The genomic study of threatened wild free-ranging mouse lemurs, is beneficial for research, conservation, and society

Is it possible to improve genetic science, grow opportunity in an impoverished nation, while improving the conservation of a threatened species?

Auburn professor Sarah Zohdy, as part of a multi-institution research team, says that the Madagascar mouse lemur, a primate half the genetic distance between mice and humans, is the ideal candidate to transform the future of biomedical research, all while conserving the species and creating opportunity for the Malagasy people, according to a study published in the scientific journal, Genetics.

Zohdy, an assistant professor of disease ecology in Auburn’s School of Forestry and Wildlife Sciences and College of Veterinary Medicine, collaborated on the study “The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health,” along with several other scientists from the Department of Biochemistry and Department of Comparative Medicine at Stanford University, Howard Hughes Medical Institute, and the Department of Animal Biology at the University of Antananarivo, Madagascar.

The researchers have developed a new genetic model organism and a framework for how health and biomedical research can be conducted in a way that can simultaneously improve conservation efforts, contribute to the development and education of a poverty-stricken nation, and transform the future of biomedical research in a way that considers the biology and ecology of the organism to be critical for the advancement of our understanding of human health and well-being.

Biomedical research traditionally focuses on understanding a model organism to improve our understanding of human health and disease and lead to advanced treatments and even cures. Fruit flies, zebrafish, and mice are well-studied laboratory model organisms, which in the last century, have dramatically improved our understanding of human development, genomics, and disease.

“We have a very thorough understanding of these organisms at the genomic and phenomic levels, possibly more than any other organisms on earth,” said Zohdy. “The animal model closest to humans physiologically is the mouse. However, it is now recognized that nearly 50 percent of the time the mouse model, or knockout, created to better understand human disease fails to present with the same symptoms as humans.”

A knockout mouse is a genetically modified mouse where an existing gene has been inactivated or replaced with an artificial piece of DNA. This allows researchers to better understand the role of the gene in relation to its normal behavior or physiology.

“For decades, scientists have relied on mice, fruit flies, and worms as genetic models, but despite all their success, these organisms routinely fail to mimic many aspects of primate biology, including many human diseases,” said Mark Krasnow, professor of biochemistry at Stanford University.

Frustrated by the lack of a good study model, Krasnow and his colleagues turned to the mouse lemur, the smallest primate in the world, found only on the island of Madagascar.

Though plentiful on the island, mouse lemurs, like all lemurs are threatened due to habitat loss, and many species are considered endangered or critically endangered. Also problematic, the mouse lemur only produces four to six babies per year, thus normal research methods of producing genetic knockouts using this species would require more time since they do not reproduce as frequently.

Realizing the limitations of studying the mouse lemur in a traditional lab environment, Krasnow turned to Zohdy, an ecologist who has studied the natural history of wild mouse lemurs in the eastern rainforests of Madagascar.

Zohdy’s long-term research in Madagascar has produced a well-established field protocol with more than 500 individually identifiable wild mouse lemurs, many of which have been captured and recaptured annually for nearly 10 years.

It was during their initial meeting in 2010 in Madagascar that Zohdy discussed with Krasnow the societal and ecological benefits of studying the wild free-ranging mouse lemur.

“Through noninvasive advanced imaging and phenotyping technologies, it is possible to phenotype and understand the physiology of the wild lemurs. We have an identified population which can be studied and then returned immediately back to the wild on the same branch they were captured,” stated Zohdy.

“Instead of introducing mutations in mice or fruit flies, we are doing something much more similar to what is done in humans,” he said. “We are looking at all the wonderful genetic variation already existing in nature, since there are so many millions of mouse lemurs out there. We calculate that most knockout mutations are already present in nature, and all we have to do is find them. And because the cost of sequencing a genome is rapidly dropping, it’s now possible to sequence the genomes of thousands of mouse lemurs to see what mutations they are carrying.”

In doing so, the researchers could accomplish in a few years for a tiny fraction of the cost what the International Knockout Mouse Consortium will accomplish in 10 years, at a cost of nearly $1 billion, he said.

Establishing a field study in Madagascar, the researchers are building capacity on the island by teaching local Malagasy guides and students about mouse lemurs and training them in the use of modern genomic techniques.

“Technology is so advanced today that the ideal way to build capacity and educational programs in Madagascar while simultaneously working with a new model organism was to bring the 21st-century world of genomics to Madagascar,” said Zohdy.

At Zohdy’s research center and field site in Ranomafana, Madagascar at Centre ValBio, the research team has created a sophisticated molecular biology and genetics lab where the scientists are able to conduct research in the field and use it as a training opportunity for Malagasy students. This is more efficient for researchers than collecting samples for analysis at high tech laboratories in the US or Europe, and it provides revenue and educational opportunity for the local population.

The scientists report that they already have identified more than 20 individual lemurs with unique genetic traits, including obesity, high cholesterol, high blood sugar, cardiac arrhythmias, progressive eye disease, and motor and personality disorders. The lemurs have also been found to develop a form of dementia and accumulate plaques in the brain that resemble those of Alzheimer’s patients.

“I hope that this research will build awareness and improve our understanding of the biology and ecology of mouse lemurs, and all lemurs, to become a model example of the intersection of field ecology and modern advanced genomics,” said Zohdy. “Ultimately I hope this framework can be used to advance modern genomics in a way that can also be used to help conserve the natural world.”

The full article is available at http://www.genetics.org/content/206/2/651.