modifies associated proteins. The protein features a DNA-binding zinc finger array and a PR/SET domain with histone methyltransferase activity.
The zinc finger array enables PRDM9 to recognize and bind to specific DNA sequences within the genome. This binding allows the protein to target specific regions. The PR/SET domain then modifies surrounding nucleosomes by adding methyl groups to histone H3 at lysines 4 and 36. This dual methylation activity is characteristic of PRDM9 among mammalian chromatin-modifying enzymes. These modifications mark specific sites in the genome, designating them as locations for genetic events.
Guiding Genetic Recombination
PRDM9 plays a role in guiding genetic recombination during meiosis, the cell division that produces reproductive cells. This process ensures genetic diversity in offspring. In humans and mice, recombination does not occur randomly across the genome but is concentrated at specific regions known as recombination hotspots.
PRDM9’s zinc finger array binds to particular DNA sequences within these hotspots. Upon binding, PRDM9’s histone methyltransferase activity trimethylates histone H3 at lysine 4 and lysine 36 in nucleosomes. This localized chromatin modification creates an environment for the initiation of DNA double-strand breaks (DSBs). These breaks precede the exchange of genetic material between homologous chromosomes.
PRDM9 also facilitates the association of these marked hotspots with the chromosome axis, where DSBs are formed. The protein forms complexes with other factors involved in repairing these DNA breaks. By dictating where these breaks occur, PRDM9 positions the recombination events that reshuffle parental genetic information.
Evolutionary Significance
The PRDM9 gene exhibits rapid evolution across different species. It is among the fastest evolving genes in the mammalian genome. This change is noticeable in its zinc finger array, which determines its DNA binding specificity. The variation in PRDM9’s binding sites is linked to a concept known as the “hotspot paradox,” where recombination can lead to the erosion of the DNA sequences that PRDM9 recognizes. This constant erosion necessitates the rapid evolution of PRDM9 to target new sequences, ensuring continued recombination.
Differences in PRDM9 variants between populations can lead to altered recombination patterns. Such variations can result in reduced fertility or sterility in hybrid offspring, contributing to reproductive isolation. This suggests PRDM9 contributes to new species formation by creating barriers to gene flow. While PRDM9 determines recombination hotspots in many mammals, including humans and mice, its presence and function vary across the animal kingdom. For instance, birds do not possess a functional PRDM9 gene, indicating alternative mechanisms for guiding recombination.
Implications for Fertility and Health
Variations in the PRDM9 gene can affect human fertility and health. Alterations in the zinc finger array can change the protein’s DNA-binding preferences, shifting recombination hotspot locations. This can lead to an imbalanced distribution of recombination events. Such deviations can affect chromosome segregation during meiosis.
Abnormal chromosome segregation can increase the risk of aneuploidies, conditions with an abnormal number of chromosomes. These chromosomal abnormalities are a cause of reproductive issues, including infertility and recurrent miscarriages. While PRDM9’s role is complex and involves interactions with many other proteins, its function is important for successful reproduction. Understanding PRDM9’s variations can offer insights into the causes of certain reproductive disorders.