The human fungal pathogen Aspergillus fumigatus can produce the highest known number of meiotic crossovers

Abstract

Sexual reproduction involving meiosis is essential in most eukaryotes. This produces offspring with novel genotypes, both by segregation of parental chromosomes as well as crossovers between homologous chromosomes. A sexual cycle for the opportunistic human pathogenic fungus Aspergillus fumigatus is known, but the genetic consequences of meiosis have remained unknown. Among other Aspergilli, it is known that A. flavus has a moderately high recombination rate with an average of 4.2 crossovers per chromosome pair, whereas A. nidulans has in contrast a higher rate with 9.3 crossovers per chromosome pair. Here, we show in a cross between A. fumigatus strains that they produce an average of 29.9 crossovers per chromosome pair and large variation in total map length across additional strain crosses. This rate of crossovers per chromosome is more than twice that seen for any known organism, which we discuss in relation to other genetic model systems. We validate this high rate of crossovers through mapping of resistance to the laboratory antifungal acriflavine by using standing variation in an undescribed ABC efflux transporter. We then demonstrate that this rate of crossovers is sufficient to produce one of the common multidrug resistant haplotypes found in the cyp51A gene (TR34/L98H) in crosses among parents harboring either of 2 nearby genetic variants, possibly explaining the early spread of such haplotypes. Our results suggest that genomic studies in this species should reassess common assumptions about linkage between genetic regions. The finding of an unparalleled crossover rate in A. fumigatus provides opportunities to understand why these rates are not generally higher in other eukaryotes.

Pan-azole- and multi-fungicide-resistant Aspergillus fumigatus is widespread in the United States

“…Previous work from others found evidence of very high recombination rates in A. fumigatus with recombination frequently occurring between clades ( 16 , 60 ). Our isolates also showed signatures of recombination between clades in PCA and ADMIXTURE analysis ( Fig.…”

Antifungal Resistance in Pulmonary Aspergillosis

“…Each of these reproduction modes varies in the type and amount of variation created, the specific conditions that support the reproduction mode, as well as the frequency of this mode occurring (►Table 1). [18][19][20][21] Asexual reproduction is the most common reproductive mode for A. fumigatus. A fungal colony is initiated from the germination of a single spore that will give rise to a network of hyphae.…”

“…A recent study showed the highest crossover during the sexual reproduction of A. fumigatus compared to any other known organism, with an average of 29.9 crossovers per chromosome pair. 19 Thus, sexual reproduction is a very effective way to create genetic variation but is unlikely to occur in the human host due to the specific conditions required for sexual reproduction to occur (►Table 1). The parasexual cycle involves the fusion of genetically compatible haploid hyphae to form a heterokaryon.…”

Emerging Antifungal Resistance in Fungal Pathogens

“…The TR 34 /L98H resistance allele, along with TR 46 /Y121F/T289A (Table 1 ), is associated with itraconazole and voriconazole resistance respectively and has been isolated within and outside the clinic [ 27 ]. A contributing factor for the generation of novel drug resistance alleles could be attributed to the high recombination rate observed in A. fumigatus [ 28 ]; a recent example of a pan-azole resistance phenotype, attributed to TR 34 /L98H/T289A/I364V/G448S, could be the result of such recombination [ 29 ]. Thus, the pandemic potential of drug-resistant A. fumigatus has already been demonstrated, primarily due to human activity by using clinical antifungals in horticultural products [ 30 ], and global spread is likely due to ease of dispersal via conidia on air currents [ 2 ].…”