Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex
- Duke University Medical Center, United States
- Broad Institute, United States
- Westerdijk Fungal Biodiversity Institute, Netherlands
- CNRS, University Evry, France
- Ruhr-University Bochum, Germany
Abstract
Sexual reproduction is a ubiquitous and ancient trait of eukaryotic life. While sexual organisms are usually faced with the challenge of finding a compatible mating partner, species as diverse as animals, plants, and fungi have repeatedly evolved the ability to reproduce sexually without an obligate requirement for another individual. Here, we uncovered the underlying mechanism of self-compatibility (homothallism) in Cryptococcus depauperatus, a fungal species sister to the clinically relevant human fungal pathogens Cryptococcus neoformans and Cryptococcus gattii species complexes. In contrast to C. neoformans or C. gattii, which grow as a yeast in the asexual stage, and produce hyphae, basidia, and infectious spores during the sexual stage, C. depauperatus grows exclusively as hyphae decorated with basidia and abundant spores and appears to be continuously engaged in sexual reproduction. By combining the insights from comparative genomics and genetic analyses of mutants defective in key mating and meiosis genes, we demonstrate the sexual cycle of C. depauperatus involves meiosis, and reveal that self-compatibility is orchestrated by the expression, in the same cell, of an unlinked mating receptor (Ste3a) and pheromone ligand (MFa) pair seemingly derived from opposite mating types of a heterothallic (self-sterile) ancestor. We identified a putative mating-type (MAT) determining region containing genes phylogenetically aligned with MAT<strong>a</strong> alleles of other species, and a few MATa gene alleles scattered and unlinked throughout the genome, but no homologs of the mating-type homeodomain genes SXI1 (HD1) and SXI2 (HD2). Comparative genomic analyses suggested a dramatic remodeling of the MAT locus possibly owing to reduced selective constraints to maintain mating-type genes in tight linkage, associated with a transition to self-fertility. Our findings support C. depauperatus as an obligately sexual, homothallic fungal species and provide additional insight into the repeated transitions between modes of sexual reproduction that have occurred throughout the fungal kingdom.
Data availability
Sequencing reads and genome assemblies of C. depauperatus CBS7841 and CBS7855 were submitted to GenBank under BioProjects PRJNA200572 and PRJNA200573, respectively. All other genomic data (RNA-seq and Illumina sequence of C. depauperatus CBS7841 can1 mutants) are available under BioProject PRJNA803141. Source data files have been provided for Figures 1 to 7.
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Cryptotoccus SequencingNCBI BioProject, PRJNA200572.
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Cryptotoccus SequencingNCBI BioProject, PRJNA200573.
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Cryptococcus depauperatus raw sequence readsNCBI BioProject, PRJNA803141.
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Cryptococcus neoformans var. grubii H99 genomeNCBI BioProject, PRJNA411.
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Cryptotoccus SequencingNCBI BioProject, PRJNA200571.
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Cryptotoccus SequencingNCBI BioProject, PRJNA191370.
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Cryptococcus floricola strain DSM 27421 Genome sequencing and assemblyNCBI BioProject, PRJNA496466.
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Cryptococcus wingfieldii strain CBS7118 Genome sequencing and assemblyNCBI BioProject, PRJNA496468.
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WGS sequencing of strain JEC21 (serotype D)NCBI BioProject, PRJNA13856.
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Cryptococcus gattii WM276 RefSeq GenomeNCBI BioProject, PRJNA62089.
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Kwoniella mangroviensis CBS 8507NCBI BioProject, PRJNA352839.
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Kwoniella mangroviensis CBS 10435NCBI BioProject, PRJNA202099.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (AI50113-17)
- Joseph Heitman
National Institute of Allergy and Infectious Diseases (AI39115-24)
- Joseph Heitman
National Institute of Allergy and Infectious Diseases (AI33654-04)
- Joseph Heitman
National Institutes of Health (U54HG003067)
- Christina A Cuomo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Antonis Rokas, Vanderbilt University, United States
Publication history
- Preprint posted: March 30, 2022 (view preprint)
- Received: March 31, 2022
- Accepted: June 15, 2022
- Accepted Manuscript published: June 17, 2022 (version 1)
- Version of Record published: July 19, 2022 (version 2)
Copyright
© 2022, Passer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex
eLife 11:e79114.
https://doi.org/10.7554/eLife.79114
Further reading
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Background: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases.
Methods: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption.
Results: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 21 associations persisted after adjusting for genetically-predicted alcohol consumption. Genetically-predicted higher alcohol consumption was associated with increased risk of duodenal cancer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain after adjustment for genetic predisposition to smoking initiation.
Conclusion: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases.
Funding: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.
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Drosophila melanogaster reproductive behaviors are orchestrated by fruitless neurons. We performed single-cell RNA-sequencing on pupal neurons that produce sex-specifically spliced fru transcripts, the fru P1-expressing neurons. Uniform Manifold Approximation and Projection (UMAP) with clustering generates an atlas containing 113 clusters. While the male and female neurons overlap in UMAP space, more than half the clusters have sex differences in neuron number, and nearly all clusters display sex-differential expression. Based on an examination of enriched marker genes, we annotate clusters as circadian clock neurons, mushroom body Kenyon cell neurons, neurotransmitter- and/or neuropeptide-producing, and those that express doublesex. Marker gene analyses also show that genes that encode members of the immunoglobulin superfamily of cell adhesion molecules, transcription factors, neuropeptides, neuropeptide receptors, and Wnts have unique patterns of enriched expression across the clusters. In vivo spatial gene expression links to the clusters are examined. A functional analysis of fru P1 circadian neurons shows they have dimorphic roles in activity and period length. Given that most clusters are comprised of male and female neurons indicates that the sexes have fru P1 neurons with common gene expression programs. Sex-specific expression is overlaid on this program, to build the potential for vastly different sex-specific behaviors.
