# Structure, function, and evolution of the Cryptococcus MAT locus

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $517,436

## Abstract

The Cryptococcus genus spans a diverse group of fungal species from environmental saprophytes to
common human pathogens. In fact, the Cryptococcus neoformans and Cryptococcus gattii species complexes
cause >220,000 life-threatening infections each year in both immunocompromised and immunocompetent
patients, leading to >180,000 deaths, >15% of all HIV/AIDS-related deaths, and >70% mortality in low-income
countries. In studies supported by this award, we defined the structure, function, and evolution of a large genomic
region in Cryptococcus species that has co-evolved with pathogenesis, the fungal mating type (MAT) locus. The
Cryptococcus MAT locus is a large, complex gene cluster that controls sexual reproduction, infectious spore
production, and pathogenicity. We elucidated how these sex- and virulence-determining genes evolved from a
nonpathogenic ancestral state. Our studies reveal bipolar/inbreeding mating systems are shared by all of the
pathogenic species, and evolved from an ancestral outbreeding/tetrapolar system. Similar transitions occurred
in other fungal pathogens of plants and animals, suggesting convergent evolution in concert with host adaptation.
 In the prior award period, we made major advances characterizing the association of fungal MAT locus
evolution with virulence: 1) we sequenced the genomes/MAT loci of 24 species spanning all Cryptococcus
pathogens and aligned nonpathogens; 2) we defined Cryptococcus centromeres and implicated inter-
centromeric recombination in mating type and genome transitions; 3) we demonstrated the MAT-encoded RPL22
genes have essential, specialized functions. In the current proposal, we hypothesize that mating-type transitions
drove pathogen emergence resulting in a gene complex linked to virulence and infectious spore production.
 Our recent studies reveal unique aspects of MAT biology allowing us to propose new aims to test this
hypothesis. Aim 1 focuses on MAT locus structure and evolution, utilizing RNA-Seq and sRNA analysis to
define mRNA, asRNA, lncRNA, and siRNA produced by MAT during asexual/sexual reproduction, engineering
translocations to model tetrapolar-bipolar transition with CRISPR, and conducting Hi-C analysis to examine
nuclear organization of MAT and centromeres. Aim 2 will elucidate MAT functions linked to virulence and
development involving 1) MAT-encoded lncRNA ASM1, 2) diverged, specialized, essential ribosomal genes we
hypothesize operate as an ancestral imprinting system ensuring sexual reproduction fidelity, and 3) modeling in
mice of the role of a newly recognized host factor controlling immune protection against cryptococcal infections:
host GM-CSF signaling. Auto-antibodies against the GM-CSF cytokine are a major risk factor for lineage-specific
Cryptococcus infections, suggesting unique host features might play a role in evolution of infections due to
human pathogenic species. These studies will advance understanding of dynamic microbial genome evolution,
associating spe...

## Key facts

- **NIH application ID:** 10047587
- **Project number:** 2R01AI050113-16A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** JOSEPH HEITMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,436
- **Award type:** 2
- **Project period:** 2002-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047587

## Citation

> US National Institutes of Health, RePORTER application 10047587, Structure, function, and evolution of the Cryptococcus MAT locus (2R01AI050113-16A1). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10047587. Licensed CC0.

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