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Durham, N.C. -- An infectious fungus has been found to defy
the most basic tenet of sexual reproduction – that successful
mating requires individuals of the opposite sex, according to
Howard Hughes Medical Institute researchers at Duke University
Medical Center.

In the April 21, 2005, issue of Nature, the researchers
reported that, in the infectious fungus Cryptococcus
neoformans, members of the same "sex" can mate and produce
offspring. Infection with the fungus can prove life-threatening
in humans, and the findings might improve understanding of the
fungal biology that underlies the infectious process, the
researchers said. Discovery of the same-sex mating might also
help elucidate basic principles governing the evolution of sex,
they said.

"Sex is generally beneficial as a means to produce offspring
with different gene combinations that can adapt more rapidly to
new environments," said HHMI investigator Joseph Heitman, M.D.,
Ph.D., of Duke, senior author of the study.

"The findings suggest for the first time that the fungus has
developed a novel type of sexual cycle, allowing sexual
reproduction between members of the same mating type," he
added. "That ability might confer an advantage for the fungus
because patients infected with it predominantly harbor a single
mating type, reducing the possibility of normal fungal sexual
reproduction."

The potentially life-threatening fungus C. neoformans
invades the central nervous system to cause disease, most
commonly in immune-compromised patients such as organ
transplant recipients and cancer patients -- whose immune
systems are crippled by immunosuppressive drugs or chemotherapy
-- and people with HIV/AIDS. The fungus' global importance as a
health threat has therefore risen in parallel with the
increased use of such therapies and with the worldwide HIV/AIDS
pandemic.

In plants and animals, sexual identity is governed by sex
chromosomes. In fungi, however, sexual identity is determined
by so-called "mating type loci," genes arranged contiguously,
but which typically do not span an entire chromosome. C.
neoformans exists in two mating types, a and alpha, determined
by a single genetic region, or locus.

Most fungal isolates taken from people infected by C.
neoformans are of the alpha mating type, said study lead author
and post-doctoral fellow Xiaorong Lin, Ph.D., also of Duke.

"Organisms, including fungi, usually exist in an
approximately one-to-one sex ratio," Lin said. "Yet in
Cryptococcus neoformans, one mating type predominates, leaving
them with apparently few chances to mate. It's been a
mystery."

In 1996, another group discovered that those alpha isolates
could undergo fruiting and produce spores, a process that
resembles sexual reproduction. However, researchers thought
that the unisexual fruiting occurred strictly through the
asexual division of cells into identical clones, Heitman
said.

That left scientists with a conundrum. C. neoformans has a
defined sexual cycle involving both mating types. "Yet, how can
sexual reproductive potential be maintained in an organism with
a largely unisexual population structure?" Heitman asked. "The
fruiting of alpha strains provided a clue."

In their laboratory experiments, the researchers found that,
rather than being an asexual process, the hallmarks of mating
occur during fruiting of alpha isolates. Unisexual fruiting
involves the fusion of cells followed by meiosis, enabling
genetic exchange between members of the same sex, they
reported.

Meiosis is the process whereby cells divide into two
"haploid" cells, each with half the number of chromosomes.
Unlike diploid animals and plants, C. neoformans normal state
is haploid, Heitman explained.

Furthermore, the team showed, strains lacking components
required for mating -- including pheromones, pheromone
receptors and other genes with known roles in mating --
exhibited a defect in fruiting.

The newly described mating strategy might allow a single
mating strain to expand rapidly by cell division, yet retain
its ability to generate diversity by undergoing sex, said
Heitman. That diversity might provide an advantage when faced
with new environmental challenges, he said.

While the findings have no immediately obvious clinical
implications, Heitman said, "the more we know about the
biological cause of any disease, the better positioned we are
to develop cost-effective diagnostic or therapeutic
interventions."

The fungal strategy may also contribute to scientists'
general understanding of the conditions that favor evolutionary
transitions between self-fertilization and sexual reproduction
among unrelated individuals, known to occur in the fungal,
plant and even animal kingdoms, the researchers said.

Christina Hull, now at the University of Wisconsin, Madison,
also contributed to the research. The work was supported by the
National Institute of Allergy and Infectious Disease, the Damon
Runyon Cancer Research Fellowship and the Burroughs Wellcome
Fund.