August 11, 2011

New genetic study suggests zebrafish sex is complicated affair

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Jeffrey Smith, M.D., Ph.D., and colleagues have identified two genes involved in sex determination in zebrafish. (photo by Susan Urmy)

New genetic study suggests zebrafish sex is complicated affair

Unlike humans, zebrafish don’t have the typical X and Y sex chromosomes. So what makes a boy zebrafish a boy, and a girl zebrafish a girl?

In the inaugural issue of the new journal G3: Genes, Genomes, Genetics, Vanderbilt University Medical Center investigators reported two genes that may determine sex in this important species.

Zebrafish are increasingly popular in the research world, especially in studies of embryonic development and as disease models.

But, as a newcomer to the research scene, much remains unknown about their genetics.

Zebrafish do not have the so-called “heteromorphic sex chromosomes” (the X and Y chromosomes) that determine sex in humans and several other species.

Researchers have known that environmental factors (for example, water temperature) can alter the proportion of males and females in a zebrafish population. But the genes involved in sex determination have remained unknown.

“We were surprised that nobody knew what determined sex in zebrafish, considering where it is in the world of science,” said Jeffrey Smith, M.D., Ph.D., associate professor of Medicine and Cancer Biology and senior author on the study.

The female zebrafish, left, is larger than the male zebrafish.

The female zebrafish, left, is larger than the male zebrafish.

The recent findings are the result of an ongoing project in Smith’s lab to develop genetic resources for investigators using zebrafish for research.

Using a 2,000-pound computer to mine genetic sequence, they identified more than 1 million genetic variants that could be used to locate genes associated with traits of interest to zebrafish researchers.

“But that only works if you know where those variants reside in the genome. Location, location, location,” Smith said. So his lab has been working to map these variants on the zebrafish genome.

To demonstrate the utility of the genetic resource they’ve built, Smith chose to search for locations within the fish genome associated with sex determination.

They identified two sites where the sequence significantly varied between males and females — on chromosome 5 and chromosome 16.

Within the two sites, they identified telltale changes in candidate genes dmrt1 (on chromosome 5) and cyp21a2 (on chromosome 16), both of which have been shown to play roles in sex determination in other species.

Specifically, DMRT1 has been linked to sex reversal in humans — loss of the DMRT1 gene causes a person who is genetically male (has an X and a Y chromosome) to be fully female. And mutation in the human version of CYP21A2 is one of the more common causes of pseudohermaphroditism (hybrid sex) in humans.

But both of these loci together only accounted for about 20 percent of the variance in the trait — meaning there are other factors, perhaps several other factors, that also govern sex in zebrafish.

“These are great candidates to go forward for study as sex-determining genes in zebrafish. But demonstrating causality will be difficult because of the lack of a one-to-one correlation between inheritance and sex in zebrafish," he noted. “Welcome to complex traits!”

The most important outcome, Smith said, is the development of the genetic resource, which can be used by zebrafish researchers studying development, disease or other traits.

“The resource is now in place. Our trait happened to be sex determination, but the same tools can be used to study any other trait of interest.”

Additional contributing authors were Kevin Bradley, Joan Breyer, David Melville, Ela Knapik, M.D., from Vanderbilt, and Karl Broman from the University of Wisconsin, Madison.

The research was supported by grants from the National Institute of General Medical Sciences and the National Institute of Diabetes and Digestive and Kidney Disorders.