Searching for Disease Clues in Genetic Diversity

Over the last few years, scientists have discovered hundreds of genetic variants linked to disease. But the vast majority of that research has focused on people of European, Asian, and African descent. A new effort to catalog genetic diversity among people in Mexico–who along with other Latin Americans have a unique ancestry–could shed light on diseases that affect these groups disproportionately, and on why some drugs may work more or less effectively in these populations. The research might also help uncover rare genetic variants responsible for a significant portion of the genetic risk of disease.

“If personalized medicine is going to become a global phenomenon, then scientists need to understand the genomes of all the world’s populations,” says Gerardo Jimenez-Sanchez, former director of the National Institute of Genomic Medicine, in Mexico. (The institute, created in 2004, and known by the acronym INMEGEN, is analogous to the U.S. National Human Genome Research Institute.)

Hispanics are a relatively young–about 500-year-old–amalgam of three major continental groups–European, Native American, and African–and make up about 15 percent of the world’s population. “Within that area is so much environmental and genetic variability that you can really leverage the intrinsic diversity to your scientific advantage,” says Esteban Burchard, a physician and scientist at the University of California, San Francisco. For example, if a certain disease is much more common in one ancestral group, scientists need only screen the DNA inherited from that group in a person of mixed ancestry. That significantly cuts the amount of DNA that must be examined in order to find genes linked to the disease.

Researchers hope to capture some of that diversity with the recently announced Slim Initiative for Genomic Health, a $65 million partnership between the Broad Institute, a genomics research institute in Cambridge, MA, and the Carlos Slim Health Institute, a nonprofit based in Mexico City. The research will focus on the genetic basis of type 2 diabetes in Mexican and Latin American populations, as well as on the genomics of cancer worldwide.

“Most work on diabetes was done in European populations, and much will be learned from looking at other populations,” says Eric Lander, director of the Broad. “Even if the fundamental mechanisms are the same in all populations, particular genetic variants will be different, so it will be easier to find some genes in some populations.” Type 2 diabetes occurs at a particularly high frequency in Latin American populations, and “there’s reason to think that the Native American contribution to the gene pool has some effect,” he adds. While the specific details of the initiative are still being planned, it will encompass both gene sequencing and microarray-based studies. Much of the initial work will be done at the Broad.

However, the original HapMap almost entirely excluded Native Americans, largely due to political opposition from indigenous groups. And most Hispanics are part Native American–a recent study in Mexico City found that 70 percent of participants’ ancestry was Native American, says Burchard. “That means the HapMap doesn’t apply to contemporary Latino populations,” he says.

The first draft of the Mexican HapMap has already revealed a unique distribution of genetic variations, called SNPs (single nucleotide polymorphisms). “We can clearly see different components in the admixture pattern in the Mexican population,” says Jimenez. “We can also observe that the Mexican population is a range of admixture from those individuals who are very European to those who are very indigenous.” Scientists will use this information to design future studies that can more effectively identify disease-linked genes.

Researchers are now using the map to analyze Mexican ancestry–the country is home to 65 indigenous groups–and to run genome-wide association studies of cardiovascular disease, obesity, type 2 diabetes, and age-related macular degeneration. Preliminary research revealed a genetic variation linked to high levels of cholesterol and triglycerides that appears to be common only in Latin American people.

Jimenez, who chairs the Biotechnology Commission of the Organization for Economic Cooperation and Development, says the findings will prove important for the burgeoning field of personalized medicine, and for pharmaceutical companies developing genetically targeted drugs. “You can’t extrapolate the risk of disease from Europeans,” he says. “You need to make sure you develop products and services based on the genetic makeup of Mexican populations. Genomic medicine is not something we can develop in the U.S. and export to the world.”