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We are at the dawn of the efforts to describe and understand the origins of genetic diversity in Argentina from high-throughput data. This knowledge is a primary step in the intent of deciphering the specific genetic bases of diseases and drug response in the country. Similarly to other populations across the Americas, genetic ancestry in Argentinean populations traces back into African, European and Native American ancestors, reflecting a complex demographic history with multiple migration and admixture events in pre- and post-colonial times. However, little is known about the sub-continental origins of these three main ancestries. We present new high-throughput genotyping data for 87 admixed individuals across Argentina. This data was combined to previously published data for admixed individuals in the region and then compared to different reference panels specifically built to run population structure analyses at a sub-continental level. Concerning the European and African ancestries, we confirmed previous results about their main origins, and we provide new insights into the presence of other origins that reflect historical records. As for the Native American ancestry, leveraging genotype data for archaeological samples in the region in order to gain temporal depth in our analyses, we could identify four Native American components segregating in modern Argentinean populations. Three of them are also found in modern South American populations and are specifically represented in Central Chile/Patagonia, Lowlands and Central Andes geographic areas. The fourth one may be specific to the Central Western region of Argentina. Identifying such component has not been straightforward since it is not well represented in any genomic data from the literature. Altogether, we provide useful insights into the multiple population groups from different continents that have contributed to present-days genetic diversity in Argentina. We encourage the generation of massive genotype data locally to further describe the genetic structure in Argentina. Author Summary The human genetic diversity in Argentina reflects demographic mechanisms during which the European colonists invaded a territory where Native American populations were settled. During colonial period, the slave trade also prompted many African people to move to Argentina. Little is known about the origins of the Native American and African components in Argentinean populations nowadays. Genotyping data for 87 admixed individuals throughout Argentina was generated and data from the literature was re-analyzed to shed light on this question. We confirmed that most of the European genetic ancestry comes from the South, although several individuals are related to Northern Europeans. We found that African origins in Argentina trace back from different regions. As for the Native American ancestry, we identified that it can be divided into four main components that correspond to Central Chile/Patagonia, Lowlands, Central Andes and Central Western region of Argentina. In order to understand the specificity of the genetic diversity in Argentina, we should not rely on knowledge generated in other populations. Instead, more effort is required to generate specific massive genomic knowledge at the local level.

Artigo sobre as representações do campesinato que o cinema documental da primeira etapa da Revolução construiu, através da análise de uma série de filmes, organizada em eixos temáticos: Esta tierra nuestra (1959), de Tomás Gutiérrez Alea, ¿Por qué nació el Ejército Rebelde? (1960), de José Massip e Tierra olvidada (1960), de Oscar Torres. A análise permitiu identificar a representação de dois campos opostos que delimitam um “eles-passado opressor” de um “nós-atualidade de redenção”., Artículo sobre las representaciones que el cine documental de la primera etapa de la Revolución hizo del campesinado a través del análisis de una serie de films organizada en ejes temáticos: Esta tierra nuestra (1959), de Tomás Gutiérrez Alea, ¿Por qué nació el Ejército Rebelde? (1960), de José Massip y Tierra olvidada (1960), de Oscar Torres. El análisis permitió identificar la representación de dos campos opuestos que delimitan un “ellos-pasado opresivo” de un “nosotros-hoy de redención”., The article is about the representations that the documentary film of the first stage of the Revolution made of the peasantry through the analysis of a series of films organized in thematic axes: Esta tierra nuestra (1959), by Tomás Gutiérrez Alea, ¿Por qué nació el Ejército Rebelde? (1960), by José Massip and Tierra olvidada (1960), by Oscar Torres. The analysis allowed to identify the representation of two opposing fields that delimit an “them-oppressive past” from a “we-today’s redemption”., Article traite des représentations des paysans dans le cinéma documentaire de la première étape de la Révolution, à travers l’analyse d’une série de films organisés selon des axes thématiques : Esta tierra nuestra (1959), de Tomás Gutiérrez Alea, ¿Por qué nació el Ejército Rebelde? (1960), de José Massip et Tierra olvidada (1960), d’Óscar Torres. Les analyses nous ont permis d’identifier la représentation de deux champs opposés : d’une part, « ils – passé oppressif » et de l’autre « nous – présent de rédemption ».

Non‐alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep‐coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype‐oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein‐level impact of the observed mutations. To determine whether the observed changes are tissue‐specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase‐γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28‐fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4‐fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the ‘missing heritability’ of NAFLD. Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Scian, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina Fil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina Fil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: San Martino, Julio. Hospital Diego Thompson; Argentina Fil: Castaño, Gustavo Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina

Supplemental Digital Content is available in the text, The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n = 90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1–3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R = 0.50, P = 0.000382) and PPARGC1A-mRNA levels (R = −0.57, P = 0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4 ± 0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8 ± 0.8), means ± standard deviation, P = 0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10–1.97; P = 0.005). The p.Ile1762Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and transcriptional levels, and Type 2 diabetes. Our results suggest that 5-hmC might be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and PPARGC1A expression. Genetic diversity at TET loci suggests an “epigenetic” regulation of programmed liver-cell death and a TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program.

Trabajo presentado en la Annual Meeting of the Society for Molecular Biology & Evolution (SMBE 2012), celebrada en Dublín del 23 al 26 de junio de 2012., The signature of Natural Selection may be detected not only upon coding regions of individual genes, but also in related functional elements (e.g. regulatory regions or introns) or multiple genes (e.g. functional modules or metabolic pathways). Indeed, genome-wide comparative genomics, using alignments between reference assemblies has allowed the identification of regulatory elements and functional modules bearing the signatures of adaptation and/or purifying selection in the lineages of various species, particularly humans and great apes. In the present study, we took a two-pronged approach: First, we focused on the coding regions of genes in four functional modules reported to be enriched with genes presenting signatures of different type s of selection in the human and chimpanzee lineages. These modules are complement and coagulation ca scade (with genes under positive selection), regulation of actin cytoskeleton (under purifying selection) and two KEGG pathways of common human neurodegenerative diseases, Alzheimer’s and Parkinson, with no clear trends of selection. Second, we studied regulatory regions aroun d these genes, including introns, UTRs, miRNA, lncRNA, promoters (5kb) and trailers (5kb). We have performed genomic capture and sequencing for the abov e target regions (totalling ~450 genes) in 20 chimpanzee individuals (Pan troglodytes troglodytes) so that, after SNP calling, we are able to study the signature of selection using both polymorphism and divergence da ta. By means of a combination of tests (frequency spectra and variations of the McD onald-Kreitman test) we are able to study the ralationship between ancestral and recent selective patterns and to dissect whether selection acted preferentially in conding or non-coding regions of the pathways under study.

We have developed a web tool, PupaSuite, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect, specifically oriented to help in the design of large-scale genotyping projects. PupaSuite uses a collection of data on SNPs from heterogeneous sources and a large number of pre-calculated predictions to offer a flexible and intuitive interface for selecting an optimal set of SNPs. It improves the functionality of PupaSNP and PupasView programs and implements new facilities such as the analysis of user's data to derive haplotypes with functional information. A new estimator of putative effect of polymorphisms has been included that uses evolutionary information. Also SNPeffect database predictions have been included. The PupaSuite web interface is accessible through http://pupasuite.bioinfo.cipf.es and through http://www.pupasnp.org.