Detecting signals of selection in the genomes of Native Americans and admixed Latin Americans

The peopling of the Americas represents the last major expansion of human populations worldwide. As the first humans moved into the continent they were exposed to new environments requiring them to adapt. The subsequent colonization of the continent by Europeans, along with the African slave trade, involved a major admixture process that was accompanied by new selective pressures, most notably exposure to new pathogens. Applying current and novel methods to genome-wide SNP data of Native and admixed Latin Americans, this PhD thesis provides an analysis of the adaptive history in the Americas. I show that prior to the European contact, candidate regions of selection in Native Americans include genes associated with metabolic traits, highlighting a possible adaptation to dietary changes. Using novel and existing methods to detect selection post-admixture, I show that genes related to immune response were probably under selection in admixed Latin Americans. As an example on the evolution of an adaptive trait, I also conduct a Genome Wide Association Study on a sample of over 6,000 Latin Americans for skin, eye and hair pigmentation. I report eighteen independent genome-wide significant signals of association, including five novel variants. One of the novel variants associated to skin pigmentation is common in East Asians and Native Americans, but is almost absent everywhere else in the world. I show that this variant was selected in East Asians after their split from Europeans, and likely carried by the first Americans to the Americas

Biominerals formed by DNA and calcium oxalate or hydroxyapatite: a comparative study

Biominerals formed by DNA and calcium oxalate (CaOx) or hydroxyapatite (HAp), the most important and stable phase of calcium phosphate) have been examined and compared using a synergistic combination of computer simulation and experimental studies. The interest of this comparison stems from the medical observation that HAp- and CaOx-based microcalcifications are frequently observed in breast cancer tissues, and some of their features are used as part of the diagnosis. Molecular dynamics simulations show that (1) the DNA double helix remains stable when it is adsorbed onto the most stable facet of HAp, whereas it undergoes significant structural distortions when it is adsorbed onto CaOx; (2) DNA acts as a template for the nucleation and growth of HAp but not for the mineralization of CaOx; and (3) the DNA double helix remains stable when it is encapsulated inside HAp nanopores, but it becomes destabilized when the encapsulation occurs into CaOx nanopores. Furthermore, CaOx and HAp minerals containing DNA molecules inside and/or adsorbed on the surface have been prepared in the lab by mixing solutions containing the corresponding ions with fish sperm DNA. Characterization of the formed minerals, which has been focused on the identification of DNA using UV–vis spectroscopy, indicates that the tendency to adsorb and, especially, encapsulate DNA is much smaller for CaOx than for HAp, which is in perfect agreement with results from molecular dynamics simulations. Finally, quantum mechanical calculations have been performed to rationalize these results in terms of molecular interactions, evidencing the high affinity of Ca2+ toward oxalate anions in an aqueous environment.Postprint (author's final draft

Dissolving hydroxyolite: a DNA molecule into its hydroxyapatite mold

In spite of the clinical importance of hydroxyapatite (HAp), the mechanism that controls its dissolution in acidic environments remains unclear. Knowledge of such a process is highly desirable to provide better understanding of different pathologies, as for example osteoporosis, and of the HAp potential as vehicle for gene delivery to replace damaged DNA. In this work, the mechanism of dissolution in acid conditions of HAp nanoparticles encapsulating double-stranded DNA has been investigated at the atomistic level using computer simulations. For this purpose, four consecutive (multi-step) molecular dynamics simulations, involving different temperatures and proton transfer processes, have been carried out. Results are consistent with a polynuclear decalcification mechanism in which proton transfer processes, from the surface to the internal regions of the particle, play a crucial role. In addition, the DNA remains protected by the mineral mold and transferred proton from both temperature and chemicals. These results, which indicate that biomineralization imparts very effective protection to DNA, also have important implications in other biomedical fields, as for example in the design of artificial bones or in the fight against osteoporosis by promoting the fixation of Ca2+ ions.Peer ReviewedPostprint (published version

Clinicopathological and prognostic characterization of oral lichenoid disease and its main subtypes : a series of 384 cases

To clinicopathologically characterize the diagnosis of oral lichenoid disease (OLD) and its main subtypes: oral lichen planus (OLP) and oral lichenoid lesion (OLL), in order to correctly asses their prognosis. Ambispective cohort study of 384 patients with diagnosis of OLD, based on pre-established clinical and histopathological criteria. We have analysed 272 (70.8%) women and 112 (29.2%), whose mean age was 57.1+/-11.8 years (range 21-90); minimum follow-up time was 36 months. A specific protocol was designed for this study, where we gathered the data of each patient, including malignant transformation. OLP was diagnosed in 229 cases (77.9%) and OLL in 85 (22.1%). Tobacco consumption was found in 20.3% of the patients and alcohol intake in 41.1%. Liver pathology was present in 10.7% of the cases, thyroid pathology in 11.5%, arterial hypertension in 15.6%, diabetes mellitus in 7.6%, psycho-emotional disorders in 33.3%, skin involvement in 12% and genital involvement in 4.9%. Ten patients (2.6%) developed an oral squamous cell carcinoma, 5 (1.7%) with OLP and 5 (5.9%) with OLL. OLD is a potentially malignant disorder of the oral mucosa which has to be correctly diagnosed as either OLP or OLL, since the risk of malignancy of these subtypes is significantly different

Mineralization of DNA into nanoparticles of hydroxyapatite

Encapsulation of DNA into hydroxyapatite (HAp) has been investigated using a rational approach that involves computer simulation and experimental techniques. The temporal evolution of the radial distribution functions derived from atomistic molecular dynamics simulations of Ca2+, PO4 3− and OH−-containing aqueous solutions in the presence and absence of B-DNA has been used to conclude that the backbone of the double helix acts as a template for HAp growth. More specifically, results reveal the formation of calcium phosphate clusters at the first stages of the simulations, which subsequently reorganize to nucleate HAp. This effect is produced in the absence and, especially, presence, of DNA indicating that the biomolecules do not inhibit but even promote mineral growth. Furthermore, computer simulations suggest that the diffusion of the OH− anions through the inorganic solution is the limiting step for the nucleation of the biomineral. Nanocapsules and crystalline nanorods of HAp containing DNA molecules inside have been prepared by mixing solutions containing Ca2+ and PO4 3− ions with fish sperm DNA at high pH. The dimensions and morphology of such nanostructures have been examined by transmission electron microscopy, while the characterization of the biomineral has been focused on the identification of DNA inside HAp using infrared, X-ray photoelectron and UV-vis spectroscopies, as well as gel electrophoresis. The biominerals reported in this work are important for biomedical applications requiring the protection of DNA from aggressive environmental conditionsPostprint (published version

A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation

We report a genome-wide association scan for facial features in B6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P valueso5 10 8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of B3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar funtion

Genetic legacy of state centralization in the Kuba Kingdom of the Democratic Republic of the Congo

Few phenomena have had as profound or long-lasting consequences in human history as the emergence of large-scale centralized states in the place of smaller scale and more local societies. This study examines a fundamental, and yet unexplored, consequence of state formation: its genetic legacy. We studied the genetic impact of state centralization during the formation of the eminent precolonial Kuba Kingdom of the Democratic Republic of the Congo (DRC) in the 17th century. We analyzed genome-wide data from over 690 individuals sampled from 27 different ethnic groups from the Kasai Central Province of the DRC. By comparing genetic patterns in the present-day Kuba, whose ancestors were part of the Kuba Kingdom, with those in neighboring non-Kuba groups, we show that the Kuba today are more genetically diverse and more similar to other groups in the region than expected, consistent with the historical unification of distinct subgroups during state centralization. We also found evidence of genetic mixing dating to the time of the Kingdom at its most prominent. Using this unique dataset, we characterize the genetic history of the Kasai Central Province and describe the historic late wave of migrations into the region that contributed to a Bantu-like ancestry component found across large parts of Africa today. Taken together, we show the power of genetics to evidence events of sociopolitical importance and highlight how DNA can be used to better understand the behaviors of both people and institutions in the past

Fully automatic landmarking of 2D photographs identifies novel genetic loci influencing facial features

We report a genome-wide association study for facial features in > 6,000 Latin Americans. We placed 106 landmarks on 2D frontal photographs using the cloud service platform Face++. After Procrustes superposition, genome-wide association testing was performed for 301 inter-landmark distances. We detected nominally significant association (P-value < 5×10− 8) for 42 genome regions. Of these, 9 regions have been previously reported in GWAS of facial features. In follow-up analyses, we replicated 26 of the 33 novel regions (in East Asians or Europeans). The replicated regions include 1q32.3, 3q21.1, 8p11.21, 10p11.1, and 22q12.1, all comprising strong candidate genes involved in craniofacial development. Furthermore, the 1q32.3 region shows evidence of introgression from archaic humans. These results provide novel biological insights into facial variation and establish that automatic landmarking of standard 2D photographs is a simple and informative approach for the genetic analysis of facial variation, suitable for the rapid analysis of large population samples.- Introduction - Results And Discussion -- Study sample and phenotyping -- Trait/covariate correlation and heritability -- Overview of GWAS results and integration with the literature -- Follow-up of genomic regions newly associated with facial features: Replication in two human cohorts -- Follow-up of genomic regions newly associated with facial features: effects in the mouse -- Genome annotations at associated loci - Conclusion - Methods -- Study subjects -- Genotype data -- Phenotyping -- Statistical genetic analysis -- Interaction of EDAR with other genes -- Expression analysis for significant SNPs -- Detection of archaic introgression near ATF3 and association with facial features -- Annotation of SNPs in FUMA -- Shape GWAS in outbred mic

Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample.Instituto Multidisciplinario de Biología Celula

Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample.Instituto Multidisciplinario de Biología Celula