While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN Brazil Initiative, the most comprehensive up-to-date genomic analysis of any Latin-American population. A population-based genomewide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6-8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within-Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/ South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes.Latin America | population genetics | Salvador SCAALA | Bambuí Cohort Study of Ageing | Pelotas Birth Cohort Study L atin Americans, who are classical models of the effects of admixture in human populations (1, 2), remain underrepresented in studies of human genomic diversity, notwithstanding recent studies (3, 4). Indeed, no large genome-wide study on admixed South Americans has been conducted so far. Brazil is the largest and most populous Latin-American country. Its over 200 million inhabitants are the product of post-Columbian admixture between Amerindians, Europeans colonizers or immigrants, and African slaves (1). Interestingly, Brazil was the destiny of nearly 40% of the African diaspora, receiving seven times more slaves than the United States (nearly 4 million vs. 600,000).Here, we present results of the EPIGEN Brazil Initiative (https:// epigen.grude.ufmg.br), the most comprehensive up-to-date genomic analysis of a Latin-American population. We genotyped nearly 2.2 million SNPs in 6,487 admixed individuals from three population-based cohorts from different regions with distinct demographic and socioeconomic backgrounds and sequenced the whole genome of 30 individuals from these populations at an To whom correspondence should be addressed. Email: edutars@ic...

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American, and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, whereas the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared with the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, with respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1750 and 1850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural, and political debate regarding ancestry, admixture, and the mestizaje process in the Americas.

Gastric cancer is one of the most lethal types of cancer and its incidence varies worldwide, with the Andean region of South America showing high incidence rates. We evaluated the genetic structure of the population from Lima (Peru) and performed a case-control genetic association study to test the contribution of African, European, or Native American ancestry to risk for gastric cancer, controlling for the effect of non-genetic factors. A wide set of socioeconomic, dietary, and clinic information was collected for each participant in the study and ancestry was estimated based on 103 ancestry informative markers. Although the urban population from Lima is usually considered as mestizo (i.e., admixed from Africans, Europeans, and Native Americans), we observed a high fraction of Native American ancestry (78.4% for the cases and 74.6% for the controls) and a very low African ancestry (<5%). We determined that higher Native American individual ancestry is associated with gastric cancer, but socioeconomic factors associated both with gastric cancer and Native American ethnicity account for this association. Therefore, the high incidence of gastric cancer in Peru does not seem to be related to susceptibility alleles common in this population. Instead, our result suggests a predominant role for ethnic-associated socioeconomic factors and disparities in access to health services. Since Native Americans are a neglected group in genomic studies, we suggest that the population from Lima and other large cities from Western South America with high Native American ancestry background may be convenient targets for epidemiological studies focused on this ethnic group.

BackgroundArchaeology reports millenary cultural contacts between Peruvian Coast-Andes and the Amazon Yunga, a rainforest transitional region between Andes and Lower Amazonia. To clarify the relationships between cultural and biological evolution of these populations, in particular between Amazon Yungas and Andeans, we used DNA-sequence data, a model-based Bayesian approach and several statistical validations to infer a set of demographic parameters.ResultsWe found that the genetic diversity of the Shimaa (an Amazon Yunga population) is a subset of that of Quechuas from Central-Andes. Using the Isolation-with-Migration population genetics model, we inferred that the Shimaa ancestors were a small subgroup that split less than 5300 years ago (after the development of complex societies) from an ancestral Andean population. After the split, the most plausible scenario compatible with our results is that the ancestors of Shimaas moved toward the Peruvian Amazon Yunga and incorporated the culture and language of some of their neighbors, but not a substantial amount of their genes. We validated our results using Approximate Bayesian Computations, posterior predictive tests and the analysis of pseudo-observed datasets.ConclusionsWe presented a case study in which model-based Bayesian approaches, combined with necessary statistical validations, shed light into the prehistoric demographic relationship between Andeans and a population from the Amazon Yunga. Our results offer a testable model for the peopling of this large transitional environmental region between the Andes and the Lower Amazonia. However, studies on larger samples and involving more populations of these regions are necessary to confirm if the predominant Andean biological origin of the Shimaas is the rule, and not the exception.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-014-0174-3) contains supplementary material, which is available to authorized users.

old extending this approach well into the next decade of life. The acute GVHD rate in this group was predictably higher (grade 2 and 3, 7 of 15 ϭ 47%) than their pediatric experience (20%) 2 ; however, the GVHD appeared easily treated by single agent prednisone. With the extensive transplant experience that this group and others have reported, [3][4][5][6][7] there is certainly a place for full ablative HSCT in pediatric patients with SCD, and this new experience now suggests that the same is true for young adults eligible for this approach. These accumulating reports continue to confirm a very favorable benefit to risk ratio making this a truly exciting time for patients and physicians contemplating HSCT for SCD.Myeloablative conditioning and the ensuing risk of GVHD, however, require robust organ function. We now have transplanted 23 patients with severe disease at our center with nonmyeloablative conditioning, their ages ranging from 17 to 65 years. All patients are alive, and engraftment was achieved in 20 (87%). Importantly, 5 of the first 10 patients reported 8 are now off immunosuppression with continued stable mixed chimerism. Equally important, none of the engrafted patients has experienced any GVHD. In addition, 3 patients have produced offspring naturally (1 male and 2 female). This larger experience suggests that with this nonmyeloablative approach, the risk of rejection is similar, the risk of GVHD is lower, long-term immunosuppression is not absolutely required, and stable mixed chimerism is achievable. It is important to note that nearly half (10 of 23) of our patients would be ineligible for myeloablative transplantation because of comorbidities including cirrhosis and poor lung function.Thus for patients in their second and third decade of life, options include both full and nonmyeloablative transplant conditioning, with the choice depending on organ involvement, potential transplant-related complications, and the desire for future fertility. It is our opinion that patients in this age group should be transplanted as a part of an ongoing clinical trial. HSCT for SCD remains under-utilized and the time to seriously consider this therapeutic option is now.

Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer inHAND2-AS1(heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 inDUOX2(dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral–host interaction.

53 4169-007, Portugal. 54 21 CIBIO/InBIO: Research Center in Biodiversity and Genetic Resources, Vairão, 4485-55 661, Portugal. 56 Abstract 76 The Transatlantic Slave Trade transported more than 9 million Africans to the Americas 77 between the early 16th and the mid-19th centuries. We performed genome-wide 78 analysis of 6,267 individuals from 22 populations and observed an enrichment in West-79 African ancestry in northern latitudes of the Americas, whereas South/East African 80 ancestry is more prevalent in southern South-America. This pattern results from distinct 81 geographic and geopolitical factors leading to population differentiation. However, we 82 observed a decrease of 68% in the African gene pool between-population diversity 83 within the Americas when compared to the regions of origin from Africa, underscoring 84 the importance of historical factors favoring admixture between individuals with 85 different African origins in the New World. This is consistent with the excess of West-86 Central Africa ancestry (the most prevalent in the Americas) in the US and Southeast-87 Brazil, respect to historical-demography expectations. Also, in most of the Americas, 88 admixture intensification occurred between 1,750 and 1,850, which correlates strongly 89 with the peak of arrivals from Africa. This study contributes with a population genetics 90 perspective to the ongoing social, cultural and political debate regarding ancestry, race, 91 and admixture in the Americas.92 93 Significance Statement 94 Differently from most genetic studies, that have estimated the overall African ancestry 95 in the Americas, we perform a finer geographic analysis and infer how different African 96 groups contributed to North-, South-American and Caribbean populations, in the 97 context of geographic and geopolitical factors. We also perform a formal comparison of 98 information from demographic history records of the Transatlantic Slave Trade with 99 inferences based on genomic diversity of current populations. Our approach reveals the 100 6 distinct regional African ancestry roots of different populations from North-, South-101 America and the Caribe and other important aspects of the historical process of 102 mestizaje and its dynamics in the American continent. 103 104 157(from Ghana, mean: 18%) ( Fig. 2A and B, SI Appendix, Table S3). 158The Western Africa-associated ancestry cluster has its highest proportions in Puerto 159 Ricans (38% of African ancestry), Colombians (27%) and US African-Americans (19-160 20%, purple in Fig. 1, SI Appendix, Table S1), while Brazilians have the lowest 161 proportion (<9%), limited to a Mandinka-like (Gambia) contribution and with no 162

ABSTRACT. Admixture occurs when individuals from parental populations that have been isolated for hundreds of generations form a new hybrid population. Currently, interest in measuring biogeographic ancestry has spread from anthropology to forensic sciences, direct-to-consumers personal genomics, and civil rights issues of minorities, and it is critical for genetic epidemiology studies of admixed populations. Markers with highly differentiated frequencies among human populations are informative of ancestry and are called ancestry informative markers (AIMs). For tri-hybrid Latin American populations, ancestry information is required for Africans, Europeans and Native Americans. We developed two multiplex panels of AIMs (for 14 SNPs) to be genotyped by two mini-sequencing reactions, suitable for investigators of medium-small laboratories to estimate admixture of Latin American populations. We tested the performance of these AIMs by comparing results obtained with our 14 AIMs with those obtained using 108 AIMs genotyped in the same individuals, for which DNA samples is available for other investigators. We emphasize that this type of comparison should be made when new admixture/population structure panels are developed. At the population level, our 14 AIMs were useful to estimate European admixture, though they overestimated African admixture and underestimated Native American admixture. Combined with more AIMs, our panel could be used to infer individual admixture. We used our panel to infer the pattern of admixture in two urban populations (Montes Claros and Manhuaçu) of the State of Minas Gerais (southeastern Brazil), obtaining a snapshot of their genetic structure in the context of their demographic history.