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Researcher will examine puzzle of sex chromosome dosage with new NSF grant

University of Kansas

LAWRENCE -- It's a little-known fact, but roughly half the human population is walking around with a severe imbalance of chromosomes. We call them "males." It works like this: Normal chromosomes, dubbed "autosomes," are present in two copies, one from a mother and one from a father. Genes on these chromosomes have a gene dosage of two.

Usually, an imbalance of gene dosage is highly detrimental to cell function, especially when the gain or loss of a whole chromosome affects the balance of hundreds of genes. The exception is with special, gender-determining "sex chromosomes," where males somehow function quite normally with gene dosage that is substantially out of balance with the rest of the genome.

"In humans, females have two X chromosomes, but males have one X and one Y," said Jamie Walters, assistant professor of ecology and evolutionary biology at the University of Kansas. "The Y is actually a highly degraded version of the X chromosome that has lost nearly all of the genes that were originally present on the X. This means that in males the gene dose of the X is one. But autosomes still have a gene dose of two, and there's an imbalance between the X and autosomes."

Walters has just earned a three-year grant from the National Science Foundation to study gene dosage using butterflies and moths as model species. He said if this disparity in gene dosage occurred in any "normal" chromosome (autosome), that individual would be very sick, if it could live at all.

"But for the sex chromosomes, about half the population has a major gene dosage imbalance and doing just fine," he said, referring to males. "This situation occurs in pretty much all animals that have sex chromosomes, which is the vast majority of animals."

Walters wants to know why sex chromosomes allow a seemingly disastrous gene dosage imbalance to occur without negative effects.

"In most species, there's a special mechanism specific to the sex chromosomes that compensates for this difference in gene dosage," he said. "This mechanism is called 'sex chromosome dosage compensation' (SCDC). What's even more interesting is that the details of how SCDC works is quite different between species. Some of the molecular mechanisms are relatively well-described in classic model research species like fruit flies, nematode worms and mammals -- in all three cases the mechanisms are distinctly different."

The KU researcher said the importance of SCDC is revealed by these three different lineages of animals that independently have evolved different cellular mechanisms to address the same biological puzzle posed by sex chromosomes and genetically determined sex.

"This convergence points to the great important of SCDC as a phenomenon in biology," Walters said. "Understanding the similarities and differences in these mechanisms from different species, and in their evolutionary histories, should tell us a great deal about fundamental principles about how genomes function and evolve."

He hopes to shed light on the mechanism by looking at species that are exceptions to the norm. According to Walters, many animals such as birds and snakes have "reversed" sex chromosomes, where the female has the genetic imbalance.

"Strikingly, for reasons that scientists don't yet understand, there is not SCDC in these species," he said. "These are relatively recent discoveries, from the last couple of years, and researchers are still struggling to understand why the uncompensated gene imbalance does not cause big problems for the XY females."

This is where Walters' long research interest in the genetics and evolution of butterflies and moths comes into play. These species have "reversed" genes, where the female has the genetic imbalance, he said.

"But unlike birds and snakes -- and like flies and mammals -- moths and butterflies do appear to have SCDC that mitigates gene dosage differences between the sexes. So, in essence, moths and butterflies appear to be 'an exception to the exception' when it comes to patterns of SCDC." Walters said the primary goal of his NSF grant is to expand the sampling of SCDC to many other species of moths and butterflies -- and to a related group of insects, the caddis flies, which share the same "reversed" sex chromosome.

"This provides and assessment of how widespread SCDC is for this group of insects," he said. "A second goal of the grant is to better characterize how sex chromosomes evolved in this group of insects. We don't know much about the origins of X and Y chromosomes in moths and butterflies, and understanding this is essential for understanding the patterns of SCDC we hope to uncover."

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