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.

Letter to the editor Recurrent KRAS G12V pathogenic mutation in adenomatoid odontogenic tumours Dear Editor, The adenomatoid odontogenic tumour (AOT) is a non-aggressive encapsulated tumour, being usually diagnosed in association with an unerupted permanent maxillary canine [1,2]. There are scarce reports of multiple AOTs [3-5] and a patient with Schimmelpenning syndrome (SS) with AOT was reported [6]. SS is characterized by sebaceous nevi, associated with ipsilateral abnormalities of the central nervous system, resulting from postzygotic autosomal dominant HRAS or KRAS lethal mutations that survive by somatic mosaicism [7]. RAS mutations were previously reported in lesional tissue (including nevus sebaceous) of a patient, but not in normal skin or blood leukocytes, consistent with a somatic mosaicism [7]. We evaluated one AOT sample from a SS patient having multiple AOTs (index patient) and two sporadic AOTs (samples #1 and #2) for mutations in a panel of 50 oncogenes and tumour suppressor genes, including RAS family, by using Ion AmpliSeq TM Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, USA). After filtering by missense variants, candidate variants from the panel were defined as those pathogenic variants in regions with a depth greater than X500 and frequency greater than 5%. Only KRASc.35G > T (KRASG12V) fit this criteria, and was validated by TaqMan Ò Mutation Detection Assay using the probes KRAS_476_mu and KRAS_rf (Applied Biosystems, Foster City, USA). We further interrogated the KRASG12V mutation in six extra AOTs (samples #3-8) by the TaqMan Ò Assay. This KRAS mutation was detected in the three samples, as well as in four (samples #3, #4, #5 and #7) out of six additional samples. The mutation was validated by Sanger sequencing (Fig. 1). No other pathogenic mutation interrogated was detected. Blood leukocytes from the index patient were negative for KRASG12V mutation. To determine the specificity of the KRASG12V mutation in the context of odontogenic tumours, we evaluated three ameloblastomas, two dentinogenic ghost cell tumours and two normal oral mucosa samples using the TaqMan Ò Assay, being all negative for the mutation. Constitutively activation of the MAPK pathway by BRAFV600E mutation was reported in ameloblastoma [8-10], and in ameloblastic carcinoma [11]. We describe a recurrent oncogenic mutation in an upstream activator of MAPK, KRAS, in AOT. RAS mutations are found in 30% of human cancers and 80% of KRAS mutations occur at codon 12, being highly frequent in lung adenocarcinoma, pancreatic and colon carcinomas [12]. In our series, seven out of nine AOTs exhibited the KRASG12V mutation. The KRAS mutation was identified in the index patient sample and in sporadic AOTs, a candidate to driver mutation in these lesions. Driver mutations confer growth advantage to tumour cells and are positively selected during cancer evolution [13].

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

Coccoloba cereifera (Polygonaceae) is an extremely rare endemic shrub found exclusively in the rupestrian fields of Serra do Cipó, southeastern, Brazil. We assessed the genetic diversity and structure across the single occurrence area of C. cereifera. The genetic variation at 13 microsatellite loci was estimated from 139 individuals sampled in nine patches. The number of alleles per locus varied from two to ten; the expected and observed heterozygosity ranged from 0.324 to 0.566 and 0.337 to 0.529, respectively. Microsatellites detected low but statistically significant levels of differentiation among patches (F ST = 0.123, R ST = 0.105), whereas Mantel test results showed a weak but significant pattern of isolation by distance (r 2 = 0.31, P \ 0.002). Bayesian clustering indicated two subdivisions connected via admixture. Habitat heterogeneity across the drainage basin of the Rio Indequicé is likely limiting gene flow within patches of the geographically restricted population. While there is currently no evidence for a direct genetic risk to species survival, the apparent natural segregation occurring within the species could be exacerbated by future land use changes and the influx of alien species which could lead to demographic reductions in population size leading to a reduction in genetic diversity and an increase in population subdivision. We suggest that maintaining the integrity of the habitat within the small range of the species and continued monitoring of the effects of alien species would be the wisest use of management resources.