Geographic patterns of genome admixture in Latin American Mestizos.

The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region.

Y chromosome structural and functional changes in human malignant diseases.

The main Y chromosome abnormalities found in testicular cancer and other malignant diseases are microdeletions, entire chromosome loss and transcription deregulation of several genes mapping in the non-recombinant part of the Y chromosome. Yet, the role of these changes in the origin or evolution of malignancies is uncertain. The Y chromosome has experienced a long and intricate evolutionary history of deleterious, compensatory, and advantageous mutations. It is proposed that the compensatory mechanisms preventing Y decay in cancer cells are no longer working, and that deletions and gene down-expression reflect a very fast process of Y attrition. From this perspective, Y chromosome aberrations, mutations and unbalanced gene expression very likely play no role in the etiology of cell transformation, although in some forms of cancer, Y abnormalities may influence tumor progression.

Brief communication: Restricted geographic distribution for Y-Q* paragroup in South America.

We analyzed 21 paragroup Q* Y chromosomes from South American aboriginal and urban populations. Our aims were to evaluate the phylogenetic status, geographic distribution, and genetic diversity in these groups of chromosomes and compare the degree of genetic variation in relation to Q1a3a haplotypes. All Q* chromosomes from our series and five samples from North American Q* presented the derivate state for M346, that is present upstream to M3, and determined Q1a3* paragroup. We found a restrictive geographic distribution and low frequency of Q1a3* in South America. We assumed that this low frequency could be reflecting extreme drift effects. However, several estimates of gene diversity do not support the existence of a severe bottleneck. The mean haplotype diversity expected was similar to that for South American Q1a3* and Q1a3a (0.478 and 0.501, respectively). The analysis of previous reports from other research groups and this study shows the highest frequencies of Q* for the West Corner and the Grand Chaco regions of South America. At present, there is no information on whether the phylogenetic status of Q* paragoup described in previous reports is similar to that of Q1a3* paragroup though our results support this possibility.

Y chromosome instability in testicular cancer.

Approximately 15-25% of male infertility cases carry extensive azoospermic factor (AZF) deletions. Moreover, about 80% of Finnish testicular germ cell tumors (TGCT) and about 23-25% of TGCTs from other geographic regions carry short and interstitial AZF deletions. In infertility cases the AZF deficiency occurs in the germ cells of the proband father giving rise to mosaic sperm populations comprising non-deleted and deleted sperms. Fertilization of an oocyte by a Y deleted sperm will give rise to an AZF-deleted and infertile F1 male. In TGCTs the AZF deletions take place in the initial stages of embryogenesis producing individuals that are a mosaic of Y deleted and non-deleted cell lineages. Carcinoma in situ (CIS) is a premalignant lesion that some believe may develop in gonads of male embryos before the ninth week of age due to transformation of a totipotent primordial germ cell. If the transformed cell carries AZF deletions the resultant CIS will also have Y deletions. CIS will differentiate into seminoma or into embryonal carcinoma and non-seminomas in about 1 x 10(-3) of the young adults carrying premalignant CIS outgrowths; if the CIS lesion has AZF deletions the derived forms of testicular cancer will also exhibit these deletions. AZF deletions play no role in the development of testicular cancers. On the other hand, they are a marker of Y chromosome instability and eventually of a more generalized pattern of genome instability associated with the appearance of TGCT. Genetic factors such as malfunction of metabolizing genes, DNA repairing genes, Y-linked or X-linked genes have been considered as possible causes of AZF deletions in testicular cancer. Yet, the exact identification of the genes involved remains elusive. AZF deletions have also been identified in non-Hodgkin lymphomas and in colorectal cancers, two forms of malignancy that have been found to be associated with TGCTs.

Mosaic AZF deletions and susceptibility to testicular tumors.

We tested for azoospermia factor (AZF) deletions 17 loci corresponding to AZF subintervals a-d in 17 cases of testicular tumors occurring in Finns. While DNA samples from 48 CEPH and 32 Finnish males showed no deletions, patients with testicular cancer displayed AZF deletion mosaicisms in various non-tumor tissues (13 cases) and specific deletion haplotypes in tumor tissues (10 cases). Two of the cases with AZF deletions were testicular non-Hodgkin lymphomas indicating that Y-microdeletions appear also in malignancies other than seminoma and non-seminoma tumors. In good agreement with this assumption, we detected one AZF deletion in normal cells from 1 of 5 HNPCC cases, heterozygous for an MLH1 mutation. We propose that AZF deletions occur in early embryogenesis due to mutations of TSPY, mismatch repair (MMR), or X-specific genes. Since fathers of testicular, tumor cases did not exhibit AZF deletions, we assumed they were not carriers of the mutation inducing AZF deletion-mosaicisms. Therefore, tumor cases should have received the MMR gene or X mutations via the maternal lineage, or for the case of TSPY and MMR genes via a sperm carrying a mutation occurred in the paternal germ-cell line. We consider AZF microdeletions in non-tumor cells to be part of a broader pattern of chromosome instability producing susceptibility to testicular tumors. Clonal transformation and expansion of one of these tumor-susceptible cell lineages give rise to testicular tumors showing genome anomalies characteristic of testicular cancers (i12p, LOH and genetic imbalance for various autosomal regions, Y- and autosomal MSI, specific AZF deletion haplotypes).

Prevalence of dopamine and 5HT2C receptor polymorphisms in Amerindians and in an urban population from Argentina.

We report on the frequency of DRD2A1, DRD3A1, DRD4/2R-10R, and 5HT2CA1 variants in the population of the city of La Plata (Argentina) and in Amerindians from Argentina, Paraguay, and Chile. In the Amerindian sample, the prevalence of DRD2A1 and DRD4/4R variants were, respectively, significantly lower and significantly higher than frequencies reported in other Native Americans. Comparison of average allele and genotype frequencies between La Plata and Amerindians showed significant differences for 5HT2CA1 and DRD4. As La Plata is a population with predominant European and Amerindian components, we used mtDNA and Y-specific markers to subdivide the La Plata sample into two strata: Amerindian La Plata and non-Amerindian La Plata. Significant variations between the two strata were detected for DRD2A1, DRD3A1, and DRD4/4R allele frequencies, and for the homozygous DRD4/4R/4R genotype. Several controversial reports suggest a possible association between a variant of DRD and/or 5HT2C receptor genes and the clinical expression of several psychiatric disorders. We suggest that ethnic variations in the prevalence of the allelic forms of these genes may be a confounding factor to be taken into consideration in studies of association between dopaminergic and serotonergic receptor genotypes and neuropsychiatric and mood disorders.

Characterization of admixture in an urban sample from Buenos Aires, Argentina, using uniparentally and biparentally inherited genetic markers.

In this study we analyzed a sample of the urban population of La Plata, Argentina, using 17 mtDNA haplogroups, the DYS 199 Y-chromosome polymorphism, and 5 autosomal population-associated alleles (PAAs). The contribution of native American maternal lineages to the population of La Plata was estimated as 45.6%, whereas the paternal contribution was much lower (10.6%), clearly indicating directional mating. Regarding autosomal evidence of admixture, the relative European, native American, and West African genetic contributions to the gene pool of La Plata were estimated to be 67.55% (+/-2.7), 25.9% (+/-4.3), and 6.5% (+/-6.4), respectively. When admixture was calculated at the individual level, we found a low correlation between the ancestral contribution estimated with uniparental lineages and autosomal markers. Most of the individuals from La Plata with a native American mtDNA haplogroup or the DYS199*T native American allele show a genetic contribution at the autosomal level that can be traced primarily to Europe. The results of this study emphasize the need to use both uniparentally and biparentally inherited genetic markers to understand the history of admixed populations.

Unequal contributions of male and female gene pools from parental populations in the African descendants of the city of Melo, Uruguay.

In admixed populations, genetic contributions from males and females of specific parental populations can be of different proportions due to past directional mating during the process of genetic admixture. In this research paper, we provide evidence of such male- and female-specific differential admixture components of African, European, and American Indian origin in an admixed population from the city of Melo, in the northeastern region of Uruguay. From data on 11 autosomal markers from a sample of 41 individuals of mixed African descent, we estimated 47% African, 38% European, and 15% Amerindian contributions. In contrast, 6 mtDNA site-specific polymorphic markers showed that the mtDNA genome of these individuals was 52% African, 19% European, and 29% Amerindian, while from 3 Y-specific polymorphic sites, we estimated 30% African, 64% European, and 6% Amerindian contributions. We argue that this heterogeneity of admixture estimates results from disproportionate unions of European males with African and American Indian females from which this mixed African population was formed. Also, we argue that the asymmetry of the admixture estimates from the three sets of markers (autosomal, mtDNA, and Y-linked) is a result of the changes in the direction of mating during the history of the population. Implications of such evidence of directional mating are discussed, indicating the need of further demographic data for a quantitative assessment of the impact of directional mating on genetic structure of admixed populations.

De una terapéutica de enfermedad a una terapéutica personalizada / From a disease therapeutic to a personalized therapeutic

La amplia decodificación del genoma humano y la simplificación de las técnicas empleadas para detectar polimorfismos y expresión génica han acelerado el desarrollo de la Medicina Predictiva, nueva rama de la Medicina, que permite evaluar el riesgo de padecer enfermedades con componente genético desde la vida prenatal. La Terapéutica Individual o Personalizada es un complemento de la Medicina Predictiva y también deriva del Proyecto Genoma Humano. En la Terapéutica Generalizada que se utiliza actualmente, los medicamentos son diseñados para controlar, mejorar o curar una enfermedad. Alternativamente, la principal finalidad de la Terapéutica Individual es producir medicamentos especialmente diseñados para el enfermo con el propósito de obtener una mejor respuesta terapéutica y evitar los efectos colaterales de la droga. La Farmacogenética y la Farmacogenómica son las dos disciplinas que generan la información necesaria para el diseño de la droga personalizada. La primera disciplina analiza el genotipo individual que metaboliza la droga y predice la estructura molecular de la droga que mejor se adapta al metabolismo del individuo. La Farmacogenómica estudia las mutaciones genéticas y las variaciones en la expresión génica involucradas en la forma clínica de las enfermedades con el fin de producir compuestos químicos específicos para el genotipo patogénico y de transcripción del paciente. La Terapéutica Individual ya ha producido cambios estructurales en el campo de la investigación farmacológica y en las estrategias comerciales de los laboratorios productores de drogas. Se espera que origine modificaciones marcadas en la práctica de la medicina clínica durante el transcurso de esta década.