For more than 150 years, Uruguayan identity was marked by the absence of Indigenous populations, distinguishing it from other South American countries. The extermination of Indigenous peoples was attributed to the Salsipuedes genocide of 1831. This work examines historical data, but primarily genetic evidence, to demonstrate that the extermination was not complete. 34% of the population has Charrua maternal ancestry, while the biparental contribution reaches 14%. Genetic information is discussed in the context of history, demography, and especially national identity, with an emphasis on the invisibilization of Indigenous peoples.

For more than 150 years, Uruguayan identity was marked by the absence of Indigenous populations, distinguishing it from other South American countries. The extermination of Indigenous peoples was attributed to the Salsipuedes genocide of 1831. This work examines historical data, but primarily genetic evidence, to demonstrate that the extermination was not complete. 34% of the population has Charrúa maternal ancestry, while the biparental contribution reaches 14%. Genetic information is discussed in the context of history, demography, and especially national identity, with an emphasis on the invisibilization of Indigenous peoples.

This study investigates the relationship between genetic ancestry, breast cancer subtypes, and survival outcomes among 951 locally advanced breast cancer cases from Argentina, Brazil, Chile, Mexico, and Uruguay, participating in the Molecular Profile of Breast Cancer Study. Array-based genotyping and ADMIXTURE analysis were used for genetic ancestry evaluation. Breast cancer subtypes were defined by IHC and the gene expression-based PAM50 algorithm. The distribution of genetic ancestry, including European, Indigenous American (IA), African (AFR), and East Asian components, revealed a heterogeneous genetic admixture across countries, with the highest IA ancestry observed in Chile (30.9%) and Mexico (30.8%). Testing the relationship between genetic ancestry and breast cancer subtypes demonstrated that a 10% increase in European ancestry was significantly associated with a 14% decrease in the odds of developing HER2-enriched breast cancer, after adjustment by age, nodal status, and the AFR component (adj. P = 0.021, luminal A as reference). Accordingly, a 10% increase in IA ancestry was associated with a 21% increase in the probability of having HER2-enriched breast cancer (adj. P = 0.022). IA ancestry also significantly increased overall survival after adjustment by age, nodal status, and AFR ancestry, although this result is controversial and may be affected by the size and heterogeneity of the Molecular Profile Breast Cancer Study cohort. Our research confirms previous findings of a high prevalence of HER2-dependent breast tumors among Hispanic/Latina women and strengthens the hypotheses of the existence of either population-specific genetic variant(s) or of other ancestry-correlated factors that impact HER2 expression in breast cancer consistently across different Latin American regions. SIGNIFICANCE:The evidence in this work supports the idea that factors linked to genetic ancestry influence the prevalence of breast cancer subtypes in Latin America, potentially affecting treatment needs in the region.

BACKGROUND:Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders characterized by progressive proximal weakness. LGMD D3 is an extremely rare autosomal dominant myopathy caused by pathogenic variants in the HNRNPDL gene encoding a protein related to RNA processing. To date, only six countries and seven families have been reported worldwide: Brazil, China and Italy with the pathogenic variant c.1132G>A p.(Asp378Asn), Uruguay, Argentina and Spain with the pathogenic variant c.1132G>C p.(Asp378His). METHODS:The study was conducted in the city of Nueva Palmira in Uruguay between March 2019 to August 2024. Forty-nine patients with LGMD D3 and 10 asymptomatic individuals carrying the mutation were examined. Serum CK, electromyography, MRI, and pulmonary function testing results were reviewed when available. Whole exome sequencing and screening test for the mutation were performed. Statistical analysis was done using STATA 16.1. RESULTS:LGMD D3 in Uruguay presents as a slowly progressive adult-onset scapulo-pelvic-peroneal dystrophy. Pathogenic variant c.1132G>C p.(Asp378His) was confirmed in all participants. Estimated prevalence of LGMD D3 was 3.75/1000 in Nueva Palmira. Mean age of onset differed by sex, with men presenting younger (p = 0.006). Characteristic MRI features were observed. CONCLUSIONS:LGMD D3 presents with a distinctive scapulo-pelvic-peroneal phenotype. To our knowledge, this is the largest LGMD D3 cluster and the first report of sex-dependent age of onset. Our study illustrates how genetic isolation can lead to high LGMD D3 prevalence in an admixed population and explores its potential origin.

The "Perpetuity Monument" ossuary located in the city of Paysandu, Uru- guay, received during its history the deceased of both the general popula-tion and combatants of the war event known as the "Defense of Paysandu" (1864). This place functioned as a public cemetery between 1851 and 1881, and the ossuary was built in 1854. In order to contribute to historical, cul-tural and patrimonial knowledge, this project aimed at characterizing the remains of the ossuary, and to establish a possible relationship between the collective imagination that suggests that the remains of the combat-ants were deposited there, and the results obtained. A total of 13 skulls and associated remains were recovered and studied through bioanthro-pological methods, establishing gender, age and ancestry, and observing possible indicators of violence. Additionally, in order to expand the in-formation on ancestry, mitochondrial DNA was extracted and analyzed from six skulls. The final sample was made up of 13 adult individuals: 9 male, 3 female, and 1 of undetermined gender, and typical characteristics of crossbred population. In relation to possible indicators of violence, it was observed that indicators are present in 5 individuals in the sample. The results are consistent with what was expected: high percentage of male individuals with signs of violence, probably associated with the de-fense of Paysandu.

El osario del “Monumento a Perpetuidad”, ubicado en la ciudad de Paysandú, Uruguay, recibió durante su historia fallecidos tanto de población general, como de combatientes del evento bélico conocido como la “Defensa de Paysandú” (1864). Este lugar funcionó como cementerio público entre 1851 y 1881, habiéndose construido el osario en 1854. Con el objetivo de aportar al conocimiento histórico, cultural y patrimonial, se busca caracterizar los restos del osario y establecer una posible relación entre el imaginario colectivo, que plantea que los restos de los combatientes fueron depositados allí, y los resultados obtenidos. Se recuperaron 13 cráneos y restos asociados, que se estudiaron a través de métodos bioantropológicos, estableciéndose sexo, edad y ancestralidad, y observándose posibles indicadores de violencia. Adicionalmente, para ampliar la información sobre ancestralidad, se extrajo y analizó ADN mitocondrial de seis cráneos. La muestra final se compuso de 13 individuos adultos, 9 masculinos, 3 femeninos y uno de sexo indeterminado, y características típicas de una población mestizada. En relación con posibles indicadores de violencia, se observa que están presentes en cinco individuos de la muestra. Los resultados son coincidentes con lo esperado: alto porcentaje de individuos masculinos con signos de violencia, probablemente asociados a la defensa de Paysandú.

Uruguay has one of the highest per capita milk intakes worldwide, even with a limited supply of lactose-free products; furthermore, the admixed nature of its population is well known, and various frequencies of lactase persistence (LP) are observed in the source populations. We aimed to contribute to the understanding of the relation between allelic variants associated with LP, milk consumption, digestive symptoms, and genetic ancestry in the Uruguayan population. Samples of saliva or peripheral blood were collected from 190 unrelated individuals from two regions of Uruguay, genotypes for polymorphic sites in a fragment within the LCT enhancer were determined and allelic frequencies calculated in all of them. Data were collected on frequency of milk and dairy consumption and self-reported symptoms in a subsample of 153 individuals. Biparental and maternal ancestry was determined by analyzing individual ancestry markers and mitochondrial DNA. Twenty-nine percentage of individuals reported symptoms attributed to the ingestion of fresh milk, with abdominal pain, bloating and flatulence being the most frequent. European LP-associated allele T-13910 showed a frequency of 33%, while other LP-associated alleles like G-13915 and T-14011 were observed in very low frequencies. Associations between self-reported symptoms, fresh milk intake, and C/T-13910 genotype were statistically significant. No evidence of association between genetic ancestry and C/T-13910 was found, although individuals carrying one T-13910 allele appeared to have more European ancestry. In conclusion, the main polymorphism capable of predicting lactose intolerance in Uruguayans is C/T-13910, although more studies are required to unravel the relation between genotype and lactase activity, especially in heterozygotes.

Uncovering causal relationships between exposures and outcomes can be difficult in observational studies because of the potential for confounding and reverse causation to produce biased estimates. Conversely, randomized controlled trials (RCTs) provide the strongest evidence for causality but they are not always feasible. Mendelian randomization (MR) is a method that aims to strengthen causal inference using genetic variants as proxies or instrumental variables (IVs) for exposures, to overcome the above-mentioned biases. Since allele segregation occurs at random from parents to offspring, and alleles for a trait assort independently from those for other traits, MR studies have frequently been compared to "natural" RCTs. In biological anthropology (BA) relationships between variables of interest are usually evaluated using observational data, often remaining descriptive, and other approaches to causal inference have seldom been implemented. Here, we propose the use of MR to investigate cause and effect relationships in BA studies and provide examples to show how that can be done across areas of BA relevance, such as adaptation to the environment, nutrition and life history theory. While we consider MR a useful addition to the biological anthropologist's toolbox, we advocate the adoption of a wide range of methods, affected by different types of biases, in order to better answer the important causal questions for the discipline.

With regard to the origin of its population and microevolutionary processes, Uruguay exhibits distinctive features that distinguish it from other countries in Latin America, while at the same time sharing several similarities. In this article, we will focus on the variability of paternal genetic lineages in two geographical regions with different histories that can be considered as examples of distinct populations for the continent. In general terms, the genetic diversity is a result of different demographic processes related to the American conquest and colonisation. These resulted in distinct ancestral components which vary geographical and depend on the distribution by sex within these components. In Uruguay, native maternal haplogroups are significantly more frequent in the North. Although there are several studies about the geneticvariability of Uruguay, little is known about male genetic lineages.

Introduction: Genetic variants related to bone morphogenetic proteins (BMP2, BMP4, GREM1, SMAD7) signaling pathway have been associated with colorectal cancer, mainly in Caucasian populations.Objective: To describe the association of variants in members of the BMP signaling pathway in a Mexican population, characterized by its indigenous American and Caucasian ancestry.Methods: Genotyping of 1,000 colorectal cancer cases and 1,043 control individuals recruited in Mexico City, Monterrey, and Torreón was carried out using the Sequenom platform.Associations between colorectal cancer and variants were studied with univariate and multivariate analyses.Results: Variants rs4444235, rs12953717 and rs4939827 replicated the association with the neoplasm (p ≤ 0.05).Caucasian ancestry showed association with the tumor.Conclusions: The study replicated the associations between colorectal cancer and SMAD7 and BMP4 variants, with an association being observed with the Caucasian component of the ethnic mix.

La población uruguaya ha sido tradicionalmente considerada como "sin indios". Luego de casi 150 años, en 1996 se comenzó a interrogar a la población sobre "etnia o raza", lo cual culminó en el Censo de 2011. En este, 2,5% de la población reconoció como ancestría principal la indígena, y 5,1% declaró tener ancestros indígenas. Estos datos no son coherentes con los observados al estudiar ancestría genética materna o autosómica (35 y 14% de aporte indígena, respectivamente). Se analizan los hechos y procesos que condujeron a la invisibilización de los indígenas y sus descendientes a partir de fuentes históricas, y en particular, en su distribución geográfica y nivel socioeconómico. Se analiza también el género de quienes pasaron a formar pate de la sociedad nacional, y la falta de voz de las mujeres durante un largo período, puesto que fueron mujeres indígenas quienes mayoritariamente se intergraron a la sociedad nacional.

Introducción: Los amplia mayoría de los estudios de asociación de genoma completo (GWAS) se basan enpoblaciones europeas y si bien han logrado identificar regiones genómicas asociadas a diversaspatologías aún hay una gran porción de la variabilidad no explicada por esas regiones. Respecto alcáncer color-rectal (CRC) hay publicados GWAS en poblaciones europeas que identificaron regiones genomicas asociados a CRC. Sin embargo estos estudios pueden no haber sido lo suficientemente amplios para detectar SNPs asociados a un riesgo relativo bajo o moderado.(1) Las poblaciones mestizadas latinoamericanas son una buena oportunidad de identificar SNPs asociados a CRC, no detectados en otras poblaciones. Objetivo: identificar SNPs asociados en genomas de individuos mestizados mexicanos y examinar los SNPs identificados en otras poblaciones. Materiales y Métodos: Se colectaron muestras de 1712 individuos de tres ciudades mexicanas, y segenotiparon 1.114.890 SNPs. Se utilizaron los genomas disponibles en 1000 Genomes para considerar el sesgo debido a la ancestrıa (2). La imputación de genotipos, para aumentar la densidad de SNPs en ciertas regiones, se realizó o mediante el software Eagle v2.4 (3) para determinar la fase y para imputar SNPs se uso Minimac3 (4) usando como genomas de referencias 2504 individuos de 26 poblaciones mundiales (1000Genomes) (5). Resultados: A partir del GWAS se detectaron 8 SNPs no previamente identificados, mientras que aquellos SNPs ubicados en genes que habían sido detectados previamente en poblaciones europeas, no mostraron asociación. Regiones descritas como asociadas a CRC El test de asociación por gen, que considera el efecto combinado de todos los SNPs del gen (SKAT)(6), permitió detectar asociación en la muestra mexicana en 5 de 16 de estos genes. Este análisis se realizó en 16 genes encontrados en la bibliografía, se consideraron 15.174 SNPs. Conclusiones: Se proponen 8 regiones asociadas a CRC que deben seguir estudiandose para determinar su rol en el desarrollo del CRC. Se logra replicar parcialmente la asociación de los genes descritos en poblaciones europeas al considerar el conjunto de SNPs dentro de los genes, evidenciando la necesidad de considerar la totalidad de las variantes del gen para determinar la asociacion con CRC.

INTRODUCTION:Genetic variants related to bone morphogenetic proteins (BMP2, BMP4, GREM1, SMAD7) signaling pathway have been associated with colorectal cancer, mainly in Caucasian populations.OBJECTIVE:To describe the association of variants in members of the BMP signaling pathway in a Mexican population, characterized by its indigenous American and Caucasian ancestry.METHODS:Genotyping of 1,000 colorectal cancer cases and 1,043 control individuals recruited in Mexico City, Monterrey, and Torreón was carried out using the Sequenom platform. Associations between colorectal cancer and variants were studied with univariate and multivariate analyses.RESULTS:Variants rs4444235, rs12953717 and rs4939827 replicated the association with the neoplasm (p ≤ 0.05). Caucasian ancestry showed association with the tumor.CONCLUSIONS:The study replicated the associations between colorectal cancer and SMAD7 and BMP4 variants, with an association being observed with the Caucasian component of the ethnic mix.

The prehistory of the people of Uruguay is greatly complicated by the dramatic and severe effects of European contact, as with most of the Americas. After the series of military campaigns that exterminated the last remnants of nomadic peoples, Uruguayan official history masked and diluted the former Indigenous ethnic diversity into the narrative of a singular people that all but died out. Here we present the first whole genome sequences of the Indigenous people of the region before the arrival of Europeans, from an archaeological site in eastern Uruguay that dates from 2,000 years before present. We find a surprising connection to ancient individuals from Panama and eastern Brazil, but not to modern Amazonians. This result may be indicative of a migration route into South America that may have occurred along the Atlantic coast. We also find a distinct ancestry previously undetected in South America. Though this work begins to piece together some of the demographic nuance of the region, the sequencing of ancient individuals from across Uruguay is needed to better understand the ancient prehistory and genetic diversity that existed before European contact, thereby helping to rebuild the history of the Indigenous population of what is now Uruguay.

Recientemente, diversos estudios sobre la población uruguaya han demostrado que está conformada por desiguales aportes de europeos, africanos y pueblos originarios, entre otros. El aporte indígena es mayor cuando se analiza la contribución por línea materna, aunque su origen étnico/geográfico no es claro, ni tampoco cuándo ni cómo llegaron los distintos grupos. Para aportar al conocimiento del poblamiento prehistórico e histórico del territorio y sus relaciones con otras poblaciones se analizan, por secuenciación masiva, 32 genomas mitocondriales completos (mitogenomas) de habitantes actuales del país, identificados previamente por sus regiones hipervariables como correspondientes a los cuatro haplogrupos principales de origen americano. Se determinaron siete nuevos subhaplogrupos (A2be, A2bf, B2an, C1d1h, C1b30, C1b31 y D1x), otro se redenominó (C1d1d - actual C1d1g) y se plantea la revisión de los criterios de asignación de B2b6 y D1g5. Se estimó la antigüedad de los subhaplogrupos nuevos, que varía entre 4554 y 11985 años, con la excepción de C1d1g, cuya edad fue estimada en 20736 años. Algunas secuencias pudieron ser vinculadas a distintos grupos étnicos o a diversas regiones geográficas, como Amazonia, Chaco, Pampa, o Andes. Se discuten las nuevas asignaciones desubhaplogrupos y las de algunos previamente definidos, así como su distribución geográfica y antigüedad, con relación al panorama general de América del Sur.

The Amerindian group known as the Charrúas inhabited Uruguay at the timing of European colonial contact. Even though they were extinguished as an ethnic group as a result of a genocide, Charrúan heritage is part of the Uruguayan identity both culturally and genetically. While mitochondrial DNA studies have shown evidence of Amerindian ancestry in living Uruguayans, here we undertake whole-genome sequencing of 10 Uruguayan individuals with self-declared Charruan heritage. We detect chromosomal segments of Amerindian ancestry supporting the presence of indigenous genetic ancestry in living descendants. Specific haplotypes were found to be enriched in “Charrúas” and rare in the rest of the Amerindian groups studied. Some of these we interpret as the result of positive selection, as we identified selection signatures and they were located mostly within genes related to the infectivity of specific viruses. Historical records describe contacts of the Charrúas with other Amerindians, such as Guaraní, and patterns of genomic similarity observed here concur with genomic similarity between these groups. Less expected, we found a high genomic similarity of the Charrúas to Diaguita from Argentinian and Chile, which could be explained by geographically proximity. Finally, by fitting admixture models of Amerindian and European ancestry for the Uruguayan population, we were able to estimate the timing of the first pulse of admixture between European and Uruguayan indigenous peoples in approximately 1658 and the second migration pulse in 1683. Both dates roughly concurring with the Franciscan missions in 1662 and the foundation of the city of Colonia in 1680 by the Spanish.

Population stratification (PS) is a confounding factor in genome-wide association studies (GWASs) and also an interesting process itself. Latin American populations have mixed genetic ancestry, which may account for PS. We have analyzed the relatedness, by means of the identity-by-descent (IBD) estimations, in a sample of 1805 individuals and 1.006.703 autosomal mutations from a case-control study of colorectal cancer in Mexico. When using the recommended protocol for quality control assessment, 402 should have been removed due to relatedness. Our purpose was to analyze this value in the context of an admixed population. For that aim, we reanalyzed the sample using two software designed for admixed populations, obtaining estimates of 110 and 70 related individuals to remove. The results showed that the first estimation of relatedness was an effect of the higher Native American contribution in part of the data samples, being a confounding factor for IBD estimations. We conclude in the importance of considering PS and genetic ancestry in order to avoid spurious results, not only in GWAS but also in relatedness analysis.