Macaques, Humans, and Genomes: mGAP - A New Genetic Webtool To Discover Natural Occurring Diseases in Macaques

Rhesus macaques at the Oregon National Primate Research Center (ONPRC). Photo courtesy of Betsy Ferguson, Ph.D., ONPRC.
Rhesus macaques at the Oregon National Primate Research Center (ONPRC). Photo courtesy of Betsy Ferguson, Ph.D., ONPRC.
March 23, 2020

At the Oregon National Primate Research Center (ONPRC), a group of monkeys climb and swing across their large outdoor enclosure. At first glance, the small, fur-covered primates appear to bear little resemblance to their human handlers. Their DNA, however, tells a different story. The rhesus macaque (Macaca mulatta) shares about 93 percent of its genome with humans.1 For this reason, researchers study the rhesus macaque to understand primate evolution, comparative physiology, and the genetic basis of human diseases as well as addressing numerous scientific questions.

The ONPRC is one of the seven National Primate Research Centers (NPRCs) that support biomedical research across the United States. To select a natural occurring genetic disease model, researchers must identify monkeys with specific genetic variants—subtle, but important alterations in their DNA sequences—that are likely to be associated with a disease or trait of interest. Between the thousands of research animals and the large, complex data sets made possible by modern sequencing techniques, identifying such disease models can be a daunting task.

Dr. Betsy Ferguson and her colleagues have pioneered efforts to compile genotype and phenotype data from macaques across the research community, making the information easily accessible to investigators. In 2016, she launched the Macaque Genotype And Phenotype Resource (mGAP). Supported by a R24 grant (R24OD021324) from the Office of Research Infrastructure Programs (ORIP), mGAP is “the first public website providing searchable, annotated macaque genetic variant data along with animal genotype data.”2

Dr. Ferguson, a professor in the Divisions of Genetics and Neuroscience at the ONPRC, and in the Department of Molecular and Medical Genetics at Oregon Health & Science University, said she is excited by mGAP’s swift and widespread impact across the biomedical research community. Since its launch, mGAP has enabled the identification of nine naturally occurring genetic disease models, including Batten disease and Bardet-Biedl syndrome.3,4 The six other NPRCs have now contributed rhesus macaque sequence files to be included in mGAP.

“I have shown mGAP to a number of people with different backgrounds, and everyone has a ‘wow’ moment,” Dr. Ferguson said. “It’s incredible—for all the amount of effort and time and people that have contributed to our understanding of the human sequence and variant effects—that (mGAP) is pushing us in a new direction to make variant data more accessible and interpretable.”

Dr. Ferguson explained that mGAP has developed alongside technological advancements in sequencing. Her colleague, Dr. Benjamin Bimber, developed an analysis pipeline (defined methodology for identifying variants) and a website to store the data that are collected. As of January 2020, mGAP’s website is accessed by 300 registered investigators from 125 institutions.

mGAP users are accessing the wealth of biological information on macaques housed at ONPRC. Each macaque possesses a unique genetic sequence made up of nearly 3 billion bases.1 The genome is life’s blueprint; each base helps dictate how an organism lives, grows, and develops. The genome influences every aspect of life, and a single mutation can impart considerable effects on phenotype. Stature, personality, and health, for instance, are all governed in part by the genome. By searching deep within the genome, researchers can begin to piece together the underlying structure that accounts for life’s biological variation.

Researchers compare genetic variants in macaques to those that have been established within the human genome. However, the massive size of this animal’s genome—and the thousands of rhesus macaques housed in NPRCs across the United States that could be included in the database—creates challenges for researchers. mGAP provides a centralized location to consolidate existing knowledge. Dr. Ferguson’s team overlaps the human and macaque genomes, highlighting variants predicted to contribute to a certain disease or trait in humans. mGAP also contains links to predicted phenotypic effects associated with the highly damaging variants. Taken together, mGAP enables research that crosses species and disciplines.

mGAP also contains numerous resources for investigators. For Dr. Ferguson, mGAP’s most promising application is in developing new animal models for diseases. These models mimic their human counterparts and offer insights into how certain diseases develop—and how they might be treated. The rhesus macaque may possess the key to understanding rare diseases that otherwise are difficult to study. Gene therapy, Dr. Ferguson explained, represents a new future for those with rare genetic conditions.

“Many genetic diseases were something that you could never adequately treat … the therapies that were envisioned are now possible,” Dr. Ferguson added. “I think that is one of the most exciting things coming from this; the monkeys are now being used (to advance) those lifesaving therapies.”

 

A rhesus macaque at the Oregon National Primate Research Center (ONPRC). Photo courtesy of Betsy Ferguson, Ph.D., ONPRC.
Figure 1. A rhesus macaque at the Oregon National Primate Research Center (ONPRC). Photo courtesy of Betsy Ferguson, Ph.D., ONPRC.

 

In the future, Dr. Ferguson envisions creating a translational avenue to enable transformational treatments for people—especially children—with rare genetic conditions. mGAP has exceeded her team’s initial expectations. In 2016, the team’s goal was to sequence 1,000 animals in total. Four years later, that goal has doubled.

Other NPRCs have expressed interest in establishing partnerships with mGAP to include data from their stocks. Dr. Ferguson is now partnering with two centers—the Tulane NPRC and the Yerkes NPRC—to sequence hundreds more high priority animals. As mGAP continues to grow, Dr. Ferguson has turned her attention to broadening the resource’s breadth and impact across the biomedical field.

“In the beginning, our goal was to make this resource something that would expand the utility of the primates beyond just these primate centers and tap into the needs of the human biomedical research community,” Dr. Ferguson emphasized. “This is getting out into the broader community, and people are recognizing how (mGAP) can enhance their own work.”

References
1Rhesus Macaque Genome Sequencing and Analysis Consortium, Gibbs RA, Rogers J, et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007;316(5822):222–234. doi: 10.1126/science.1139247.
2Bimber BN, Yan MY, Peterson SM, Ferguson B. mGAP: the macaque genotype and phenotype resource, a framework for accessing and interpreting macaque variant data, and identifying new models of human disease. BMC Genomics. 2019;20(1): 176. doi: 10.1186/s12864-019-5559-7. PMC6402181.
3McBride JL, Neuringer M, Ferguson B, et al. Discovery of a CLN7 model of Batten disease in non-human primates. Neurobiology of Disease. 2018;119:65–78. doi: 10.1016/j.nbd.2018.07.013. PMC6200145.
4Peterson SM, McGill TJ, Puthussery T, et al. Bardet-Biedl Syndrome in rhesus macaques: A nonhuman primate model of retinitis pigmentosa. Experimental Eye Research. 2019;189:107825. doi: 10.1016/j.exer.2019.107825.