In eukaryotes, crossover (CO) during meiosis is the core mechanism for the exchange of genetic material between homologous chromosomes, and plays a decisive role in ensuring the accuracy of gamete chromosome separation and population genetic diversity. However, although a large number of DNA double-strand breaks (DSBs) are generated as recombination precursors during meiosis, the final CO event is strictly restricted. Each chromosome usually produces only 1-3 COs, and their spatial distribution is highly uneven, mainly concentrated at the distal end of the chromosome. In addition, CO frequency and distribution often show significant differences between male and female individuals (i.e., sexual heterogeneity), and its molecular mechanism has not yet been clarified. In crop genetic improvement, due to the limitations of CO number and distribution, large genomic regions are difficult to achieve effective recombination, which has become an important bottleneck for combining excellent alleles and breaking bad linkage in precision breeding.
On June 12, 2025, a research team from the Max Planck Institute for Plant Breeding Research in Germany published a research paper entitled "Maximizing meiotic crossover rates reveals the map of Crossover Potential" in Nature Communications. This study successfully increased the recombination frequency by up to 12 times through genetic intervention, and proposed the concept of "Crossover Potential" (COP) for the first time, systematically mapping its distribution at the genome-wide scale, and providing an important theoretical basis for further understanding the recombination frequency and distribution polymorphism, sexual heterogeneity, and crop genetic breeding strategies.
This study found that simultaneous mutations of ZYP1 (a transverse filament protein of the meiotic synaptonemal complex that regulates class I COs) and RECQ4 (a helicase that inhibits class II COs) in Arabidopsis can significantly increase the number of COs. The number of COs in female gametes increased by an average of about 12 times (up to about 27 times), and in males by about 4.5 times (up to about 10 times), setting a record for the highest known CO frequency. It is worth noting that even if factors that promote the formation of class I or class II COs, such as HEI10 overexpression or FIGL1 mutation, are further introduced into this ultra-high recombination background, the total number of COs no longer increases, suggesting that there is a "biological upper limit" to the CO frequency determined by resource limitations.
Figure 1. ZYP1 and RECQ4 double mutations greatly increase CO frequency and reveal the upper limit of recombination. (Jing, et al., 2025)
In-depth analysis shows that class I and class II CO pathways compete for recombination intermediates. HEI10oe can enhance the generation of class I COs, but simultaneously inhibit class II COs, and vice versa. This "intermediate competition model" believes that the type I and type II CO pathways share a limited set of precursor resources (recombination intermediates formed by DNA double-strand breaks), and their total amount constitutes the main bottleneck limiting the total number of COs. It is worth noting that despite the significant increase in the number of COs, the mutant plants still showed about 75% normal fertility, and no chromosome aneuploidy or obvious meiotic abnormalities were observed, indicating that plants can tolerate extremely high levels of recombination at the physiological level.
In multiple high recombination frequency mutants, the researchers integrated about 50,000 recombination events and found that despite the significant increase in recombination frequency, the distribution pattern of CO on the chromosome scale remained highly consistent, mainly enriched in the distal region of the chromosome, while the near-centromere region remained a recombination "cold zone". More importantly, in these high recombination backgrounds, the distribution map of CO between male and female individuals almost completely overlapped, which was significantly different from the CO distribution pattern showing sex-specific differences in the wild type.
Based on this discovery, the research team proposed the concept of COP to describe the potential ability of different regions of the genome to form COs under the condition of removing regulatory restrictions, independent of sex and specific regulatory factors. In the context of high recombination, COP is fully released due to the removal of regulatory restrictions, thus revealing a common, sex-independent recombination map. The proposal of COP provides a new explanatory perspective for understanding the formation mechanism of chromosome recombination maps.
Through in-depth feature analysis of COP, it was found that its distribution pattern in the genome is closely related to multiple genomic and epigenetic features. COP is strongly positively correlated with chromatin openness, active histone modifications (such as H3K4me3), and gene expression density, and negatively correlated with DNA methylation, heterochromatin marks (such as H3K9me2), transposon density, etc. Furthermore, the research team constructed a prediction model based on machine learning, using 17 genomic and epigenomic features, and successfully explained 94% of the variation in COP distribution. Among them, only the first 7 key features can accurately predict about 93% of COP distribution, showing a high prediction accuracy. This result shows that the COP map is mainly determined by the local sequence composition of the chromosome and the chromatin state, rather than being completely dependent on the activity of a specific recombination regulatory pathway. This not only provides theoretical support for the precise regulation of CO distribution through genomic and epigenetic interventions, but also lays an important methodological foundation for establishing a data-driven CO prediction model based on multi-omics features.
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