Sexual reproduction ensures genetic diversity: A mother and father who aren’t related each contribute half of their DNA, which is scrambled together to provide the instructions for forming a new individual. This stirring of the genetic pot allows the offspring to be unique while preventing any harmful mutations in the parents’ genes from accumulating. But a new study finds that a deadly species of fungi has found a way to produce diverse offspring from identical parents, perhaps allowing this pathogen to become drug resistant.
“The finding turns our view of the function of sex by 180 degrees,” says microbial geneticist Joseph Heitman of Duke University in Durham, North Carolina. “These fungi use sexual reproduction not just to mix up already existing genetic diversity, but to actually produce it from scratch.”
The fungus in question, Cryptococcus neoformans, infects people with weakened immune systems and is notoriously difficult to treat, causing about 600,000 deaths worldwide every year, including about one-third of AIDS-related deaths. The fungus’s ability to become drug resistant has long been a puzzle due to a lack of variation among individual cells. C. neoformans exists in two distinct “mating types,” analogous to the sexes in animals. But the vast majority of the cells found in nature are of only one mating type. In previous research, Heitman and colleagues showed that “unisexual” mating within one type does occur and that the parents in this type of reproduction commonly have exactly the same genetic makeup. Because the fungus can also reproduce asexually, by producing an outgrowth that separates into a new individual, “the key question raised was, why have sex if there was no preexisting genetic diversity to mix up in the offspring?” Heitman says.
Research from other labs provided some clues. Sexual reproduction can result in a condition called aneuploidy, in which the offspring have extra copies of certain chromosomes. Aneuploidy has traditionally been considered harmful. In humans, disorders like Down syndrome and some cancers result from extra copies of chromosomes. But Judith Berman, a yeast geneticist at the University of Minnesota, Twin Cities, has shown that in another species, Candida albicans, some cells with extra chromosomes are more resistant to drugs.
Although aneuploidy does not bring in new genetic sequences, it does make possible another kind of genetic diversity—in which the extra genes produce extra proteins, resulting in an organism that differs from its parents. In the new study, published yesterday in PLOS Biology, Heitman and colleagues set out to explore whether genetically identical, unisexually reproducing C. neoformans cells were using aneuploidy to generate offspring that differed from themselves. The investigators started by allowing C. neoformans cells to reproduce asexually or unisexually. As expected, the offspring of the former method were identical to the parents.
But about 7% of the offspring produced by unisexual reproduction responded differently than their parents to temperature and drug treatment; they also had other quirks, such as increased production of the pigment melanin, a known virulence factor. Two-thirds of these unconventional cells contained an extra chromosome. Cells carrying an additional copy of either chromosome 9 or 10 became drug resistant, living longer than their parents when treated with the antifungal drug fluconazole. Offspring with extra copies of chromosome 9 or 13 proved as virulent as their parents when injected into mice.
Overall, duplications of chromosomes led to changes that were detrimental under some conditions (the presence of a drug) or neutral under others (higher or lower temperatures).
Although the study doesn’t point to immediate treatment possibilities, Heitman says that many researchers are studying the mechanisms that allow cells to tolerate the many extra proteins produced by the additional genes, which might reveal a weakness to target. The fact that genetic diversity produced from scratch through unusual types of sexual reproduction can lead to antifungal drug resistance suggests that this process may occur in other fungal infections, Heitman believes. The mechanism may also underlie infections caused by some parasites, including Giardia, which causes intestinal illness, and Leishmania, which causes skin sores, organ damage, and anemia, he says.
Berman agrees that the possibility that aneuploidy can confer benefits “isn’t what the textbooks say is supposed to happen. If it’s a mechanism of drug resistance we need to take that into account.” For example, Berman says, future treatments might combine antifungal drugs with compounds still to be developed that can hinder the formation of aneuploid cells.