Insights into the Y chromosome human diversity in Uruguay.

BACKGROUND: 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. AIMS: The aim of this work is to present an updated study of the male genetic variability of the Uruguayan population. METHODS: We analyzed 13 biallelic markers and 27 STRs located in the male-specific region of the Y chromosome for 157 males: 98 from the capital, Montevideo, and 59 from Tacuarembó. RESULTS: Almost all haplogroups found in both locations are European (99% and 93.2% respectively). One Sub-Saharan African haplogroup was found in Montevideo (1%) and 2 in Tacuarembó (3%), while Native haplogroups were found only in Tacuarembó, evidencing a strong sex-biased admixture. By crossing genetic and genealogical information we could relate European haplogroups with different waves and times of migrations. DISCUSSION: Network analysis indicated a very diverse male population, suggesting that European migrants came from heterogeneous geographic locations and in different waves. Tacuarembó has closer population affinities with Iberian populations while Montevideo is more diverse. Male population expansion expansion, can be explained by the large number of migrants that arrived during the XIX century and the first half of the XX century. CONCLUSIONS: The Uruguayan male gene pool is the result of several migration waves with diverse origins, with strong sex-biased admixture that can be explained by the European migration, the violence against the indigenous males, and the segregation of the Africansadmixture that can be explained due to European migration, violence against Natives, and segregation against African males.admixture that can be explained due to European migration, violence against Natives, and segregation against African males.admixture that can be explained due to European migration, violence against Natives, and segregation against African males.admixture that can be explained due to European migration, violence against Natives, and segregation of hte Africans.

DNA polymorphisms associated with lactase persistence, self-perceived symptoms of lactose intolerance, milk and dairy consumption, and ancestry, in the Uruguayan population.

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.

Genetic Admixture Analysis in the Population of Tacuarembó-Uruguay Using Alu Insertions.

Tacuarembó is a department located in northeastern Uruguay, whose population is the result of several migration waves from Europe and Near East, as well as Africans and Afro-descents mostly from Brazil; these waves settled with the territory's various Native ethnic groups (Charrúa, Minuán, and Guaraní). In the past, this population has been the focus of genetic studies showing this trihybrid origin, with greater contributions of Natives and Africans than in other Uruguayan regions. In this study we analyzed eight Alu insertions (A25, ACE, APOA1, B65, D1, F13B, PV92, TPA25) to provide valuable information for ancestrality and genetic differentiation and to compare with both previous studies on the Tacuarembó population and Alu frequencies in other Uruguayan populations. The European contribution to Alu and classical markers was almost equal to that of a previous study using 22 classical markers (63% vs. 65%), while African contribution was higher (30% vs. 15%), and Native American contribution shows an important difference in Alu: 7% versus 20%. We found no significant differences in genetic differentiation between Tacuarembó and Montevideo but significant differences between Tacuarembó and Basque descendants from Trinidad. Our results support previous findings obtained with classical markers that demonstrate the trihybrid composition of the Tacuarembó population, correlated with historical records. Thus, Alu insertions provide interesting information in light of the admixture process in the Uruguayan population.

Differential admixture in Latin American populations and its impact on the study of colorectal cancer.

Genome-wide association studies focused on searching genes responsible for several diseases. Admixture mapping studies proposed a more efficient alternative capable of detecting polymorphisms contributing with a small effect on the disease risk. This method focuses on the higher values of linkage disequilibrium in admixed populations. To test this, we analyzed 10 genomic regions previously defined as related with colorectal cancer among nine populations and studied the variation pattern of haplotypic structures and heterozygosity values on seven categories of SNPs. Both analyses showed differences among chromosomal regions and studied populations. Admixed Latin-American samples generally show intermediate values. Heterozygosity of the SNPs grouped in categories varies more in each gene than in each population. African related populations have more blocks per chromosomal region, coherently with their antiquity. In sum, some similarities were found among Latin American populations, but each chromosomal region showed a particular behavior, despite the fact that the study refers to genes and regions related with one particular complex disease. This study strongly suggests the necessity of developing statistical methods to deal with di- or tri-hybrid populations, as well as to carefully analyze the different historic and demographic scenarios, and the different characteristics of particular chromosomal regions and evolutionary forces.

Effect of genetic ancestry on leukocyte global DNA methylation in cancer patients.

BACKGROUND: The study of genetic variants alone is not enough to explain a complex disease like cancer. Alterations in DNA methylation patterns have been associated with different types of tumor. In order to detect markers of susceptibility for the development of cutaneous melanoma and breast cancer in the Uruguayan population, we integrated genetic and epigenetic information of patients and controls. METHODS: We performed two case-control studies that included 49 individuals with sporadic cutaneous melanoma and 73 unaffected controls, and 179 women with sporadic breast cancer and 209 women controls. We determined the level of global leukocyte DNA methylation using relative quantification of 5mdC by HPLC, and we compared methylation levels between cases and controls with nonparametric statistical tests. Since the Uruguayan population is admixed and both melanoma and breast cancer have very high incidences in Uruguay compared to other populations, we examined whether individual ancestry influences global leucocyte DNA methylation status. We carried out a correlation analysis between the percentage of African, European and Native American individual ancestries, determined using 59 ancestry informative markers, and global DNA methylation in all participants. RESULTS: We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001). Additionally, we found a negative correlation between African ancestry and global DNA methylation in cancer patients (p <0.005). CONCLUSIONS: These results support the potential use of global DNA methylation as a biomarker for cancer risk. In addition, our findings suggest that the ancestral genome structure generated by the admixture process influences DNA methylation patterns, and underscore the importance of considering genetic ancestry as a modifying factor in epigenetic association studies in admixed populations such as Latino ones.

The mitochondrial DNA history of a former native American village in northern Uruguay.

OBJECTIVES: In 1828, between 8,000 and 15,000 Indians from the Jesuit Missions were brought to Uruguay. There, they were settled in a village, presently named Bella Unión, in the northwest corner of the country. According to historic sources, the Indians abandoned the settlement shortly thereafter, with the village subsequently repopulated by "criollos" and immigrants from abroad. As a first approach to reconstruct the genetic history of the population, data about the living population genetic structure will be used. Based on the analysis of the maternal lineages of the inhabitants of Bella Unión, and of those from two nearby villages, we expect to partially answer what happened with the first and subsequent inhabitants. METHODS: We analyzed the maternal lineages of the present inhabitants of Bella Unión and neighboring localities through the sequencing of the mitochondrial DNA control region. RESULTS: A total of 64.3%, 5.7%, and 30% of the mtDNAs were of Native, African, and West Eurasian origin, respectively. These figures are quite similar to that of the population of Tacuarembó, which is located in northeastern Uruguay. The four main Native American founding haplogroups were detected, with B2 being the most frequent, while some rare subhaplogroups (B2h, C1b2, D1f1) were also found. When compared with other Native American sequences, near- matches most consistently pointed to an Amazonian Indian origin which, when considered with historical evidence, suggested a probable Guaraní-Missionary-related origin. CONCLUSIONS: The data support the existence of a relationship between the historic and present inhabitants of the extreme northwest Uruguay, with a strong contribution of Native Americans to the mitochondrial DNA diversity observed there.

Breast cancer risk and genetic ancestry: a case-control study in Uruguay.

BACKGROUND: Uruguay exhibits one of the highest rates of breast cancer in Latin America, similar to those of developed nations, the reasons for which are not completely understood. In this study we investigated the effect that ancestral background has on breast cancer susceptibility among Uruguayan women. METHODS: We carried out a case-control study of 328 (164 cases, 164 controls) women enrolled in public hospitals and private clinics across the country. We estimated ancestral proportions using a panel of nuclear and mitochondrial ancestry informative markers (AIMs) and tested their association with breast cancer risk. RESULTS: Nuclear individual ancestry in cases was (mean ± SD) 9.8 ± 7.6% African, 13.2 ± 10.2% Native American and 77.1 ± 13.1% European, and in controls 9.1 ± 7.5% African, 14.7 ± 11.2% Native American and 76.2 ± 14.2% European. There was no evidence of a difference in nuclear or mitochondrial ancestry between cases and controls. However, European mitochondrial haplogroup H was associated with breast cancer (OR = 2.0; 95% CI 1.1, 3.5). CONCLUSIONS: We have not found evidence that overall genetic ancestry differs between breast cancer patients and controls in Uruguay but we detected an association of the disease with a European mitochondrial lineage, which warrants further investigation.

Questioning the "melting pot": analysis of Alu inserts in three population samples from Uruguay.

The way that immigrants integrate into recipient societies has been discussed for decades, mainly from the perspective of the social sciences. Uruguay, as other American countries, received diffferent waves of European immigrants, although the details of the process of assimilation, when it did occur, are unclear. In this study we used genetic markers to understand the process experienced by the Basques, one of the major migration waves that populated Uruguay, and their relation to other immigrants, as well as to Native American and African descendants. For this purpose, we analyzed the allele frequencies of 10 ALU loci (A25, ACE, APOA1, B65, D1, F13B, PV92, TPA25, HS2.43, and HS4.65) in three samples from Uruguay (two of Basque descendants, one of non-Basque descendants) from two locations: Montevideo and Trinidad. No departure from Hardy-Weinberg expectations was observed, with the exceptions of the APOA1 and D1 loci in the non-Basque descendants' samples. Our data show that the major genetic contribution in the three samples comes from Europe (78-88%), with minor African (10-15%) and Native American (0-10%) contributions. Genetic distances reveal that Basque descendants from Trinidad cluster with Europeans, whereas both Montevideo samples cluster together and are separate from other populations, showing two diffferent types of integration, related to the general characteristics of each regional population.

A new mitochondrial C1 lineage from the prehistory of Uruguay: population genocide, ethnocide, and continuity.

Uruguayan population has been considered as of European descent, as its Native populations victims of genocide apparently disappeared in the 19th century. Contradicting this national belief, genetic studies have shown a substantial Native contribution. However, the continuity between prehistoric, historic, and present populations remains unproved. With the aim of adding elements to prove a possible population continuity, we studied a mitochondrial lineage, part of haplogroup C1, analyzing the complete genome of a modern Uruguayan individual and the hypervariable region I (HVRI) in prehistoric, historic, and contemporary individuals. Several individuals carried the mutations that characterize this lineage: two from an archaeological mound located in the east of the country, the Charrúa Indian chief Vaimaca Perú and five individuals from the present population. The lineage was initially characterized by its HVRI sequence, having the four typical C1 mutations and adding 16051G and 16288C; other mutations were also found: 16140C was found in all but the oldest individual, dated 1,610 years BP, while 16209C, 16422C, and 16519C were found only in some individuals. Hypervariable region II showed the typical C1 mutations and 194T. The coding region, analyzed in modern individuals, was characterized by 12378T, while other mutations found were not common to all of them. In summary, we have found and described a new lineage that shows continuity from prehistoric mound builders to the present population, through a representative of the extinct Charrúa Indians. The lineage appeared at least 1,600 years ago and is carried by approximately 0.7% of the modern Uruguayan population. The continuity of the lineage supports alternative perspectives about Uruguayan national identity and the meaning of the genocide, best labeled as ethnocide because of its consequences. It also contributes to the discussion about who the prehistoric mound builders were, and to the origin, at least in the maternal line, of a Charrúa Indian. From a more general perspective, we can conclude that the characteristics, evolution, and expansion of founder haplogroup C in America have not yet been elucidated.

A South American Prehistoric Mitogenome: Context, Continuity, and the Origin of Haplogroup C1d.

Based on mitochondrial DNA (mtDNA), it has been estimated that at least 15 founder haplogroups peopled the Americas. Subhaplogroup C1d3 was defined based on the mitogenome of a living individual from Uruguay that carried a lineage previously identified in hypervariable region I sequences from ancient and modern Uruguayan individuals. When complete mitogenomes were studied, additional substitutions were found in the coding region of the mitochondrial genome. Using a complete ancient mitogenome and three modern mitogenomes, we aim to clarify the ancestral state of subhaplogroup C1d3 and to better understand the peopling of the region of the Río de la Plata basin, as well as of the builders of the mounds from which the ancient individuals were recovered. The ancient mitogenome, belonging to a female dated to 1,610±46 years before present, was identical to the mitogenome of one of the modern individuals. All individuals share the mutations defining subhaplogroup C1d3. We estimated an age of 8,974 (5,748-12,261) years for the most recent common ancestor of C1d3, in agreement with the initial peopling of the geographic region. No individuals belonging to the defined lineage were found outside of Uruguay, which raises questions regarding the mobility of the prehistoric inhabitants of the country. Moreover, the present study shows the continuity of Native lineages over at least 6,000 years.

Association between diabetes type 1 and DQB1 alleles in a case-control study conducted in Montevideo, Uruguay.

We studied HLA DQB1 allele frequencies and the relative risk (RR) of various genotypes in 72 type 1 diabetic patients and 40 control individuals in Uruguay. This is a tri-racial (Caucasian, Black and Indo-American) mixed population. The products of the polymerase chain reaction amplifications were hybridized with oligonucleotides by allele-specific oligonucleotide reverse or dot blot methods. Significant differences between these two groups were observed only for allele DQB1*0302 (35%, RR = 7.34, P<0.001). The frequency of the alleles carrying a non-aspartic acid residue at position 57 was significantly higher in the diabetic patients (85 vs 53%, P<0.001). In contrast, the frequency of Asp alleles was negatively associated with type 1 diabetes (RR = 0.20, P<0.001). The genotype DQB1*0302/DQB1*0201 (33%, RR = 5.41, P<0.05) was positively associated with this disease. The genotype frequencies associated with type 1 diabetes in our population were significantly different from what is known for Caucasian and Black populations as well as compared with another admixed population, from Chile.

Control region variability of haplogroup C1d and the tempo of the peopling of the Americas.

BACKGROUND: Among the founding mitochondrial haplogroups involved in the peopling of the Americas, haplogroup C1d has been viewed as problematic because of its phylogeny and because of the estimates of its antiquity, apparently being much younger than other founding haplogroups. Several recent analyses, based on data from the entire mitochondrial genome, have contributed to an advance in the resolution of these problems. The aim of our analysis is to compare the conclusions drawn from the available HVR-I and HVR-II data for haplogroup C1d with the ones based on whole mitochondrial genomes. METHODOLOGY/PRINCIPAL FINDINGS: HVR-I and HVR-II sequences defined as belonging to haplogroup C1d by standard criteria were gathered from the literature as well as from population studies carried out in Uruguay. Sequence phylogeny was reconstructed using median-joining networks, geographic distribution of lineages was analyzed and the age of the most recent common ancestor estimated using the ρ-statistic and two different mutation rates. The putative ancestral forms of the haplogroup were found to be more widespread than the derived lineages, and the lineages defined by np 194 were found to be widely distributed and of equivalent age. CONCLUSIONS/SIGNIFICANCE: The analysis of control region sequences is found to still harbor great potential in tracing microevolutionary phenomena, especially those found to have occurred in more recent times. Based on the geographic distributions of the alleles of np 7697 and np 194, both discussed as possible basal mutations of the C1d phylogeny, we suggest that both alleles were part of the variability of the haplogroup at the time of its entrance. Moreover, based on the mutation rates of the different sites stated to be diagnostic, it is possible that the anomalies found when analyzing the haplogroup are due to paraphyly.

HLA class I antigen and HLA-A, -B, and -C haplotype frequencies in Uruguayans.

HLA class I antigens were determined for 959 unrelated Uruguayans. The predominant HLA alleles were A2, Cw4, and B35, and the most frequently observed two-loci haplotypes were A2-B44 and B35-Cw4. The most frequent three-loci HLA haplotype was A2-Cw5-B44. We compared the Uruguayan sample with similar data from other populations.

Population structure and admixture in Cerro Largo, Uruguay, based on blood markers and mitochondrial DNA polymorphisms.

Recent studies of the Uruguayan population revealed different amounts of Amerindian and African genetic contributions. Our previous analysis of Afro-Uruguayans from the capital city of the Department of Cerro Largo showed a high proportion of African genes, and the effects of directional mating involving Amerindian women. In this paper, we extended the analysis to a sample of more than 100 individuals representing a random sample of the population of the whole Department. Based on 18 autosomal markers and one X-linked marker, we estimated 82% European, 8% Amerindian, and 10% African contributions to their ancestry, while from seven mitochondrial DNA site-specific polymorphic markers and sequences of hypervariable segment I, we determined 49% European, 30% Amerindian, and 21% African maternal contributions. Directional matings between Amerindian women and European men were detected, but differences involving Africans were not significant. Data about the specific origins of maternal lineages were also provided, and placed in a historical context.

Cromatina sexual en liquido amniotico / Sexual cromatine in amniotic liquid

Se realiza un estudio de la cromatina sexual encontrada en conteos de cien células de una muestra de 50 embarazadas, asi como de los recién nacidos hijos de las mismas, con el objetivo de conocer la eficacia del estudio del líquido amniótico en el diagnóstico prenatal del sexo y conocer además la efectividad de diferentes técnicas de coloración. Para esto se obtuvieron muestras de líquido amniótico y analizamos muestras de mucosa bucal en los recién nacidos. Se comprobó que el diagnóstico prenatal del sexo mediante el estudio del líquido amniótico no es certero en el ciento por ciento de los casos, que no existen diferencias significativas entre las dos técnicas de coloración utilizadas y que los valores de cromatina sexual en los recién nacidos, son muy bajos

Polimorfismo genético del pepsinógeno A urinario en la provincia de Villa Clara (Cuba) / Genetic polymorphism of urinary pepsinogen A in Villa Clara Province (Cuba)

Los patrones electroforéticos del pepsinógeno A (PGA) se determinaron en una muestra de 401 orinas de niños sanos de la raza blanca. En nuestro estudio sólo se consideró la presencia o ausencia del fenotipo electroforético 5 (Pg5) y se señaló como Pg5+ o como Pg5, respectivamente. Dicha isoproteína está determinada por el gen D, la cual se comporta como un carácter autosómico dominante. Las frecuencias fenotípicas encontradas fueron: Pg5+ = ,850 y Pg5 = ,150. La frecuencia génica calculada para el alelo D es de ,613. Debido a la asociación entre el cáncer del estómago y el fenotipo Pg5+, el mismo pudiera definir un grupo de riesgo en nuestra población

Análisis del polimorfismo genetico de la G-6FD eritrocitaria en la región central de Cuba / Genetics polimorphism analisys of the eritrocytarious G-6FD in the central part of Cuba

La G-6FD eritrocitaria es uno de los pocos sistemas polimorficos ÿ ligados al cromosoma X. Los estudios realizados demuestran que ÿ esta enzima es un buen marcador genetico, ya que se puede ÿ analizar a traves del mismo, la estructura genetica de la ÿ poblacion en estudio. Se estudio un total de 2489 individuos del ÿ sexo masculino y 384 del sexo femenino para determinar la ÿ frecuencia de la deficiencia de la G-6FD. Ademas se realizo ÿ estudio electroforetico de actividad catalitica a una muestra ÿ representativa. Las tecnicas empleadas son las propuestas por ÿ Butler (1969-1975) y por la OMS (1967). Nuestros resultados ÿ demuestran: 1) una alta prevalencia de deficientes en G-6FD en ÿ nuestra poblacion (4 porciento en blancos, 7.9 porciento en mulatos y 11.5 en ÿ negros), 2) la presencia de variantes electroforeticas ÿ polimorficas, siendo la mas frecuente la GdA, 3) la actividad ÿ catalitica de la G-6FD no mostro diferencias entre los grupos ÿ raciales, ni entre los sexos, aun cuando se encontro una mayor ÿ dispersion de los valores en las mujeres, 4) el analisis del ÿ flujo genico y mezcla racial esta de acuerdo con otros marcadores ÿ geneticos que se han analizado en esta region, pero los valores ÿ de M tienden a ser mayores, los cuales se han interpretado como consecuencia de la accion de la seleccion ÿ la

Estandarización de las técnicas para la caracterización de la glucosa 6 fosfato deshidrogenasa eritrocitaria / Standardization techinique for erythrocyte glucose 6 phosphate dehydrogenase characterization

Se comparan dos técnicas bioquímicas para la determinación de los niveles de glutation reducido y su estabilidad. Se establecen los valores normales de las determinaciones utilizadas durante la caracterización de la variente enzímatica en las condiciones de nuestro laboratorio, para lo que se emplea un grupo control. Se concluye que la utilización de un blanco de acetilfenilhidracina permite emplear sin dificultad la técnica del ditiobis para la cuantificación de glutation reducido, la cual resulta más sensible que la del nitroprusiato. Los resultados obtenidos en el grupo control no revelan diferencias significativas con respecto a los encontrados por otros autores

Variaciones fenotípicas de las heterocigotos para las hemoglobinas S y C / Phenotypic variations of heterozygotes for hemoglobins S an C

Se estudiaron algunas características cuantitativas sanguíneas en un grupo de heterocigotos AS y AC. Se encontró que cuando la concentración de HbS es menor que el 30%hay cambios cuantitativos en las constantes corpusculares, hemoglobina A2 y hemoglobina fetal con relación al grupo control, lo cual puede estar asociado al número de genes alfa ausentes en el individuo