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ABSTRACT: Sardinia has been used for genetic studies because of its historical isolation, genetic homogeneity and increased prevalence of certain rare diseases. Controversy remains concerning the genetic substructure and the extent of genetic homogeneity, which has implications for the design of genome-wide association studies (GWAS). We revisited this issue by examining the genetic make-up of a sample from North-East Sardinia using a dense set of autosomal, Y chromosome and mitochondrial markers to assess the potential of the sample for GWAS and fine mapping studies. We genotyped individuals for 500K single-nucleotide polymorphisms, Y chromosome markers and sequenced the mitochondrial hypervariable (HVI-HVII) regions. We identified major haplogroups and compared these with other populations. We estimated linkage disequilibrium (LD) and haplotype diversity across autosomal markers, and compared these with other populations. Our results show that within Sardinia there is no major population substructure and thus it can be considered a genetically homogenous population. We did not find substantial differences in the extent of LD in Sardinians compared with other populations. However, we showed that at least 9% of genomic regions in Sardinians differed in LD structure, which is helpful for identifying functional variants using fine mapping. We concluded that Sardinia is a powerful setting for genetic studies including GWAS and other mapping approaches.
European journal of human genetics: EJHG 02/2012; 20(9):956-64. · 3.56 Impact Factor
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Tábita Hünemeier,
Carlos Eduardo Guerra Amorim,
Soledad Azevedo,
Veronica Contini,
Víctor Acuña-Alonzo,
Francisco Rothhammer,
Jean-Michel Dugoujon,
Stephane Mazières,
Ramiro Barrantes,
María Teresa Villarreal-Molina,
Vanessa Rodrigues Paixão-Côrtes,
Francisco M Salzano,
Samuel Canizales-Quinteros, Andres Ruiz-Linares,
Maria Cátira Bortolini
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ABSTRACT: Culture and genetics rely on two distinct but not isolated transmission systems. Cultural processes may change the human selective environment and thereby affect which individuals survive and reproduce. Here, we evaluated whether the modes of subsistence in Native American populations and the frequencies of the ABCA1*Arg230Cys polymorphism were correlated. Further, we examined whether the evolutionary consequences of the agriculturally constructed niche in Mesoamerica could be considered as a gene-culture coevolution model. For this purpose, we genotyped 229 individuals affiliated with 19 Native American populations and added data for 41 other Native American groups (n = 1905) to the analysis. In combination with the SNP cluster of a neutral region, this dataset was then used to unravel the scenario involved in 230Cys evolutionary history. The estimated age of 230Cys is compatible with its origin occurring in the American continent. The correlation of its frequencies with the archeological data on Zea pollen in Mesoamerica/Central America, the neutral coalescent simulations, and the F(ST)-based natural selection analysis suggest that maize domestication was the driving force in the increase in the frequencies of 230Cys in this region. These results may represent the first example of a gene-culture coevolution involving an autochthonous American allele.
PLoS ONE 01/2012; 7(6):e38862. · 4.09 Impact Factor
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Jorge Mauricio Cuartas Arias,
Carlos A Palacio Acosta,
Jenny Garcia Valencia,
Gabriel J Montoya,
Juan C Arango Viana,
Omer Campo Nieto,
Andrés F Flórez,
Beatriz E Camarena Medellin,
Winston Rojas Montoya,
Carlos A Lopez Jaramillo,
Javier Gutierrez Achury,
Carlos Cruz Fuentes,
Gabriel Bedoya Berrio, Andres Ruiz-Linares
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ABSTRACT: To identify and characterize high-order gene-to-gene interactions in antisocial personality disorder (ASPD).
Participants for case-control study were selected from the inmate male population in Bellavista prison from Medellin. The study included 310 individuals with ASPD and 200 with no ASPD. Diagnoses were made according to a best-estimate procedure based on a semistructured interview (diagnostic interview for genetic studies 3.0). We genotyped some single-nucleotide polymorphisms in candidate genes with main serotonin pathway effects. The gene-gene interaction was examined using the multifactor dimensionality reduction method version 2.0.α. We assessed model sizes of 2 and 3 loci and counted the number of replicates that contained the causal loci in the final best model that was identified using 10-fold cross validation.
We find epistatic interaction with catechol-O-methyl transferase (COMT), tryptophan hydroxylase, and 5-HTR2A (serotonin receptor) with ASPD. This data supports an important role of polymorphism in serotonin receptors and low enzyme activity of COMT for susceptibility to ASPD.
This study suggests that gene interactions between genetic variants in COMT, 5-HTR2A and tryptophan hydroxylase gene would be associated with ASPD and influence the dopamine rewards pathways and modulate serotonin levels in ASPD.
Psychiatric genetics 06/2011; 21(3):115-24. · 2.33 Impact Factor
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Nicolas Pineda-Trujilo,
Federico Uribe,
Fabiola Montoya,
Juan-Manuel Alfaro,
Guillermo Latorre,
Alberto Villegas,
Javier Ceron,
Andres-Felipe Perez,
Mariano Ospina,
Andres Naranjo,
Abel Serrano,
Ivan Duque,
Debora Castrillon,
Alberto Abad,
Gabriel Bedoya,
Vital Balthazar, Andres Ruiz-Linares
Journal of Genetics 12/2010; 89(4):457-61. · 1.09 Impact Factor
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ABSTRACT: The 546-base pair enhancer of limb expression HACNS1, which is highly constrained in all terrestrial vertebrates, has accumulated 16 human-specific changes after the human-chimpanzee split. There has been discussion whether this process was driven by positive selection or biased gene conversion, without considering population data. We studied 83 South Amerindian, 11 Eskimo, 35 Europeans, 37 Bantu, and non-Bantu Sub-Saharan speakers, and 28 Brazilian mestizo samples and found no variation in this DNA region. Similar lack of variability in this region was found in four Africans, five Europeans or Euro-derived, two Asians, one Paleo-Eskimo, and one Neandertal sequence, whose whole genomes are publicly available. No difference was found. This result favors the interpretation of past positive and present conservative selection, as would expected in a region which influences Homo-specific traits as important as opposable thumbs, manual dexterity, and bipedal walking. Am J Phys Anthropol, 2010. © 2010 Wiley-Liss, Inc.
American Journal of Physical Anthropology 11/2010; 143(3):478-81. · 2.82 Impact Factor
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ABSTRACT: Comparative studies of linkage disequilibrium (LD) can provide insights into human demographic history. Here, we characterize LD in six Native American populations using seven microsatellite markers in Xq13, a region of the genome extensively studied in populations around the world. Native Americans show relatively low diversity and high LD, in agreement with recent genome-wide survey and a scenario of sequential founder effects accompanying human population dispersal around the globe. LD in Native Americans is similar to that observed in some recently described small population isolates and higher than in large European isolates (e.g., Finns), which have been extensively analyzed in medical genetics studies. Haplotype analyses are consistent with a colonization of the New World by a differentiated East Asian population, followed by extensive genetic drift in the Americas.
American Journal of Physical Anthropology 07/2010; 142(3):476-80. · 2.82 Impact Factor
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Stephane Bourgeois,
Vania Yotova,
Sijia Wang,
Sylvie Bourtoumieu,
Claudia Moreau,
Roman Michalski,
Jean-Paul Moisan,
Kim Hill,
Ana M Hurtado, Andres Ruiz-Linares,
Damian Labuda
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ABSTRACT: Most genetic studies on the origins of Native Americans have examined data from mtDNA and Y-chromosome DNA. To complement these studies and to broaden our understanding of the origin of Native American populations, we present an analysis of 1,873 X-chromosomes representing Native American (n = 438) and other continental populations (n = 1,435). We genotyped 36 polymorphic sites, forming an informative haplotype within an 8-kb DNA segment spanning exon 44 of the dystrophin gene. The data reveal continuity from a common Eurasian ancestry between Europeans, Siberians, and Native Americans. However, the loss of two haplotypes frequent in Eurasia (18.8 and 7%) and the rise in frequency of a third haplotype rare elsewhere, indicate a major population bottleneck in the peopling of the Americas. Although genetic drift appears to have played a greater role in the genetic differentiation of Native Americans than in the latitudinally distributed Eurasians, we also observe a signal of a differentiated ancestry of southern and northern populations that cannot be simply explained by the serial southward dilution of genetic diversity. It is possible that the distribution of X-chromosome lineages reflects the genetic structure of the population of Beringia, itself issued from founder effects and a source of subsequent southern colonization(s).
American Journal of Physical Anthropology 06/2009; 140(3):417-28. · 2.82 Impact Factor
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American Journal of Medical Genetics Part A 10/2008; 146A(20):2709-12. · 2.39 Impact Factor
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Alkes L Price,
Johannah Butler,
Nick Patterson,
Cristian Capelli,
Vincenzo L Pascali,
Francesca Scarnicci, Andres Ruiz-Linares,
Leif Groop,
Angelica A Saetta,
Penelope Korkolopoulou,
Uri Seligsohn,
Alicja Waliszewska,
Christine Schirmer,
Kristin Ardlie,
Alexis Ramos,
James Nemesh,
Lori Arbeitman,
David B Goldstein,
David Reich,
Joel N Hirschhorn
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ABSTRACT: European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false-positive or false-negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European, and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data.
PLoS Genetics 02/2008; 4(1):e236. · 8.69 Impact Factor
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Alkes L Price,
Nick Patterson,
Fuli Yu,
David R Cox,
Alicja Waliszewska,
Gavin J McDonald,
Arti Tandon,
Christine Schirmer,
Julie Neubauer,
Gabriel Bedoya, [......],
Carlos A Aguilar-Salinas,
Samuel Canizales-Quinteros,
Marta Menjivar,
William Klitz,
Brian Henderson,
Christopher A Haiman,
Cheryl Winkler,
Teresa Tusie-Luna, Andres Ruiz-Linares,
David Reich
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ABSTRACT: Admixture mapping is an economical and powerful approach for localizing disease genes in populations of recently mixed ancestry and has proven successful in African Americans. The method holds equal promise for Latinos, who typically inherit a mix of European, Native American, and African ancestry. However, admixture mapping in Latinos has not been practical because of the lack of a map of ancestry-informative markers validated in Native American and other populations. To address this, we screened multiple databases, containing millions of markers, to identify 4,186 markers that were putatively informative for determining the ancestry of chromosomal segments in Latino populations. We experimentally validated each of these markers in at least 232 new Latino, European, Native American, and African samples, and we selected a subset of 1,649 markers to form an admixture map. An advantage of our strategy is that we focused our map on markers distinguishing Native American from other ancestries and restricted it to markers with very similar frequencies in Europeans and Africans, which decreased the number of markers needed and minimized the possibility of false disease associations. We evaluated the effectiveness of our map for localizing disease genes in four Latino populations from both North and South America.
The American Journal of Human Genetics 07/2007; 80(6):1024-36. · 10.60 Impact Factor
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ABSTRACT: A total of 278 individuals from two Brazilian Indian tribes (Guarani and Kaingang) living in five different localities had their mitochondrial DNA sequenced for the first hypervariable segment (HVS-I), and a fraction of them was also studied for seven biallelic Y-chromosome polymorphisms. Nineteen HVS-I lineages were detected, which showed distinct distributions in the two tribes. The G(ST) value obtained with the mtDNA data is about 5 times higher for the Guarani as compared to the Kaingang, suggesting a higher level of differentiation between the three Guarani partialities than between the two Kaingang villages. Non-Amerindian admixture varied with sex and in the Guarani was only observed through the paternal line. Using these data and those of other Tupian and Jêan tribes, it was possible to make inferences about past migratory movements and the genetic differentiation of these populations.
American Journal of Physical Anthropology 03/2007; 132(2):301-10. · 2.82 Impact Factor
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Andrea Rita Marrero,
Claudio Bravi,
Steven Stuart,
Jeffrey C Long,
Fábio Pereira das Neves Leite,
Trícia Kommers,
Claudia M B Carvalho,
Sergio Danilo Junho Pena, Andres Ruiz-Linares,
Francisco Mauro Salzano,
Maria Cátira Bortolini
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ABSTRACT: To investigate the evolutionary and demographic history of the Gaucho, a distinct population of southern Brazil, relating it to their culture, to assess possible parallel continuity.
Six binary polymorphisms, an Alu insertion polymorphism (YAP) and 12 short tandem repeat loci in the non-recombining region of the Y-chromosome, as well as the sequence of the first hypervariable segment (HVS-I) of the mitochondrial DNA (mtDNA) control region were studied in 150 unrelated males born in the Pampa region of Rio Grande do Sul.
Comparison of the results with the other Brazilian and Uruguayan populations, as well as with their putative ancestors, indicated a stronger male Spanish influence than that observed elsewhere in Brazil, a former Portuguese colony. Extensive mtDNA analyses of their Amerindian component gave clear indications of the presence there of material from extinct (Charrua), as well as extant (Guarani) tribes.
The genetic analyses contributed in a significant way to reveal that the known cultural continuity between pre- and post-Columbian Pampa populations was also accompanied by an extraordinary genetic continuity.
Human Heredity 02/2007; 64(3):160-71. · 1.79 Impact Factor
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Nicolas Pineda-Trujillo,
Maria Apergi,
Sonia Moreno,
William Arias,
Suzanne Lesage,
Alejandro Franco,
Diego Sepulveda-Falla,
David Cano,
Omar Buriticá,
David Pineda,
Carlos Santiago Uribe,
Justo Garcia de Yebenes,
Andrew J Lees,
Alexis Brice,
Gabriel Bedoya,
Francisco Lopera, Andres Ruiz-Linares
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ABSTRACT: We previously identified in two families with early onset Parkinson's Disease (PD) from the isolated population of Antioquia (Colombia), a parkin Cys212Tyr substitution caused by a G736A mutation. This mutation was subsequently observed in a Spanish family, suggesting that it could have been taken to Antioquia by Spanish immigrants. Here we screened for the G736A mutation in additional Antioquian early onset PD cases and used haplotype analysis to investigate the relationship between Spanish and Antioquian G736A chromosomes. We confirmed the occurrence of an extensive founder effect in Antioquia. Thirteen individuals (10 homozygotes) from seven nuclear families were identified with the G736A mutation. Genealogical investigations demonstrated the existence of shared ancestors between six of these families four to five generations ago and no evidence of Spanish ancestry during this period. A second parkin mutation (a duplication of exon 3), was detected in the three G736A heterozygote carriers. Haplotype data exclude a recent common ancestry between the Spanish and Antioquian patients studied here and is consistent with the introduction of the G736A mutation in Antioquia during early colonial times (about 16 generations ago).
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2007; 141B(8):885-9. · 3.70 Impact Factor
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Barbara Kremeyer,
Ibi Herzberg,
Jenny Garcia,
Emily Kerr,
Constanza Duque,
Vicky Parra,
Jorge Vega,
Carlos Lopez,
Carlos Palacio,
Gabriel Bedoya,
Jorge Ospina, Andres Ruiz-Linares
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ABSTRACT: Recent reports have implicated polymorphisms in the brain derived neurotrophic factor (BDNF) gene region in the etiology of several psychiatric phenotypes, including bipolar disorder. Significant disease association has been reported for the G allele at SNP rs6265, which encodes for Valine at position 66 of BDNF (Val66Met), an apparently functional variant of this key BDNF. Here we examined a sample of 224 bipolar type I patients and available parents (comprising a total of 212 nuclear families) ascertained in a South American population isolate (Antioquia, Colombia). We tested for transmission distortion to bipolar patients of alleles at the rs6265 polymorphism and at a microsatellite marker 1.3 kb away from this SNP. Significant excess transmission of the rs6265 G allele to cases was observed (chi(2) = 10.77, d.f. = 1, P = 0.001). Two-locus haplotype analysis showed a significant global transmission distortion (chi(2) = 16.059, d.f. = 7, P = 0.025) with an excess transmission of a haplotype comprising the rs6265 G allele and microsatellite allele 227. These results are consistent with previous studies pointing to a role for BDNF in susceptibility to mood disorders.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2006; 141B(5):435-9. · 3.70 Impact Factor
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Susan Service,
Joseph DeYoung,
Maria Karayiorgou,
J Louw Roos,
Herman Pretorious,
Gabriel Bedoya,
Jorge Ospina, Andres Ruiz-Linares,
António Macedo,
Joana Almeida Palha, [......],
Lynette Peddle,
Proton Rahman,
Giovanna Piras,
Maria Monne,
Sarah Murray,
Luana Galver,
Leena Peltonen,
Chiara Sabatti,
Andrew Collins,
Nelson Freimer
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ABSTRACT: The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping.
Nature Genetics 06/2006; 38(5):556-60. · 35.53 Impact Factor
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ABSTRACT: Mutations of the AE1 (SLC4A1, Anion-Exchanger 1) gene that codes for band 3, the renal and red cell anion exchanger, are responsible for many cases of familial distal renal tubular acidosis (dRTA). In Southeast Asia this disease is usually recessive, caused either by homozygosity of a single AE1 mutation or by compound heterozygosity of two different AE1 mutations. We describe two unrelated boys in Sarawak with dRTA associated with compound heterozygosity of AE1 mutations. Both had Southeast Asian ovalocytosis (SAO), a morphological abnormality of red cells caused by a deletion of band 3 residues 400-408. In addition, one boy had a DNA sequence abnormality of band 3 residue (G701D), which has been reported from elsewhere in Southeast Asia. The other boy had the novel sequence abnormality of band 3 (Q759H) and profound hemolytic anemia.
Pediatric Nephrology 03/2006; 21(2):212-7. · 2.52 Impact Factor
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ABSTRACT: Four biallelic and six multiallelic Y-chromosome polymorphisms were investigated in 59 Gran Canarian, 60 North African Berber and 46 Spanish subjects. These new data were merged with equivalent literature information to obtain the parental Y-chrosomomal contribution in Gran Canarians, Colombians, and Venezuelans. The results were then compared, for Gran Canarians and Colombians, to those derived from autosomal and mtDNA. In both groups, the Spanish Y-chromosome contribution was much more marked than that estimated using mtDNA. This analysis showed a usual trend in the Spanish Colonial history, characterized by a demographic collapse of the aboriginal population, but with considerable introgression of genes through native women. In accordance to D. Ribeiro's typology for peoples subjected to Colonialism, the Y-chromosomes of these admixed populations are classified as transplanted, their mtDNA as witness, and their autosome sets as new.
Genetics and Molecular Biology. 01/2004;
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Maria-Catira Bortolini,
Francisco M Salzano,
Mark G Thomas,
Steven Stuart,
Selja P K Nasanen,
Claiton H D Bau,
Mara H Hutz,
Zulay Layrisse,
Maria L Petzl-Erler,
Luiza T Tsuneto, [......],
Ana M Hurtado,
Dinorah Castro-de-Guerra,
Maria M Torres,
Helena Groot,
Roman Michalski,
Pagbajabyn Nymadawa,
Gabriel Bedoya,
Neil Bradman,
Damian Labuda, Andres Ruiz-Linares
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ABSTRACT: To scrutinize the male ancestry of extant Native American populations, we examined eight biallelic and six microsatellite polymorphisms from the nonrecombining portion of the Y chromosome, in 438 individuals from 24 Native American populations (1 Na Dené and 23 South Amerinds) and in 404 Mongolians. One of the biallelic markers typed is a recently identified mutation (M242) characterizing a novel founder Native American haplogroup. The distribution, relatedness, and diversity of Y lineages in Native Americans indicate a differentiated male ancestry for populations from North and South America, strongly supporting a diverse demographic history for populations from these areas. These data are consistent with the occurrence of two major male migrations from southern/central Siberia to the Americas (with the second migration being restricted to North America) and a shared ancestry in central Asia for some of the initial migrants to Europe and the Americas. The microsatellite diversity and distribution of a Y lineage specific to South America (Q-M19) indicates that certain Amerind populations have been isolated since the initial colonization of the region, suggesting an early onset for tribalization of Native Americans. Age estimates based on Y-chromosome microsatellite diversity place the initial settlement of the American continent at approximately 14,000 years ago, in relative agreement with the age of well-established archaeological evidence.
The American Journal of Human Genetics 10/2003; 73(3):524-39. · 10.60 Impact Factor
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Clasificación molecular de las cuatro mutaciones mas comunmente asociadas a la Talasemia Beta, Hospital San Vicente de Paúl, Medellín; 01/2000
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Andres Ruiz-Linares,
Daniel Ortiz-Barrientos,
Mauricio Figueroa,
Natalia Mesa,
Juan G. Munera,
Gabriel Bedoya,
Ivan D. Velez,
Luis F. Garcia,
Anna Perez-Lezaun,
Jaume Bertranpetit,
Marcus W Feldman,
David B Goldstein
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ABSTRACT: Recently, Y chromosome markers have begun to be used to study Native American origins. Available data have been interpreted as indicating that the colonizers of the New World carried a single founder haplotype. However, these early studies have been based on a few, mostly complex polymorphisms of insufficient resolution to determine whether observed diversity stems from admixture or diversity among the colonizers. Because the interpretation of Y chromosomal variation in the New World depends on founding diversity, it is important to develop marker systems with finer resolution. Here we evaluate the hypothesis of a single-founder Y haplotype for Amerinds by using 11 Y-specific markers in five Colombian Amerind populations. Two of these markers (DYS271, DYS287) are reliable indicators of admixture and detected three non-Amerind chromosomes in our sample. Two other markers (DYS199, M19) are single-nucleotide polymorphisms mostly restricted to Native Americans. The relatedness of chromosomes defined by these two markers was evaluated by constructing haplotypes with seven microsatellite loci (DYS388 to 394). The microsatellite backgrounds found on the two haplogroups defined by marker DYS199 demonstrate the existence of at least two Amerind founder haplotypes, one of them (carrying allele DYS199 T) largely restricted to Native Americans. The estimated age and distribution of these haplogroups places them among the founders of the New World.
