All content refers the original paper (Moreno Estrada et al. Science 2014)
Summary and personal comments
This paper is about genetic diversity among Native Mexico populations
Mexico is an interesting region/subject to study human genetic diversity since it has a complex history, with various civilizations contributing at various degree to the present-day population.
Identification of different Native Mexican populations and analysis of their genetic relationships.
The authors studies 1 million SNPs (single nucleotide polymorphisms) of 511 native Mexico individuals identified from 20 different populations covering most geographical regions of Mexico.
1) They performed a PCA (principal component analysis) and identified different clustering of indigenous populations; each cluster was geographically-well-defined across the country and followed a northwest-southeast axis.
Fig S1(A) shows the PCA based on native Mexican individuals, when analyzing ancestry from Native Mexicans, Europeans and Africans (left) or analyzing only native Mexicans after removal of Africans and Europeans (right). You can observe that PC1 differentiates Europeans and Africans ancestry from Native Mexicans (left) and that it separates different Native Mexicans subpopulations (right). (B) shows PCA based on admixed Mexican samples from cosmopolitan individuals from different Mexico states combined with ancestral reference samples (African, European and Native Mexican). You can notice that PC1 separates European from different Native Mexican clusters (left) while PC3 differentiates Native Mexican clusters in a north-to-south gradient, separating for example Yucatan and Campeche in the south from Sonora populations in the north.
2) The Wright’s fixation index FST, which analyses the diversity between individuals of a population compared to the diversity among populations, revealed a high degree of differentiation among native Mexican populations, suggesting high level of isolation of each population. For example, in Fig 1B you can observe that Seri (Ser) and Lacandon (Lac) populations have extremely high pairwise FST values (0.136), which is higher than the index of diversity between Europeans and Chinese people (FST =0.11). It is surprising to find such an important genetic diversity among populations from the same country.
3) In order to study the degree and patterns of genetic relationships among Native populations, the authors built a relatedness graph through the analysis of identical by descent (IBD) segments, which compares the number of segments (the authors chose a cut off of >13 cM segment length, according to the study of patterns of IBD haring shown in Gif S8) shared among individuals. As you can observe in Fig 1C, the great majority of connections are within a populations, with very little relationships between populations (an exception to this finding is the connection for example between Totonac (Tot) and Mayan (Mya-C) populations, who historically shared a common ancestor living in the city of Veracruz). This finding supports the hypothesis of a geographic isolation of each population, with little gene flow among populations. It is important to notice that each node represents a haploid genome, and that the more the nodes are close (=high density cluster) the more the individuals share IBD segments, as can be observed for example for Seri (Ser) and Lacandon (Lac) clusters. Of note, not all individuals from each population were used for this graphic; the number used is indicated in parenthesis beside the name of the cluster (Ser and Lac used samples from all individuals, respectively 42/42 and 44/44, while Nxp only 26/44).
4) The Treemix graph shown in Fig1D (which takes into account European, African and Asian samples in order to build a rooted tree) shows the pattern of split among the different native populations and quantify the drift of each population (longer branches mean higher drift, as it is the case for Seri (Seri) and Lacandon (Lac)), without taking into account migration. Other trees modeled after allowing for 1 to 3 events of migration are shown in Fig S9, where migration is represented by coloured arrows between populations, in a yellow-to-red intensity scale (in Fig S9C, middle, you can observe that the gene flow from NPX to NFM was more intense than the one from MYA.Y to NPX).
Analysis of the indigenous ancestry of admixed mestizo/cosmopolitan individuals from Mexico
The authors studied ancestry patterns in the admixed populations through an Ancestry Specific PCA (ASPCA). They constructed an admixture model by genotyping 20 Native Mexican populations, 16 Europeans groups, 50 African groups and 500 cosmopolitan individuals from 10 Mexican states, considered as admixed mestizos (with all 4 parents coming from the same state).
Fig 2A shows the proportion of admixture in the different samples. Dots correspond to Native Mexico populations enumerated in B, grey regions show from where cosmopolitan samples were taken. Pie charts show the proportion of each ancestry (red=European, green=African, grey=native) in cosmopolitan individuals, divided per state. Bars show the proportion of each Native Mexican ancestry. Fig 2B shows the proportion of each ancestry in each population (each bar corresponds to an individual).
For example, the states which show the highest proportion of Native ancestry in cosmopolitan individuals are Oaxaca and Campeche; when analyzing the specific native component, you can notice that in Oaxaca the most important component is Triqui and other central-southern ancestry while Campeche and Yucatan possess the highest Mayan component (in yellow/orange in bars and in Fig 2B). On the contrary, the state with the highest proportion of European ancestry in cosmopolitan individuals is Sonora. Interestingly, Seri native populations are from the same region of Mexico (Map in Fig 1A), but do not present any European ancestry (bars in Fig 2B), suggesting a high degree of separation between Seri Native Mexican population and cosmopolitan populations from the same state.
Biomedical application: study f the association between two indipendently phenotyped cohorts of native/indigenous Mexican and cosmopolitan Mexicans (Mexican Americans) to lung function.
Finally, the authors explored the possible biomedical application of their findings, in order to explore if the genetic background could have an influence for example on specific pulmonary function parameters. In particular, they focused on the values of forced expiratory pulmonary volumes (FEV1) and applied ASPCA approach to two studies including mestizo children from Mexico City (MCCAS= Mexico City Childhood Asthma Study) and from San Francisco Bay (GALA I =Genetics of Asthma in Latino Americans). They observed a significant association between FEV1, expressed as a percentile of predicted “normal” function value, and the east-west component (ASPC1), as shown in Fig 3C.
Furthermore, the authors used the results from the two studies to assess whether FEV1 values change among the different Mexican states along with changes in population ancestry. They observed that the measured FEV1 diverged from the predicted values, with a different being of nearly 5% in Sonora state and of more than 2% for the state of Yucatan. The authors consider this difference from the expected values as significant, to the point that they suggest that the genetic background, in terms of native ancestry, should be taken into account when considering a lung function measure. Nevertheless, we have no information regarding the mean difference between individuals of the same population and about the range of difference that was used to establish normality of FEV1 values in western populations. In addition to the fact that a difference of 5% of the predicted value might not be of clinical importance, the authors did not take into account other important variables that could affect FEV1 values, such as smoking habits, place of living including altitude, physcal activities. Indeed, such variables could importantly influence lung function, representing an environmental element which might act indipendently to genetic factors.
Moreno-Estrada, A., Gignoux, C., Fernandez-Lopez, J., Zakharia, F., Sikora, M., Contreras, A., Acuna-Alonzo, V., Sandoval, K., Eng, C., Romero-Hidalgo, S., Ortiz-Tello, P., Robles, V., Kenny, E., Nuno-Arana, I., Barquera-Lozano, R., Macin-Perez, G., Granados-Arriola, J., Huntsman, S., Galanter, J., Via, M., Ford, J., Chapela, R., Rodriguez-Cintron, W., Rodriguez-Santana, J., Romieu, I., Sienra-Monge, J., Navarro, B., London, S., Ruiz-Linares, A., Garcia-Herrera, R., Estrada, K., Hidalgo-Miranda, A., Jimenez-Sanchez, G., Carnevale, A., Soberon, X., Canizales-Quinteros, S., Rangel-Villalobos, H., Silva-Zolezzi, I., Burchard, E., & Bustamante, C. (2014). The genetics of Mexico recapitulates Native American substructure and affects biomedical traits Science, 344 (6189), 1280-1285 DOI: 10.1126/science.1251688