Mexican Genetics Study Reveals Huge Variation in Ancestry

In the most comprehensive genetic study of the Mexican population to date, researchers from UC San Francisco and Stanford University, along with Mexico’s National Institute of Genomic Medicine (INMEGEN), have identified tremendous genetic diversity, reflecting thousands of years of separation among local populations and shedding light on a range of confounding aspects of Latino health.

The study, which documented nearly 1 million genetic variants among more than 1,000 individuals, unveiled genetic differences as extensive as the variations between some Europeans and Asians, indicating populations that have been isolated for hundreds to thousands of years.

These differences offer an explanation for the wide variety of health factors among Latinos of Mexican descent, including differing rates of breast cancer and asthma, as well as therapeutic response. Results of the study, on which UCSF and Stanford shared both first and senior authors, appear in the June 13, 2014 online edition of the journal Science.

“Over thousands of years, there’s been a tremendous language and cultural diversity across Mexico, with large empires like the Aztec and Maya, as well as small, isolated populations,” said Christopher Gignoux, PhD, who was first author on the study with Andres Moreno-Estrada, first as a graduate student at UCSF and now as a postdoctoral fellow at Stanford. “Not only were we able to measure this diversity across the country, but we identified tremendous genetic diversity, with real disease implications based on where, precisely, your ancestors are from in Mexico.”

For decades, physicians have based a range of diagnoses on patients’ stated or perceived ethnic heritage, including baseline measurements for lung capacity, which are used to assess whether a patients’ lungs are damaged by disease or environmental factors. In that context, categories such as Latino or African-American, both of which reflect people of diverse combinations of genetic ancestry, can be dangerously misleading and cause both misdiagnoses and incorrect treatment.

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“In lung disease such as asthma or emphysema, we know that it matters what ancestry you have at specific locations on your genes,” said Esteban González Burchard, M.D., M.P.H., professor of Bioengineering and Therapeutic Sciences, and of Medicine, in the UCSF schools of Pharmacy and Medicine. Burchard is co-senior author of the paper with Carlos Bustamante, PhD, a professor of genetics at Stanford. “In this study, we realized that for disease classification it also matters what type of Native American ancestry you have. In terms of genetics, it’s the difference between a neighborhood and a precise street address.”

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The study covered most geographic regions in Mexico and represented 511 people from 20 indigenous and 11 mestizo (ethnically mixed) populations. Their information was compared to genetic and lung-measurement data from two previous studies, including roughly 250 Mexican and Mexican-American children in the Genetics of Asthma in Latino Americans (GALA) study, the largest genetic study of Latino children in the United States, which Burchard leads.

Among the results was the discovery of three distinct genetic clusters in different areas of Mexico, as well as clear remnants of ancient empires that cross seemingly remote geographical zones. In particular, the Seri people along the northern mainland coast of the Gulf of California and a Mayan people known as the Lacandon, near the Guatemalan border, are as genetically different from one another as Europeans are from Chinese.

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The study also revealed a dramatic difference in lung capacity between mestizo individuals with western indigenous Mexican ancestry and those with eastern ancestry, to the degree that in a lung test of two equally healthy people of the same age, someone from the west could appear to be a decade younger than a Yucatan counterpart. Burchard said this was clinically significant and could have important implications in diagnosing lung disease.

Significantly, the study found that these genetic origins correlated directly to lung function in modern Mexican-Americans. As a result, the research lays the groundwork for both further research and for developing precise diagnostics and possibly even therapeutics, based on these genetic variations. {snip}

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Over the past few years, researchers have begun to understand that genetic variationhas a very peculiar structure, Bustamante said. Some common genetic variants reach appreciable frequencies (e.g., 30-50 percent) in many of the world’s populations. Most of these appear to have existed in the human gene pool at the time of the great human diasporas, including the migrations out of Africa. However, Bustamante said a “huge flurry” of other mutations have arisen since then, as human populations grew due to the advent and adoption of agriculture. These are much rarer, occurring in about 1- to 2 percent of the population, and are thought to be both more recent and relevant to health and disease. These rare variants make up the bulk of genetic alterations we see in human populations.

Many of these genetic differences already are known to have a direct impact on our risk for certain diseases, such as the BRCA gene in breast cancer, or our ability to metabolize medications. But before we can develop more precise therapies or prescribe them to the right patients, we need far more knowledge of what those variants are across diverse populations, and how they affect health.

“This is driving the ball down the field toward precision medicine,” Burchard said. “We can’t just clump everyone together and call them European Americans or Mexican Americans. There’s been a lot of resistance to studying racially mixed populations, because they’ve been considered too complex. We think that offers a real scientific advantage.”