Sex genes of infectious fungus closely resemble human Y chromosome

Fungi and animals, including humans, have a lot in common when it comes to the arrangement of genes that determine their sex, according to new work by Howard Hughes Medical Institute geneticists at the Duke University Medical Center.

Regions of the genome that determine the sexual identity of the infectious fungus Cryptococcus neoformans bear striking similarities to the human Y chromosome -- the sex chromosome associated with male characteristics -- the team found. The researchers reported their findings in the December 2004 issue of the Public Library of Science Biology (now available online).

The result suggests that, despite their differences, similar evolutionary processes shaped the chromosomal sex-determining regions in both groups, said HHMI investigator Joseph Heitman, M.D., director of Duke's Center for Microbial Pathogenesis. The fungus might therefore serve as a useful model system for the study of sex chromosome evolution and the genetic changes that can lead to infertility, he said.

"The revolution in genome sciences has rapidly accelerated our ability to elucidate the process by which sex chromosomes evolved," Heitman said. "While mechanisms of sex determination are extremely diverse, our study highlights remarkable similarities among them in widely divergent groups."

The findings might also provide new insight into the process whereby the infectious fungus spurs disease, because evidence suggests a close tie between the genes involved in sexual identity and virulence, Heitman added. The work was supported by the National Institute of Allergy and Infectious Diseases.

Sexual identity is governed by sex chromosomes in plants and animals. In humans and other mammals, males have one X and one Y chromosome, while females have a pair of X's.

In fungi, sexual identity is determined by so-called "mating type loci," genes located in a contiguous region of the genome, but which typically do not span an entire chromosome. C. neoformans exists in two mating types determined by a single genetic locus. Earlier work found that this sex-determining region is unusually large in C. neoformans compared to other fungi, containing a series of more than 20 genes.

The researchers reconstructed the sequential evolutionary events that fashioned the sex-determining region of the C. neoformans genome by comparing it to that region in the related pathogenic fungal species, Cryptococcus grubii and Cryptococcus gattii.

The sex-determining genome region appears to have acquired genes in four main steps -- beginning with the acquisition of genes into two separate sex-determining regions that later fused, the team reported. Furthermore, they found that the fungal sex-determining genes exist in clusters of functionally related genes. For example, genes involved in mate recognition occur in tandem, as do those that govern spore production.

Other researchers have found that the human Y chromosome -- and the functionally-related gene clusters it contains -- has a similar history, characterized by the "sequential capture of genes" on four separate occasions, Heitman said.

The fungal mating type locus later underwent processes that suppress recombination, they found. Recombination is the process whereby each member of a pair of chromosomes exchange segments of DNA. The procedure allows for new gene combinations to form and for the repair of damaged DNA.

The human Y chromosome is also barred from recombination along most of its length, a necessary requirement to prevent genes that encode male traits from infiltrating the female X chromosome, Heitman noted.

The researchers suggest that, despite the lack of recombination, some fungal mating type gene repair might occur through the exchange of gene segments within chromosomes. Certain sex-determination genes occur in palindromic orientations –- head-to-head or tail-to-tail repeats of particular sequences –- which would make such intra-chromosomal repair possible, a pattern also found on the human Y chromosome, according to Heitman.

"These similarities suggest that further study of C. neoformans might help elucidate the genetic changes that can lead to infertility in fungi and humans, as well as the repair mechanisms that prevent its more common occurrence," Heitman said.

Their findings might also yield insight into the mechanism whereby C. neoformans invades the central nervous system to cause disease, most commonly in patients who lack a functioning immune system, such as organ transplant recipients and those with HIV/AIDS, Heitman added. A single fungal mating type spurs the vast majority of all C. neoformans infections, he explained, suggesting that sex determination and virulence are closely linked.

Collaborators on the study include James Fraser, Stephanie Diezmann, Ryan Subaran, Andria Allen, Klaus Lengeler and Fred Dietrich, Ph.D., all of Duke.