Recombination Hotspots Flank the Cryptococcus Mating-Type Locus: Implications for the Evolution of a Fungal Sex Chromosome

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Abstract
Recombination increases dramatically during meiosis to promote genetic exchange and generate recombinant progeny. Interestingly, meiotic recombination is unevenly distributed throughout genomes, and, as a consequence, genetic and physical map distances do not have a simple linear relationship. Recombination hotspots and coldspots have been described in many organisms and often reflect global features of chromosome structure. In particular, recombination frequencies are often distorted within or outside sex-determining regions of the genome. Here, we report that recombination is elevated adjacent to the mating-type locus (MAT) in the pathogenic basidiomycete Cryptococcus neoformans. Among fungi, C. neoformans has an unusually large MAT locus, and recombination is suppressed between the two >100-kilobase mating-type specific alleles. When genetic markers were introduced at defined physical distances from MAT, we found the meiotic recombination frequency to be ~20% between MAT and a flanking marker at 5, 10, 50, or 100 kilobases from the right border. As a result, the physical/genetic map ratio in the regions adjacent to MAT is distorted ~10- to 50-fold compared to the genome-wide average. Moreover, recombination frequently occurred on both sides of MAT and negative interference between crossovers was observed. MAT heterozygosity was not required for enhanced recombination, implying that this process is not due to a physical distortion from the two non-paired alleles and could also occur during same-sex mating. Sequence analysis revealed a correlation between high G + C content and these hotspot regions. We hypothesize that the presence of recombinational activators may have driven several key events during the assembly and reshaping of the MAT locus and may have played similar roles in the origins of both metabolic and biosynthetic gene clusters. Our findings suggest that during meiosis the MAT locus may be exchanged onto different genetic backgrounds and therefore have broad evolutionary implications with respect to mating-type switching in both model and pathogenic yeasts. It is hypothesized that sexual reproduction enables genetic recombination between individuals to generate diversity, thus increasing population fitness. However, a well-known meiotic feature is that recombination is not randomly distributed across the genome: “coldspots” and “hotspots” exist, implying some regions undergo exchange more frequently. In this paper, the authors report the discovery of recombination hotspots linked to the sex-determining region mating-type locus (MAT) in the human pathogenic fungus Cryptococcus neoformans. Through genetic analysis, hotspots were found to reside on both sides of MAT and are associated with DNA regions marked by high G + C base pair composition. Moreover, recombination on one side of MAT is associated with a recombination on the other. As a result, the MAT locus can be replaced onto the homologous chromosome as a unit—an effective switch of MAT. Based on these findings, they propose that the MAT-linked recombination hotspots impacted key steps during MAT evolution. This study has broader implications on how gene clusters (including those involved in metabolism or secondary metabolite production) are assembled and maintained and explains how recombination is distorted in sex-determining regions in eukaryotes.