 Could genetic differences explain why some people and not others have died of H1N1 Influenza A? That is among the questions raised by a landmark Mexican study showing significant genetic variation between Mestizos (Latin Americans of mixed European and Amerindian ancestry) and the world's other known genetic subgroups.
The study, by Mexico's National Institute of Genomic Medicine (INMEGEN), is published in the Proceedings of the National Academy of Sciences (PNAS).
Led by Dr. Gerardo Jimenez-Sanchez of INMEGEN, a team of 16 Mexican researchers, analyzed the genetic composition of 300 Mestizos from six geographically distant states in Mexico and one Amerindian population (30 members of the indigenous Zapotecas group in the state of Oaxaca).
They discovered that genetically the Mexican Mestizo and Indigenous populations are substantially different from the three other known human genetic subgroups (Yoruba from Africa, Caucasians of European descent, and the Chinese and Japanese of Asia), whose DNA make-ups were documented through the historic International HapMap Project, 2002 to 2006.
The Mexican research was undertaken to establish the comparability of Latino genomes to others in the global search for health-related genes throughout humanity.
A recent study in Asia identified a genetic characteristic in Asians that indicates a susceptibility to Hepatitis B; other studies have identified people with genetic predispositions to HIV1 or Kawasaki Disease.
While the latest work is at far too early a stage to enlighten authorities on the current outbreak of H1N1 Influenza A, it may one day help explain why, for example, with cases of that virus appearing worldwide, fatalities to date have occurred almost exclusively in Mexico.
Says Dr. Jimenez-Sanchez: "It is not possible today to say genetic variation is responsible for the unique H1N1 Influenza A mortality rate in Mexico. However, knowledge of genomic variability in the Mexican population can allow the identification of genetic variations that confer susceptibility to common diseases, including infections such as the flu."
"It will also help develop pharmacogenomics to help produce medicines tailored to people of a specific genetic group, to the creation of drugs that are both safer and more effective."
President of Mexico, Felipe Calderon Hinojosa commended the achievement. "The genomic map of the Mexican population is an essential contribution of Mexico to science and public health. This study represents an important landmark to develop genomic medicine in Mexico to improve healthcare of its population. I commend our National Institute of Genomic Medicine, INMEGEN, for such a significant milestone."
The young National Institute of Genomic Medicine in Mexico City was established in 2004 under then-Health Minister Julio Frenk, now Dean of the School of Public Health, Harvard University.
"This study makes clear that Latin Americans with mixed ancestry are different enough from other people worldwide that a full-scale genomic mapping project would be wise both scientifically and economically. It would allow doctors to analyze fewer genetic markers when diagnosing the risk that a patient will develop a disease that depends on complex factors," says Dr. Frenk.
"Mexico has created a state-of-the-art genomic medicine institution, unique in Latin America, where world-class scientific research can be developed to understand the molecular relationships between humans and germs. This valuable facility will enable Mexico to prepare for the health challenges that await us all in the future."
Dr. Edison T. Liu, President of the Human Genome Organization (HUGO) said: "This work by the INMEGEN group is important both for the scientific content which can be used to direct personalized medicine in Mexico, but also for its sociologic impact in defining the uniqueness of Mexico's genetic heritage."
"Studies such as this are helping us define the future of the genome era," says Dr. Jeffrey Trent, President of the Translational Genomics Research Institute, Phoenix, Arizona. "Gaining a clearer understanding of how genetic variation plays a role in disease, including the risk to some infections, will help tip the scales in our favour in terms of understanding and treating disease at the individual level."
"We have studied a number of genomics initiatives in the developing world and emerging economies, recently published in Nature Reviews Genetics. There is no doubt that INMEGEN is a unique institution and one of the most advanced in the world in terms of its infrastructure but, more importantly, in its linkage to the national health system. It is a model for the rest of the world," said Prof. Abdallah Daar of the McLaughlin-Rotman Centre for Global Health at the University Health Network and University of Toronto.
The INMEGEN study was financially supported by the Federal Government of Mexico, with in-kind support of the Mexican Health Foundation (FUNSALUD) and the Gonzalo Río Arronte Foundation.
Background:
The human genome project (1990-2004) identified common genetic variation, mostly Single Nucleotide Polymorphisms (SNPs), which provide the basis for genetic individuality. Genetic variants associated to susceptibility to common disease and the ability to predict disease-associated risks and response to treatments are the basis of genomic medicine.
The International HapMap Project (2002-2006) systematically analyzed genetic variation in three ancestral populations: Yoruba from Africa, Caucasian of European descent, Han Chinese and Japanese from Asia. This project created a haplotype map of these populations as a tool to identify disease-related genes in a more efficient way. This project did not include the Latin American populations, which are of recent admixture from ancestral populations that include native Indians of the region. This represented a potential risk of segregating Mexican population from genomic medicine in the future.
Mexico is developing a national platform in genomic medicine. In 2004, the Mexican government founded the National Institute of Genomic Medicine (INMEGEN) to conduct world-class scientific research, implement technological platforms and develop educational programs in genomic medicine (http://www.inmegen.gob.mx).
In addition to generating important scientific information, INMEGEN's Mexican Genome Diversity Project has produced unprecedented human and technological infrastructure in Mexico in less than 5 years. INMEGEN is the most advanced institution in Latin America with the ability to study interactions between humans and the environment, including microorganisms, enabling Mexico to prepare for future challenges. It's research aims to identify genetic variation that predisposes to common diseases in Mexicans.
A haplotype map provides a resource of significant impact to enable faster identification of disease-related genes. However, the question was whether the HapMap from ancestral populations would fit the Mexican population. This study indicates that the genetic structure in the Mexican population would identify tagSNPs that better fit this population and speed genome-wide association studies and admixture mapping at a much lower cost. This would be a corner stone to develop genomic medicine in Mexico.
Goal of the Mexican Genome Diversity Project: To determine common genomic variation in the Mexican Mestizo population and compare different regions in Mexico, as well as to compare such variability with results from the HapMap. In addition, the project produced a simple visual map of the genetics of different population groups throughout the country (http://diversity.inmegen.gob.mx).
In general, the Mestizo genomes occupy points on a linear spectrum that ranges from Amerindian to European. There are major differences between Mexican Mestizos and subgroups of the HapMap such as Africans or Chinese, although Mexican Mestizos share 96 percent of their haplotypes with the complete HapMap population.
Haplotype sharing analysis showed that all Mexican subpopulations share, on average, 86% (84-87%) of the common haplotypes when one subpopulation is used as a reference and that the proportion of shared haplotypes increases to an average of 96% (95-97%) when each subpopulation is compared to any pair of the studied subpopulations. These results support the idea that a haplotype map of the Mexican Mestizo population may help reduce the number of tagSNPs required to characterize common genetic variation in this population.
Journal references:
Irma Silva-Zolezzi, Alfredo Hidalgo-Miranda, Jesus Estrada-Gil, Juan Carlos Fernandez-Lopez, Laura Uribe-Figueroa, Alejandra Contreras, Eros Balam-Ortiz, Laura del Bosque-Plata, David Velazquez-Fernandez, Cesar Lara, Rodrigo Goya, Enrique Hernandez-Lemus, Carlos Davila, Eduardo Barrientos, Santiago March, and Gerardo Jimenez-Sanchez. Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico. Proceedings of the National Academy of Sciences, 2009; DOI: 10.1073/pnas.0903045106 Jimenez-Sanchez, G. Developing a Platform for Genomic Medicine in Mexico. Science, 2003; 300 (5617): 295 DOI: 10.1126/science.1084059 Seguin B, Hardy BJ, Singer PA, Daar AS. Genomics, public health and developing countries: the case of the Mexican National Institute of Genomic Medicine (INMEGEN). Nature Reviews Genetics, 2008; 9S5 DOI: 10.1038/nrg2442 Jimenez-Sanchez G, Silva-Zolezzi I, Hidalgo A, March S. Genomic medicine in Mexico: Initial steps and the road ahead. Genome Research, 2008; 18 (8): 1191 DOI: 10.1101/gr.065359.107
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DNA molecule, which stores genetic information in chromosomes, which in turn make up an organism's genome. This image presents only 12 base pairs, while the human genome consists of over 3 billion base pairs.
National Institute of Genomic Medicine of Mexico (Inmegen) Director Gerardo Jiménez Sánchez presented in Los Pinos the genome map of Mexicans, a stepping-stone for Latin American genomic medicine.

Previous endeavours of this kind had so far only covered some of the most ancient races on the planet, native from Africa, Europe and Asia, leaving out the recently admixed races of Latin America.

During the ceremony Jiménez, who led the project, symbolically presented President Felipe Calderón with a hard copy of the results. Calderón then uploaded the map to the Internet making it publicly available for researchers around the world. The President commented on the research being a step towards population-specific predictive medicine and medications, and particularly useful for Latin America for being genetically closer to the Mestizo peoples of those countries than genome maps published so far.

Among other results, the five year-long work found that, while sharing the 99.9% of the genome common to all humans, in the remaining portion the Mexican population has significant genetic variation from the world's other known genetic subgroups. This makes importing genome maps from other groups unfeasible, and hence justifies the study.

Also, by comparing with data sets from the HapMap Project (a map of the human genome's haplotypes, which are clusters of the possible genetic variations a human individual can present), it was found that Mexicans share 64% of their haplotypes with West Africans, 74% with East Asians and 81% with Northern Europeans.


Genetic analyses aimed at common disorders in Mexico like diabetes, obesity and breast cancer are yet to be performed. "With a drop of saliva we would be able to tell whether to prescribe a medication or not", forecast Jiménez about the applications of the genome map in the long run.

"Studies such as this are helping us define the future of the genome era", commented U.S. Translational Genomics Research Institute President Jeffrey Trent. "Gaining a clearer understanding of how genetic variation plays a role in disease, including the risk to some infections, will help tip the scales in our favour in terms of understanding and treating disease at the individual level", he added.

"It is not possible today to say genetic variation is responsible for the unique H1N1 Influenza A mortality rate in Mexico. However, knowledge of genomic variability in the Mexican population can allow the identification of genetic variations that confer susceptibility to common diseases, including infections such as the flu", said Jiménez when talking about the current swine flu outbreak.

Recently, however, Inmegen's Multifactorial Diseases Genomic Research Laboratory head Lorena Orozco revealed that one fifth of the Mexican population have genes in their immune system that can trigger an immune overreaction in presence of some diseases. According to Orozco one of these genes is responsible for symptoms similar to the ones A/H1N1 victims presented, which makes it a strong candidate for explaining these deaths.

Although blood samples were collected from 10 different states and 4 Amerindian populations, the published results are based on data from only 6 states and 1 Amerindian population. The presentation ceremony and the online publication of the research paper in the PNAS journal came just days after the Mexican Government came under criticism for its low investment in science and the resulting dependency on other countries in the beginning of the current sanitary crisis.