Reconstructing the population genetic history of the Caribbean.

The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, we investigate the population genetic history of this region by characterizing patterns of genome-wide variation among 330 individuals from three of the Greater Antilles (Cuba, Puerto Rico, Hispaniola), two mainland (Honduras, Colombia), and three Native South American (Yukpa, Bari, and Warao) populations. We combine these data with a unique database of genomic variation in over 3,000 individuals from diverse European, African, and Native American populations. We use local ancestry inference and tract length distributions to test different demographic scenarios for the pre- and post-colonial history of the region. We develop a novel ancestry-specific PCA (ASPCA) method to reconstruct the sub-continental origin of Native American, European, and African haplotypes from admixed genomes. We find that the most likely source of the indigenous ancestry in Caribbean islanders is a Native South American component shared among inland Amazonian tribes, Central America, and the Yucatan peninsula, suggesting extensive gene flow across the Caribbean in pre-Columbian times. We find evidence of two pulses of African migration. The first pulse--which today is reflected by shorter, older ancestry tracts--consists of a genetic component more similar to coastal West African regions involved in early stages of the trans-Atlantic slave trade. The second pulse--reflected by longer, younger tracts--is more similar to present-day West-Central African populations, supporting historical records of later transatlantic deportation. Surprisingly, we also identify a Latino-specific European component that has significantly diverged from its parental Iberian source populations, presumably as a result of small European founder population size. We demonstrate that the ancestral components in admixed genomes can be traced back to distinct sub-continental source populations with far greater resolution than previously thought, even when limited pre-Columbian Caribbean haplotypes have survived.

Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans.

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands.

Natural killer (NK) cells contribute to immunity and reproduction. Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.

Genetic polymorphisms at four STR loci from the HLA region in a Venezuelan population.

POPULATIONS: Whole blood samples from 74 unrelated healthy individuals were collected. The donors' sample included Venezuelan mestizos from various regions of the country, but mostly from the resident population of Caracas City. A Venezuelan mestizo is the offspring of a mating between a native Venezuelan and a person born in Europe, mainly in Spain.

HLA class II and class I polymorphism in Venezuelan patients with myasthenia gravis.

Oligotyping performed among ethnically mixed Venezuelan patients with myasthenia gravis (MG) and controls has revealed positive associations of HLA class I A*31, B*08, B*39, B*40, C*15, C*17, and class II DRB1*09 and negative associations of DQB1*06 and DQA1*02 with the disease. Sequential removal of human leukocyte antigen B (HLA-B) alleles when relative predispositional effects (RPEs) were looked for demonstrated that B*08 is the allele group with the largest contribution in the overall MG patients followed by B*39 and B*40. Several specificities (A*31, B*08, C*17, DRB1*03, DQA1*05, and DQB1*02) indicated increased frequencies among patients with thymic hyperplasia versus patients without hyperplasia or controls. Tests to identify alleles with the strongest association to MG in our patients detected DRB1*13 and B*38 as possible predisposing secondarily associated alleles in patients with hyperplasia. The associations observed disappear after Bonferoni correction of probability values and have been described in patients of Caucasian and/or Oriental ethnic background. Thus, our results reflect the heterogeneity of our population and of the patients tested and suggest a limited influence of several HLA genes in this heterogeneous disease or that these might be only markers of nearby non-HLA genes responsible for the susceptibility or resistance effect.

HLA-DP polymorphism in Venezuelan Amerindians.

Three different Venezuelan Amerindian tribes were studied for human leukocyte antigen (HLA)-DPA1 and DPB1 allelic variability using polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) and sequence-based typing in a selected group of samples. These tribes are geographically (two from the Perija Mountain range and one from the Orinoco Delta) and linguistically distinct: the Bari (from Campo Rosario and Saymaidoyi villages) and the Warao have been classified within the Chibcha linguistic family, whereas the Yucpa (from the Aroy, Marewa, and Peraya villages) are Carib speaking. Venezuelan Indians, like other Native American tribes, show a markedly reduced number of different HLA-DP alleles (range, 2-7) and haplotypes (range, 4-11) in comparison with neighboring Venezuelan mestizo and other non-Indian populations. Some HLA-DPB1 (*0402 and *1401) alleles characteristic for all Amerindian tribes are present also in these populations. Despite general similarities, each tribe and, in some cases, some subtribes show their own pattern of allele and haplotype distribution apparently more as a result of linguistic than to geographic variation.

Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases.

Cell-mediated immunity requires costimulatory activity to initiate or inhibit antigen-specific T-cell responses. CTLA-4 is an inhibitory receptor expressed by activated and regulatory T cells. The single nucleotide polymorphism (SNP) +49 A/G of the CTLA-4 gene alters intracellular distribution of CTLA-4, interleukin-2 production, and, as a consequence, T-cell proliferation. The aim of this study was to analyze the only coding SNP CTLA-4 +49 A/G polymorphism in patients with either infectious (Chagas's, Dengue, and American cutaneous leishmaniasis) or autoimmune diseases (myasthenia gravis, pemphigus, and psoriasis). No statistically significant differences were reported when all patients of each disease group were compared with healthy individuals. However, the +49 G/G genotype was moderately increased in pemphigus and myasthenia gravis. Patients with diffuse cutaneous leishmaniasis (DCL) exhibited an increased frequency of the A/G +49 genotype compared with patients with localized cutaneous leishmaniasis (LCL; p = 0.009; odds ratio [OR] = 4.25; 95% confidence interval [CI] = 1.245-14.501) and intermediate cutaneous leishmaniasis (ICL; p = 0.027; OR = 4.44; 95% CI = 1.273-15.516), indicating that the heterozygous genotype, associated with overactivation of T-cell proliferation, could confer susceptibility to the development of the more severe clinical form of cutaneous leishmaniasis. The A/A +49 genotype was increased in LCL patients compared with DCL patients (p = 0.019; OR = 0.25; 95% CI = 0.067-0.953), indicating that this genotype, which has been associated with normal proliferation of T cells, could confer protection to the development of DCL. The results indicate that the polymorphism of CTLA-4 is an important genetic factor associated with risk or protection for the development of diffuse cutaneous leishmaniasis and has influence in the pathogenesis of autoimmune diseases. However, other closely linked candidate genes in linkage disequilibrium with CTLA4, such as CD28 and ICOS, could be associated with the development of autoimmune and infectious disease.

Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes.

Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric "half" was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family.

High KIR diversity in Amerindians is maintained using few gene-content haplotypes.

Interaction between killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands influences the innate and adaptive immune response to infection. The KIR family varies in gene content and allelic polymorphism, thereby, distinguishing individuals and populations. KIR gene content was determined for 230 individuals from three Amerindian tribes from Venezuela: the Yucpa, Bari and Warao. Gene-content haplotypes could be assigned to 212 individuals (92%) because only five different haplotypes were present-group A and four group B. Six different haplotype combinations accounted for >80% of individuals. Each tribe has distinctive genotype frequencies. Despite few haplotypes, all 14 KIR genes are at high frequency in the three tribes, with the exception of 2DS3. Each population has an even frequency of group A and B haplotypes. Allele-level analysis of 3DL1/S1 distinguished five group A haplotypes and six group B haplotypes. The high frequency and divergence of the KIR haplotypes in the Amerindian tribes provide greater KIR diversity than is present in many larger populations. An extreme case being the Yucpa, for whom two gene-content haplotypes account for >90% of the population. These comprise the group A haplotype and a group B haplotype containing all the KIR genes, except 2DS3, that typify the group B haplotypes. Here is clear evidence for balancing selection on the KIR system and the biological importance of both A and B haplotypes for the survival of human populations.

Y-chromosome evidence for differing ancient demographic histories in the Americas.

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.

HLA Alleles and Dengue Virus Infection in Venezuelan Patients: A Preliminary Study

En áreas endémicas, una pequeña proporción de individuos infectados con el virus dengue desarrollan la fiebre hemorrágica del dengue (FHD),sugiriendo la existencia de factores de resistencia que pudiesen estar jugando un papel importante en el huésped. Este trabajo describe la frecuencia dealelos HLA clase I y II en pacientes con dengue y su relación con las manifestaciones clínicas de la enfermedad. El análisis de la frecuencia de especificidades HLA en los pacientes con dengue mostró frecuencias disminuidas de los alelos B*15, B*49, DRB1*02 y DRB1*03 y frecuencias incrementadas de los alelos B*57 y DRB1*15 comparado con los controles. Cuando lospacientes fueron agrupados y comparados de acuerdo a la severidad de laenfermedad, se observó una susceptibilidad incrementada a la fiebre del dengue clásico (FD) en pacientes con B*57, una susceptibilidad disminuida aldesarrollo de la FHD en pacientes A*03 y una susceptibilidad incrementada al desarrollo de la FHD en pacientes con B*40. Aunque las asociacionesobservadas proceden de un estudio poblacional caso-control relativamentepequeño y que después de la corrección por múltiples comparaciones se mantuvo únicamente la asociación con DRB1*15, los datos confirman que posiblemente los alelos HLA pueden jugar un papel en la susceptibilidad y/oresistencia a la infección por virus dengue y al desarrollo de la FHD (AU)

In endemic areas, a small proportion of individuals infected with dengue virus develop dengue hemorrhagic fever (DHF) suggesting that theremay be host specific resistance factors playing an important role. Thiswork describes the frequency of HLA class I and class II alleles in patientswith dengue and the relationship with the clinical manifestations of thedisease. The analysis of the frequency of HLA specificities in the dengue patients revealed reduced frequencies of B*15, B*49, DRB1*02 andDRB1*03 and increased frequencies of B*57 and DRB1*15 compared withcontrols. When the patients were grouped and compared according todisease severity, an association with enhanced susceptibility to denguefever (DF) in patients with B*57, an association with reduced susceptibility to DHF in patients with A*03, and an association with enhanced susceptibility to DHF in patients with B*40 was observed. Although the associations revealed in this study come from a very small case-control population and that after correction for multiple testing only the associationwith DRB1*15 is maintained, the data suggest that the HLA alleles canpossibly play a role in the susceptibility and/or resistance to dengue virusinfection and development of DHF (AU)

Antigeno HLA, anticuerpos anti-islotes, anti-insulinicos y anti-virales en niños venezolanos con diabetes mellitus tipo I recien diagnosticados / HLA antigen, anti-islets antibodies, anti-insulin and anti-virals in venezuelan children with newly diagnosed diabetes mellitus type I

En Venezuela no han sido reportados previamente los marcadores inmunológicos y genéticos en niños con Diabetes Mellitus tipo I durante el debut de la enfermedad. Nosotros tuvimos la oportunidad de estudiar a 27 niños recién diagnosticados con Diabetes Mellitus tipo I, con una edad promedio de 9.4+/- 3.2 años (Rango 1.3-14.9), 11 hembras y 16 varones. Ochenta y nueve por ciento tenían una historia familiar de Diabetes Mellitus (26 por ciento tipo I) 56.7 por ciento habían presentado una infección respiratoria superior previo al diagnóstico y 12.7 por ciento habían padecido de parotiditis o varicela. El pico de incidencia de la enfermedad fue durante los meses de febrero y octubre. Ochenta y nueve por ciento (24 pacientes) tenían HLD-DR3 y/o DR4 versus 37 por ciento observado en la población venezolana general; 86.1 por ciento (23 pacientes) fueron HLA-DQW2 y/o HLA DQS. Anticuerpos anti-islotes (ICA) fueron positivos en 37 por ciento (10 pacientes) y 4 de los mismos presentaron la prueba de fijación de complemento (CF/ICA) positiva. Tres pacientes presentaron anticuerpos anti-insulinicos. Solo 1 de 9 hermanos HLA idénticos al propósito presentó ICA positivo y CF/ICA positivo, y ésta niña desarrolló diabetes tipo I posteriormente. Se detectaron títulos de anticuerpos anti-virales significativamente positivos para citomegalovirus en 11 pacientes (40.7 por ciento); y títulos positivos para sarampión, parotiditis, herpes y varicela en un menor número de casos. No encontramos serotipos positivos a Coxsackie y Rubéola. Estos resultados confirman que la mayoría de nuestros diebéticos tipo I tiene HLA-DR3 oDR4 y que los fenotipos heterozigotos DR3/DR4 están significativamente aumentados en esta población. También podemos concluir que los haplotipos DR3DQW2 y DR4DQWS8 están asociados con un alto riesgo a desarrollar Diabetes Mellitus tipo I en nuestra población venezolana de origen étnico mixto

Marcadores genéticos y estudios epidemiológicos en la diabetes insulino dependiente en niños venezolanos / Immunogenetic markers and epidemiologics study in diabetes mellitus with insulin dependent in children venezolans

Los avances en la genética y epidemiología de la diabetes mellitus tipo I, de etiología auto-inmune y el descubrimiento de marcadores inmuno-genéticos están dilucidando la fisiología del texto proceso de destrucción de las células beta del páncreas en la fase pre-diabética que finalmente conducen a la aparición de la diabetes en su forma clínica clásica. Sólo ha sido en los últimos años que estas nuevas herramientas diagnósticas han ayudado a identificar a los individuos de alto riesgo susceptibles de desarrollar diabetes en las diferentes poblaciones mundiales, con posibilidades de tratamiento preventivos en el futuro. Nosotros, en Venezuela, hemos iniciado el estudio de nuestra población pediátrica con diabetes mellitus tipo I, encontrando que la mayoría tienen el haplotipo HLA-DR3 o DR4, en particular la asociación de HLA-DR3 con DQW2 y HLA-DR4 con DQW8. También los estudios de ADN reflejaron una meyor susceptibilidad con la ausencia de ácido aspártico en la posición 57 en la cadena de DQ beta y con la presencia de arginina en la posición 52 de la cadena DQ alfa. El marcador inmunológico más importante fue la presencia de anticuerpos anti-pancreáticos (PICA) en un 56 por ciento de los pacientes, mientras anticuerpos anti insulina (AAI) se vieron en un 8 por ciento. Sólo 11 por ciento de los familiares de 1er grado tenían antecedentes de diabetes tipo I, más de la mitad presentó alguna virosis previas al comienzo y los picos más altos de incidencia fueron en los meses de febrero a marzo y agosto a octubre