Search

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.

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.

In the study of the genetic modifications leading populations to adapt to their environment, it is important to distinguish changes resulting in an increase in biological fiteness from those slightly deleterious. Besides that the concept of neutral changes is defined since the ¿Origin of species¿ by Charles Darwin, its relevance to the overall changes defining evolutionary process was considered to be very low, if existent. But, in the late sixties, with the advances of molecular experiments and the first comparative studies in this field, neutral changes were proven to be almost sufficient to explain the amount of changes per generation observed at molecular level. Based on this observation, the first neutral models of molecular evolution were implemented and are, up today, the best statistical alternative to test for any effect of natural selection on biological sequences. In ecology the implementation of neutral models able to explain accurately the distribution and abundances of species in their ecosystems arrived later, and became popular only recently. In both fields molecular evolution and ecology, neutral models are powerful predictors based on a simple process and are great null models against to test more complicated hypotheses considering the effect of natural selection. This thesis analyzes three different biological approximations on complete genomes. Each of which states an explicit neutral model and its respective deviations. The statement of this common denominator along the three principal chapters of this thesis gives explanatory value to the results exposed. Without it, the conclusions are irrelevant. These approximations are: Informational content: This is the most simple analysis that can be done taking genomes as a container of biological information. Under this perspective, the set of nucleotides A, C, G and T are considered the fundamental and independent units of the genomes. Our first objective will be to measure the content of information of the genomes, this along a broad array of species representative of almost all the diversity of life. Ecological: the study of diversity and abundance of families of genetic elements (mostly transposable elements) in eukaryotic genomes has been already studied in a population genetic context, however, these works were hardly able to consider more than a few genetic families in a single genome. Here, taking advantage from statistical tools implemented by ecologists, we will define the neutral components explaining the distribution and abundances of all great families of genetic elements in a large and complete set of eukaryotic genomes. We will see how all eukaryotic chromosomes fit to neutral models. Systemic: this is the last approximation under which we analyzed the genomes. This level of analysis involves group of genes with similar functional characteristics, concretely we will focus in proteins acting together to accomplish a biochemical pathway or a biological function. Close to this level of analysis, several studies tried to discriminate functional enrichments among group of genes under positive selection. However, at genomic level, this kind of analysis was unable to bring significant results. Here, our objective consisted in implementing a new methodology able to distinguish the effect of natural selection directly on different functional categories. In the last chapter of this thesis we will briefly overview different tools derived from our research and that we believe, are of great interest for scientific community. These tools will be described in three sections: 1) Ecolopy where we will present a package able to fit genomic data in different neutral ecological model, 2) ETE-Evol, a plugin for a well known and efficient program for manipulating phylogenetic trees, containing a set of utilities and wrappers to broadly used softwares for the measure of the effect of natural selection on protein-coding genes, and 3) Phylemon2.0, a web server proposing a broad array of tools framed into the phylogenetic, phylogenomics and evolutionary hypothesis testing fields.

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 19-06-08