Our work demonstrates that genetic admixture has substantial geographic heterogeneity even within a small geographic region like Puerto Rico. We found that the geographic patterns of African, European, and Native American ancestry throughout Puerto Rico can be explained by historic and social factors that have taken place during and since the recent colonial period. We similarly found geographic patterning of SES across the island that did not mimic the ancestry distributions. This complexity has important implications for understanding the genetic history, social dynamics and distribution of health and disease in this population.
With the exception of a gold rush in the first decades of colonization, the economy of Puerto Rico primarily consisted of large-scale sugar production in a process similar to most of the Caribbean islands at that time 
. This triggered the importation of African slaves and their descendents continued in the industry after the abolition of slavery in 1873. Thus, the location of sugar mills and sugar production variables explain a substantial proportion of the differences in African ancestry observed in present day Puerto Rico. These factors also result in an East to West gradient in the proportion of African ancestry that has been previously described for mtDNA information 
. Sugarcane plantations were mostly located in coastal lowlands, which may explain why African ancestry decreases with distance from the coast.
The Spanish colony that imported Africans as forced labor also established a social structure to preserve the status quo of a European-descent ruling class. The African and African-admixed classes were kept in a subservient position, whether slave or free, and social class endogamy was enforced by formal laws that prevented “unequal” marriages 
. Effects of this social stratification have led to a genetic and social structure, which continues to exist in current generations of Puerto Ricans. Recently, we detected assortative mating based on African/European ancestry among Puerto Ricans living in the island and in the mainland U.S. 
. Here, we demonstrated that African ancestry is associated with lower SES, reinforcing the evidence that social perception influences not only social interactions and mating choice but also social position and class within society 
. In addition, socioeconomic status is independently influenced by geography, with differences between and within regions in a pattern that is actually similar to the African ancestry cline.
More than 130 years after the abolition of slavery and the legal guarantee of freedom of movements in 1873, elements associated with the use of an enslaved work force in a colonial economy can still explain the distribution of African ancestry in Puerto Rico. Census reports from 1899 and 1950 demonstrate patterns of African ancestry almost identical to those shown in 
. Some spatial continuity from the slave period could be expected in the first years after the abolition as most slaves were hired by their previous owners 
. However, our results demonstrate that the descendents of slaves remained in the same areas where their ancestors resided 5-6 generations ago or moved to nearby locations. This clustered distribution of ancestry is remarkable given the relatively small size of the island, a maximum of 180 km by 64 km, and the regular migration flows between Puerto Rico and the mainland U.S. In the East region, the remnants of the original slave economy can still be seen and explain a substantial proportion of the geographical variation in African ancestry. However, it is also clear that admixed individuals with African ancestry also now occupy all regions of the island, reflecting migrations and intermarriages that have occurred over the same time period, with a residual cline of decreasing African ancestry from east to west.
Conversely, the contribution of the original Native American inhabitants of Puerto Rico, the Taínos, is not explained by geographical factors. Some authors have postulated that, after their emancipation as slaves in 1542, Taínos sought shelter in the mountainous parts in the center of the island and were slowly assimilated through the following centuries 
. However, variation in Taíno contribution is neither higher in the Central region nor explained by distance to the coast or elevation as would be expected by the “mountain shelter” hypothesis.
Moreover, it is notable that Native American genetic ancestry does not correlate with social indices (e.g. SES). Socioeconomic differences between individuals are correlated with African and European ancestral contributions, but not with Native American. This ancestral component shows the smallest degree of variation between individuals (SD
7.2%, ). This can be explained by the fact that Taínos were the oldest ancestral population on the island and little to no Native American immigrants have arrived since active colonization began in 1508, in contrast to European and African ancestries. The lack of social importance of Native American ancestry among Puerto Ricans has also contributed to its small variation across the island and across individuals because mate choice was not related to degree of Taíno ancestry. Although the real level of variation could have been underestimated due to the markers used, our set of AIMs was informative to differentiate Native American ancestry from the other ancestral components (see Text S1
). Moreover, other studies have published similar levels of variation in Native American ancestry among Puerto Ricans using genomewide information 
. Previous investigations among Puerto Ricans have underscored the lack of social importance of Native American ancestry in processes such as assortative mating and the relationships between ancestry and social stress are based on perceived levels of European and African ancestry only 
. The fact that average Native American ancestry among Puerto Ricans is not much less than average African ancestry yet shows a much smaller variance among individuals reinforces the far more significant social role of African ancestry compared to Native American ancestry in this population. In contrast, in other Latin American countries Native American ancestry plays a key role in all these social processes 
Another important observation is the sex-biased admixture in Puerto Rico. In a previous article using this same census-based sample, we reported that mtDNA lineages were 61.3% Native American, 27.2% African, and 11.5% European 
. This distribution demonstrates an excess of ancestry contribution from European males and Native American females. This is a common feature in the ancestral gene pool of Latin American populations 
. Interestingly we did not observe a substantial bias for the African ancestry.
The geographic heterogeneity in genetic variation identified in this study has important implications for the identification of variants associated with disease or other clinically relevant outcomes. We have shown that variation in ancestry proportions can lead to bias in association studies 
. It has been postulated that carefully matching cases and controls by geographical origin could minimize the problem of population stratification in human populations, but even modest levels of genetic structure within a population can lead to false positive and false negative results 
. Moreover, variation in SES can also confound genetic association results 
. In Puerto Rico, SES and African ancestry increase from west to east, but they are inversely correlated irrespective of location. This is evidence that the relationship between ancestry and SES is a local phenomenon within a region and not across regions since the trends are in opposite directions. If these geographic patterns of SES and African ancestry are not considered when selecting samples, they could confound association results.
As we have shown, ancestry differences are associated with social differences and, in turn, social processes such as assortative mating discourage individuals from choosing potential mates of different ancestry. This process helps to maintain genetic stratification within Puerto Rico. The large variation in individual admixture estimates that we observe here has been previously reported for different populations across Latin America 
. In addition, the observed correlations between genetic ancestry and social indices have been consistently described for populations across the American continent 
. Thus, it is important to be mindful of genetic and social structures when carrying out biomedical research in Hispanic/Latino populations.
The microgeographic approach integrating different sources of information (e.g. genetic, geographic, historic, and social) could be relevant to detect founder effects that may influence disease prevalence. Among Hispanic/Latinos, some founder effects have already been identified with rare diseases such as Bloom Syndrome and Hermansky Pudlak Syndrome 
, and other founder effects have been associated with an elevated incidence of highly penetrant mutations for diseases such as breast cancer 
. Furthermore, in the near future we will be able to use genomewide information to reconstruct demographic events at an unprecedented fine scale. This will enable us to identify events such as migrations, kinship relations or time of arrival of ancestors to a certain population, which could be complemented by the addition of census and historical registry data. Most studies in human genetics have focused on comparisons between groups, but a complete understanding of the historical, social interactions and disease processes will require the analysis of spatial and temporal interactions between individuals and their environment.