This research program will study the genetic basis of a wide array of traits in the Mexican population: 

Cardiovascular 

• Stroke, blood pressure 

Respiratory 

• Lung cancer, tuberculosis, smoking 

Metabolic 

• Diabetes, body-mass index, dyslipidemias, fasting glucose level 

Immunological Response  

• Influenza, HIV, hepatitis, dengue and others 

In the language of human geneticists, the Mexican population is highly admixed and structured. This refers to the history of Mexico which includes European, African and Native American ancestry, yielding individuals whose genomes are mosaics of diverse ancestry. This leads to a number of fascinating questions in population genetics, and a unique opportunity in genome-wide association studies (GWAS). GWAS can be used to correlate regions of the genome with specific traits of interest in the population to understand the genetic basis of a trait. We will develop techniques to perform GWAS in admixed populations and to harness the uniquely admixed structure of the Mexican population to characterize these associations in fine detail. This is timely as recent studies have found the limitation of transferring GWAS findings between different populations [1] and the bulk of current GWAS have been carried out in individuals of only European ancestry. Having a repository of GWAS findings for a range of traits in the Mexican population will inform public health decisions and genomic medicine throughout the country. The GWAS results and techniques developed will be important for further study of admixed populations throughout Latin America.  

1. Martin AR, Gignoux CR, Walters RK, Wojcik GL, Neale BM, Gravel S, Daly MJ, Bustamante CD. Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations. Am J Hum Genet 2017;100:635–49. doi:10.1016/j.ajhg.2017.03.004. 

This research program is focused on two related avenues in evolutionary genetics: 

• Mexican population history and genomics 
• Dynamics and mechanisms of evolution 

This project provides the largest number of Mexican samples genotyped to-date. It also has the added benefit of widely-distributed sampling across the country, and sampling that includes individuals who identify as “indigenous” and those who do not. These features make the Mexican Biobank ideally suited for population genetics studies to understand the fine-scale demographic history and population structure of the present-day Mexican population, as well as the evolutionary forces that prevail in admixed structured populations like those found in present-day Mexico. 

We will study the range of ancestries that contribute to the present genetic make-up of the Mexican population. While European, Native American and African ancestries have already been documented in the Mexican population [1], this scale and breadth of the project will allow us to study these at finer resolution as well as document any further sources of ancestry. We will make a nationwide map of the ancestry composition segmented by geographic location and by whether individuals speak an indigenous language or not.  We will further reconstruct the size of the Mexican population over historic time and quantify the changes that occurred through colonization events and migrations. These analyses will complement and supplement knowledge from the disciplines of anthropology and history towards painting a more complete picture of the history and ethnic composition of the Mexican people.  

The Mexican Biobank will allow us to discover and document instances of natural selection in the Mexican population. This will inform how the population as a whole and sub-populations have adapted to varying environments and the introduction of new microbiota through colonization and migration events. We will also the study the fate of genetic variants already known to be under selection in the ancestral populations. Further, we will document the distribution of damaging genetic variants by ancestry and by geography and identify damaging variants that are private to specific sub-populations. We will also study complex traits from a population genetics perspective, determining how the heritability of different diseases varies by ancestry, and how the genetic underpinning of a trait varies over geographic space. These analyses will highlight the genetic underpinning of the immense diversity in the Mexican population and the role evolutionary forces have played in shaping this diversity.  

Beyond learning about the population history of and natural selection in the Mexican population, we will also use the unique features of the population to learn about the mechanisms of evolution. The genome-wide geographically diverse data on an admixed population will allow us to study the interplay between recombination and natural selection against damaging genetic variants or natural selection for beneficial genetic variants. We can further decipher the role of interactions between genetic variants at points of transition between different ancestries on the genome. Combining the genetic data with other available information, we can also empirically study the relationship of the distribution of damaging genetic variants with inbreeding, fertility and founder effects.  

1. Moreno-Estrada, A., et al., The genetics of Mexico recapitulates Native American substructure and affects biomedical traits. Science, 2014. 344(6189): p. 1280-5. 

This research program will measure antibody responses to a range of pathogens which are naturally circulating in the Mexican population including:

• Influenza A and B viruses
• Dengue virus
• Chikungunya virus
• Trypanosome cruzii
• Herpes simplex viruses 1 and 2
• Varicella zoster virus
• Epstein-Barr virus
• Cytomegalovirus
• Hepatitis B and C viruses
• HIV
• Human papillomaviruses
• Polyomaviruses
• Chlamydia trachomatis
• Helicobacter pylori
• Toxoplasma gondii

Serum samples from all individuals (for whom we also have genetic data) will be used to do serological testing against the above infectious agents. These pathogens are expected to have variable antibody response (sero-prevalence) in different sections of the Mexican population. Through these analyses, we will make a nationwide map of sero-prevalence for a number of infectious diseases relevant to public health and disease burden.

We will also focus on how population genetics impacts individuals’ responses to infectious pathogens. We will do this by undertaking large-scale analyses of the associations between genetic variants and human antibody responses to infectious agents. A growing number of reports have already described associations between the human leukocyte antigen (HLA) locus and variability in antibody level responses to multiple infectious pathogens [1]. Through the Mexican Biobank, we can now harness the power of admixed populations to help overcome historical challenges and fine-map the causative genetic variants in the HLA region of the genome that will undoubtedly have clinical relevance [2].

Our findings have the potential to be of immense clinical importance since we suspect that the observed associations may explain the selective failure of vaccines against pathogens such as influenza and EBV [3, 4]. In addition to facilitating our genetic inferences, these antibody measurements will supplement public health surveillance data, complementing any existing sero-prevalence data acquired through previous rounds of ENSA, and contribute to our understanding of whether infections increase the risk of developing chronic disease using the wealth of other chronic disease data that is available through ENSA.

1. Hammer, C., et al., Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses. Am J Hum Genet, 2015. 97(5): p.738-43.
2. de Martel, C., et al., Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol, 2012. 13(6): p. 607-15.
3. Lambkin, R., et al., Human genetics and responses to influenza vaccination: clinical implications. Am J Pharmacogenomics, 2004. 4(5): p. 293-8.
4. Balfour, H.H., Jr., Progress, prospects, and problems in Epstein-Barr virus vaccine development. Curr Opin Virol, 2014. 6: p. 1-5.