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La població romaní és el grup ètnic minoritari transnacional més gran d'Europa. Tenen un origen sud asiàtic i, durant la seva diàspora cap a Europa, van experimentar múltiples efectes fundadors i una barreja genètica extensa. En aquesta tesi, l’anàlisi de marcadors genètics autosòmics mostren que tots els romaní comparteixen un component genètic comú del sud d’Àsia, de l’Orient Mitjà i dels Balcans, mentre que els grups romaní de la Península Ibèrica i del Bàltic han tingut una barreja addicional amb les altres poblacions de l'entorn. Després de caracteritzar el seu panorama genètic, l’estudi d’exomes complets de romanís espanyols suggereix que el flux de gens no romanís ha contrarestat l’augment de mutacions deletèries causada pels efectes fundadors. A més, les variants clínicament rellevants es troben tant a haplotips europeus com sud-asiàtics consistent amb l’extensa barreja genètica. Aquest treball representa un pas endavant per entendre de manera exhaustiva la història demogràfica romaní i posa de manifest la necessitat d’estudiar poblacions històricament excloses per poder descriure la variació humana en la seva totalitat. The Romani people are the largest transnational minority ethnic group in Europe. They have a South Asian origin and during their diaspora to Europe, they experienced multiple founder effects and gene flow events. In this thesis, the analysis of genome-wide array data shows that Romani groups share a common South Asian, Middle Eastern and Balkan ancestry, while Iberian and Baltic groups experienced additional admixture with the surrounding non-Roma European populations. After characterising their genetic landscape, the study of whole-exome sequences from Spanish Romani suggests that non-Roma gene flow has counteracted the increase in mutational load caused by the founder effects. In addition, clinically relevant variants are traced back to both European and South Asian ancestral haplotypes consistent with the extensive gene flow. Thus, the present work represents a step forward to comprehensively depict the Romani demographic history and emphasises the need to study other underrepresented and historically excluded populations to fully capture human variation.

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variabilityworldwide. CSVS is also part of the GA4GH Beacon network., Spanish Ministry of Economy and Competitiveness SAF2017-88908-R PT17/0009/0006 PI19/00321 CIBERER ACCI-06/07/0036 PI14-948 PI171659, Regional Government of Madrid, RAREGenomicsCM B2017/BMD3721 B2017/BMD-3721, European Union (EU), European Union (EU) 676559, University Chair UAM-IIS-FJD of Genomic Medicine, Ramon Areces Foundation

[eng] The human populations of the Mediterranean region have been thoroughly studied. Nonetheless, there are numerous aspects of their demographic and epidemiological history that remain uncertain to date. The growing use of high-throughput genetic data is helping to unravel these questions. A crucial part in designing a population genetics study is to determine the type and amount of genetic data that is needed in order to obtain accurate results. In the case of analyses that deal with large-scale population processes, such as continental barriers, or that focus on some specific candidate genes, sparse genetic data with a high degree of variation could be an option that allows for larger sample sizes. However, to obtain more refined results, such as estimating the date of an admixture event, inferring historical changes in population sizes, or focusing on restricted geographic areas, it is required the use of array-based or, ideally, whole-genome sequencing data. In this doctoral thesis, I present four studies in which the density of genetic markers employed vary in accordance to the depth of the analysis. Globally, this work contributes to the knowledge in the sphere of the population genetics of Mediterranean populations. The first survey supports the role of the Mediterranean sea as a historical barrier to gene flow, making use of three single nucleotide polymorphisms (SNP) located within or around LIN28B, a gene associated with cancer. One of these markers, rs221639, shows a specially high degree of variation between Mediterranean populations. The second article analyzes the presence of a sub-Saharan genetic component in four CAD-associated genomic regions in Mediterranean populations. This component is more prevalent in the North African coast, suggesting a more intense sub-Saharan gene flow than in Southern Europe. Furthermore, D-statistics suggest potential sub-Saharan introgression at the 10q11 region, which includes CXCL12, a gene that codes for a chemokine ligand linked to cardiovascular disease with protective effects. In the third study, the level of resolution achieved by array-based genome-wide data allows to refine previous estimates of a Sephardic component present in current Iberian populations. The incorporation of neighbouring populations to the analyses shows a gene flow process from the Iberian Peninsula outwards, which could be reflecting a migration pattern followed by the expelled Sephardic Jews. Finally, I present an analysis of deep-coverage whole-genome sequencing data from the Spanish Eastern Pyrenean population. In combination with accurate genealogical information of the samples, the quality of the data allows to analyze the demographic history of the Spanish Eastern Pyreneans with a high degree of detail using, among others, haplotype-based and deep learning methods. Namely, the Spanish Eastern Pyreneans appear as a distinct group within the Iberian populations, closely related to the Basques. In addition, this human group presents fine-scale population structure, and it has undergone a historical isolation process involving a reduction of the effective size, whose epidemiological consequence has been a significant depletion of many rare and highly deleterious mutations., [spa] Las poblaciones humanas de la región Mediterránea han sido ampliamente estudiadas históricamente. Sin embargo, hay numerosas cuestiones sobre su historia demográfica y epidemiológica que siguen sin resolver. En esta tesis doctoral se recogen cuatro estudios en los que la densidad de marcadores genéticos utilizados varía en función de la profundidad del análisis. En conjunto, estos trabajos contribuyen al conocimiento en el ámbito de la genética de poblaciones humanas del Mediterráneo. En el primer artículo se corrobora el rol histórico del mar Mediterráneo como barrera genética, mediante el uso de un número reducido de polimorfismos localizados en un gen asociado al cáncer, LIN28B. El segundo artículo informa sobre la existencia de un componente subsahariano en cuatro regiones genómicas asociadas a la enfermedad de las arterias coronarias, distribuido de manera dispar entre el sur de Europa y el Norte de África. En el tercer estudio se utilizan datos genómicos obtenidos a partir de un chip de genotipado. El nivel de resolución así conseguido permite refinar estimaciones previas sobre la magnitud del componente genético de origen sefardita presente en algunas poblaciones actuales de la Península Ibérica. Este análisis se extiende a poblaciones adyacentes, y se detecta así una posible ruta migratoria seguida por los sefarditas expulsados. Por último, se presenta un análisis de la población del Pirineo catalán, utilizando en este caso datos de secuenciación de segunda generación con una profundidad de cobertura de 40×. Ello, unido a la infomación genealógica de las muestras, permite analizar la historia demográfica de la región con un alto grado de detalle. Esta población se enmarca en el contexto genético de la Península Ibérica, mostrando una alta similitud con muestras del País Vasco francés. Presenta subestructura poblacional, y ha sufrido un proceso de aislamiento histórico con reducción del tamaño efectivo, cuya implicación epidemiológica ha sido una selección purificadora de numerosas mutaciones altamente deletéreas.

[spa] El objetivo principal de esta tesis es hacer un estudio completo del mestizaje genético de Argentina. Se pretende valorar la distribución territorial y regional del mestizaje y contrastarla con la información histórica y demográfica correspondiente, evaluando asimismo los patrones de mestizaje según el tipo de marcador genético utilizado, y su utilidad e interés poblacional. La ciudad de Bahía Blanca es un punto estratégico a nivel histórico y geográfico en la Argentina, al sur de la región Pampeana y al Noreste de la región Patagónica. En el primer trabajo se analiza por primera vez una serie de 19 polimorfismos Alu (18 autosómicos y 1 del cromosoma Y) en una muestra con datos genealógicos completos de Bahía Blanca. Los marcadores Alu han demostrado ser una herramienta muy útil para caracterizar las poblaciones humanas. La muestra genotipada está compuesta por 119 individuos sanos y sin relación de parentesco, y cuyas ascendencias parentales están bien documentadas. En función de los datos genealógicos, la muestra total ha sido subdividida en dos subgrupos: Bahía Blanca Original y Bahía Blanca Mix. Los valores de frecuencias alélicas y diversidad genética en Bahía Blanca concuerdan en la franja de los valores europeos cercanos al 80% y con una menor contribución nativa americana (cerca del 20%). Sin embargo, es interesante de resaltar que al dividir la muestra en los dos subgrupos, Bahía Blanca Original se encuentra levemente más próxima a los nativos americanos en contraste a Bahía Blanca Mix. Añadiendo que las relaciones genéticas enfatizan la similitud de Bahía Blanca Original con los americanos nativos. En el segundo trabajo se analizan por primera vez en Argentina, 10 elementos Alu del cromosoma X para caracterizar la composición genética de la población de la misma ciudad, compararla con otras poblaciones a nivel mundial, y para explorar la utilidad de los marcadores del cromosoma X en el estudio de la genética poblacional humana. En la muestra de Bahía Blanca, 7 de las 10 inserciones Alu son polimórficas. Los análisis de distancias genéticas indican que la muestra de Bahía Blanca es más cercana a las muestras de Europa y Norte de África que a las muestras nativo-americanas y africanas sub-saharianas. Las relaciones genéticas, muestran la posición intermedia de Bahía Blanca comparada con los grupos de las otras regiones. Los resultados de mestizaje de la muestra de Bahía Blanca para los marcadores del cromosoma X indican proporciones similares de contribuciones parentales de las poblaciones nativo-americanas (0,472) y de las europeas (0,479), mientras que menor contribución parental africana (0,049). Estos resultados obtenidos son consistentes con los estudios genéticos en Argentina de la última década, que informan de mayor contribución nativo-americana y africana que los datos registrados en el pasado. En el tercer trabajo se analiza el mestizaje en toda la Argentina. El territorio argentino puede dividirse en 5 regiones bien definidas, basadas en la historia, la geografía y los movimientos demográficos. Estas regiones son: Noreste, Noroeste, Cuyo (Centro- Oeste), Pampeana o Central (e incluye la región Metropolitana de Buenos Aires) y Patagónica (Sur). Al realizar un estudio comparativo a nivel regional y en función del tipo de marcador utilizado, los datos indican una gran diversidad regional y que es coincidente con la historia demográfica del país, siendo un país poblacionalmente muy heterogéneo y diverso. Destaca la región del centro con una mayor contribución europea, en contraste con las regiones del norte y sur del país con mayor contribución americana nativa. Además, los datos de mezcla génica obtenidos resaltan el carácter de desequilibrio o asimetría por género en la historia poblacional de la Argentina, poniendo de relieve una mayor contribución nativa americana por el lado materno (hasta un 86%), y una mayor contribución europea por el lado paterno (hasta un 96%)., [eng] The main objective of this thesis is to make a thorough study on the genetic admixture of Argentina. Other aims are to analyze the regional distribution of the admixture frequencies, and to compare them with the corresponding historical and demographic processes. Furthermore, it also analyses the admixture patterns according to the type of genetic marker used, and its correspondence with population patterns. Alu markers are a useful tool for studies in genetics of human populations. In the first two studies of this thesis, a set of Alu markers from autosome and X chromosomes were used for the first time in the city of Bahía Blanca to characterize the current population of this city and the region. Furthermore, Alu X chromosome markers were used for the first time in any sample of Argentina for population analyses purposes. The city of Bahía Blanca occupies a strategic place in Argentina, south of the Pampean region and in the northeast corner of the Patagonia. For the first study, a set of 19 Alu polymorphisms of a sample of Bahía Blanca was analyzed. The total sample has been subdivided into two groups: Bahía Blanca Original and Bahía Blanca Mix. Allele frequencies and gene diversity values in Bahía Blanca fit well into the European ranges. Though, interestingly, when the general sample is divided, Bahía Blanca Original appears slightly closer to Amerindians in contrast to Bahía Blanca Mix. In the second study, 10 Alu elements from the X chromosome are analyzed to characterize the genetic composition of the city’s population, to compare it with other populations around the world, and to explore the usefulness of X-chromosome markers for human population genetics purposes. In the Bahía Blanca sample, 7 of 10 Alu insertion frequencies are polymorphic. Genetic relationships illustrate the intermediate position of Bahía Blanca compared with groups in other regions. Admixture results of the Bahía Blanca sample for X-chromosome markers indicate similar proportions of Native American and European parental contributions and a minor sub- Saharan African contribution. These X-chromosome data are clearly different to those estimated from autosomal Alu markers in the same populations, but with a relative similarity to ADMIX data from mtDNA in human groups of Southern Argentina that stress the Native Amerindian contribution. In the third study, the whole territory is divided into regions, according to geographical and historical data. The analysis is based on the genetic composition of the populations for each of the regions. In addition, a comparison is made based on the type of markers used. The data show a great regional diversity and heterogeneous country. On the other hand, the results underline the sex biased contribution due to sex biased migration in Argentina, where there is a major Native American contribution through the maternal via (up to 86%), and a major European contribution through the paternal via (up to 96%).

The development of new methods for inferring ancestral origins in human populations has atracted a renewed interest for human population geneticists for better understanding recent human evolutonary history or for correcting the presence of hidden population substructure in genome-wide association studies (GWAS). The algorithms for detecting population substructure present several problems such as the dependency on the assumptions of the algorithm, the type and number of considered DNA markers, the underlying demographic relationship among the considered populations and the sample size of the target populations. With this concern in mind, we have constructed an experimental model for testing the performance of currently algorithms applied for estimating population substructure which starts by designing two ideal prototypes of spatially structured populations (2D stepping stone and anisotropic). From each model we have generated a pool of 78 experimental datasets, simulating the genomic molecular diversity with Fastsimcoal2 under various migration rate conditions, performing the sampling of individuals and populations and selecting different filtering strategies: Minor Allele Frequency (MAF) and Linkage Disequilibrium (LD). Those 78 datasets (plink bed files) have been processed to evaluate the response of commonly applied algorithms to SNP data for quantifying individual population substructure: Principal Components Analysis (smartPCA), Multidimensional Scaling (MDS-PLINK), Spatial Ancestry Analysis (SPA), ADMIXTURE and SNMF. For those algorithms in which the output is a coordinate (PCA, MDS and SPA), we have evaluated the correlation (via Mantel and Procrustes tests) of these estimated coordinates with the geographic sampling coordinates of individuals in our original ideal artifacts. For ADMIXTURE and SNMF we have applied different algorithms for assessing the best K number of ancestries and we have applied CLUMPP sotware to compare their output matrices. This ideal prototype has enabled us to establish the robustness of the five algorithms, identify best performing algorithms and determine the impact of the conditions imposed on the results of these programs., Director/a: Oscar Lao

The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans., This work was supported by Wellcome Trust grant 098051.

The present thesis deals with a deep analysis of the genetic structure of extant human worldwide populations, with a special focus on the Mediterranean. Different genetic markers, 18 Alu insertions and 367 single nucleotide polymorphisms (SNPs), were analysed for the first time in general populations and Bedouins from Jordan. The same SNPs were also genotyped in a consistent set of samples from the Mediterranean Basin. Specifically, Alu markers were used to assess the genetic diversity within Jordan and to define the relationships across present-day Middle Eastern, North African, and European populations. While SNPs located in the top coronary artery disease (CAD) risk regions (1p13, 1q41, 9p21, and 10q11) were used to explore the genetic variation and the LD patterns across 19 populations from Europe, Middle East and North Africa, together with Asian and African samples from the 1000 Genomes Project. Furthermore, Tunisian and Moroccan case-control samples were used to test for the first time the applicability of European GWAS results in these four genomic regions to North African populations. Finally, simulated genomic data were used to evaluate the consistency of association results across European, Asian and Sub-Saharan African case-control samples. Neutral and CAD risk markers pointed out a low but significant geographic structure in the Mediterranean area. As a particular case in the Mediterranean context, Bedouins and general population from Jordan showed statistical differences (p=0.038). The genetic heterogeneity detected is likely related to the fact that urban areas have been subject to several external influences but Bedouins have preserved their own genetic background because of their nomadic and isolated lifestyle. The general patterns of genetic variation observed in the four CAD risk regions analysed are in agreement with the genetic structure generated by demographic processes. Despite this fact, the present work also identified potential signals of positive and balancing selection in some specific risk markers and haplotypes. Actually, potential signatures of positive selection in the 9p21 region and of balancing selection in 9p21 and 10q11 have been observed. The regions under positive or balancing selection are shared across continents but the specific markers under selection are, in some cases, continent-specific. Results from the association study in North Africa revealed significant association signals in the four genomic regions analysed in Moroccan and Tunisian samples confirming the trans-ethnic importance of these genomic regions for the risk of CAD. However, in the meta-analyses performed with the North African case-control samples, only the 9p21 and 10q11 regions showed association signals and none of the North African risk SNPs was associated with CAD in Europe. These arguments suggest the existence of continent-specific CAD risk variants in these chromosomal regions. Significant differences in the LD and in the haplotype patterns confirm the heterogeneity in the genomic structure between North Africans and Europeans. In addition, differences in the LD structure persist even across Europeans, North Africans, Asians, and Sub-Saharan Africans. Finally, the simulation study highlighted an overall consistency in effect direction across populations of different ancestry, specially between Europeans and Asians. Because simulations assumed no actual differences in genetic effect size between populations and because the rate of between-population effect size differences generated by our study was considerably lower than the rate reported from empirical studies using real data, our study supports the existence of real differences in the genetic risk architecture of complex traits between populations. In general, this study confirmed that a substantial fraction of association signals are shared across people of different ancestries. However, some discrepancies in the effect size across populations highlighted the importance of accounting for population structure in association studies., Esta tesis analiza la variación genética de muestras poblacionales europeas, africanas y asiáticas, con particular énfasis en la región mediterránea. Se usaron 18 marcadores Alu para evaluar la diversidad genética dentro de Jordania (en beduinos y en población general) y para definir la relación entre las actuales poblaciones del Mediterráneo. Por otra parte, 367 polimorfismos de un solo nucleótido (SNPs) localizados en cuatro regiones de riesgo para la enfermedad arterial coronaria (CAD) (1p13, 1q41, 9p21 y 10q11) se utilizaron para explorar la variación genética en 19 poblaciones de Europa, Oriente Medio y África del Norte, junto a las muestras asiáticas y africanas del Proyecto 1000 Genomas. Estas cuatro regiones de riesgo CAD fueron analizadas también en un conjunto de muestras de casos y controles de Marruecos y Túnez. Por último, se simularon muestras de casos y controles africanos, europeos, y asiáticos para evaluar el nivel de consistencia interpoblacional en los estudios de asociación. Como caso particular en el Mediterráneo, los beduinos y la población general de Jordania mostraron diferencias significativas (p=0,038). Los beduinos se agruparon con los norteafricanos, mientras que los jordanos generales se agruparon con las poblaciones más orientales del Mediterráneo. Los patrones generales de variación observados en las cuatro regiones de riesgo CAD mostraron una estructura genética plausiblemente modelada por procesos demográficos. A pesar de esto, el presente trabajo también detectó señales potenciales de selección natural positiva en la región 9p21 y de selección equilibradora en las regiones 9p21 y 10q11. También fueron detectadas asociaciones significativas en las cuatro regiones genómicas analizadas, previamente identificadas en europeos, en Marruecos y Túnez. Sin embargo, sólo las regiones 9p21 y 10q11 mostraron asociación en el meta-análisis realizado utilizando las muestras de casos y controles norteafricanos. El estudio de simulación destacó una alta replicabilidad de las señales de asociación entre los distintos continentes. Sin embargo, algunas discrepancias en el tamaño del efecto revelaron la posible existencia de diferencias interpoblacionales en la arquitectura del riesgo genético de caracteres complejos y destacaron la importancia de incluir la estructura poblacional en los estudios de asociación.

This study focuses on the genetic history of the Quechua-Lamistas, inhabitants of the Lamas Province in the San Martin Department, Peru, who speak their own distinct variety of the Quechua family of languages. It has been suggested that different pre-Columbian ethnic groups from the Peruvian Amazonia, like the Motilones or "shaven heads", assimilated the Quechua language and then formed the current native population of Lamas. However, many Quechua-Lamistas claim to be direct descendants of the Chankas, a famous pre-Columbian indigenous group that escaped from Inca rule in the Andes. To investigate the Quechua-Lamistas and Chankas' ancestries, we compared uniparental genetic profiles (17 STRs of Q-M3 Y-chromosome and mtDNA complete control region haplotypes) among autochthonous Amazonian and Andean populations from Peru, Bolivia and Ecuador. The phylogeographic and population genetic analyses indicate a fairly heterogeneous ancestry for the Quechua-Lamistas, while they are closely related to their neighbours who speak Amazonian languages, presenting no direct relationships with populations from the region where the ancient Chankas lived. On the other hand, the genetic profiles of self-identified Chanka descendants living in Andahuaylas (located in the Apurimac Department, Peru, in the Central Andes) were closely related to those living in Huancavelica and the assumed Chanka Confederation area before the Inca expansion. This work received funds from the National Geographic Society, the Waitt Family Foundation and IBM from the United States and from FAPEMIG and CNPq from Brazil for laboratory analysis and fieldwork

Detecting positive selection in genomic regions is a recurrent topic in human population genetics studies. Over the years, many positive selection tests have been implemented to highlight specific genomic patterns left by a selective event when compared to neutral expectations. However, there is little consistency among the regions detected in several genome-wide scans using different tests and/or populations: population-specific demographic dynamics, local genomic features or different types of selection acting along the genome at different times and selective coefficients might explain such discrepancies. The present doctoral thesis is focused in the study of this problem and the development of a innovative solution: a machine-learning classification framework that exploits the combined ability of some selection tests to uncover the different features expected under the hard sweep model, such as sweep completeness and age of onset. The method was calibrated and applied to three reference populations from The 1000 Genome Project to generate a genome-wide classification map of hard selective sweeps. This study improves the way a selective sweep is detected by overcoming the classical selection vs. no-selection classification strategy, and offers an explanation to the lack of consistency observed among selection tests when applied to real data., La detecció de selecció positiva en regions genòmiques ha estat un tema recurrent en molts estudis de genètica de poblacions humanes. En conseqüència, durant els últims anys s'han publicat molts mètodes estadístics per detectar els senyals genòmics creats per un procés de selecció molecular. No obstant això, en general hi ha poca consistència entre les regions detectades pels diferents mètodes: dinàmiques demogràfiques especifiques de població, propietats locals de les regions analitzades o diferents tipus de selecció actuant a diferents marcs temporals i intensitats podrien explicar aquestes discrepàncies. Aquesta tesi doctoral està centrada en l'estudi d'aquest problema i en el desenvolupament d'una solució: un mètode de classificació de selecció positiva basat en algoritmes d'aprenentatge automàtic. El mètode combina diferents tests per detectar selecció positiva per obtenir informació sobre el tipus i mode de selecció que afecta una regió genòmica determinada. Aquest nou mètode presenta una alta sensitivitat cap a senyals de selecció positiva i és capaç de proveir informació sobre l'edat del esdeveniment selectiu, així com del seu estat final. Aquest treball millora la forma en què la selecció positiva és detectada avui en dia i proporciona una explicació a la falta de consistència observada entre els mètodes de detecció de selecció positiva quan s'apliquen en dades reals.

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes1,2,3,4 with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians3, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations’ deep relationships and show that early European farmers had ∼44% ancestry from a ‘basal Eurasian’ population that split before the diversification of other non-African lineages., Instituto Multidisciplinario de Biología Celular

It contains associated material.-- The 1000 Genomes Project Consortium, [Background] Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes., [Results] We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively., [Conclusions] We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research. © 2014 Colonna et al., This work was supported by The Wellcome Trust (098051), an Italian National Research Council (CNR) short-term mobility fellowship from the 2013 program to VC, and an EMBO Short Term Fellowship ASTF 324–2010 to VC.

Genotype networks are a concept used in systems biology to study sets of genotypes having the same phenotype, and the ability of these to bring forth novel phenotypes. In the past they have been applied to determine the genetic heterogeneity, and stability to mutations, of systems such as metabolic networks and RNA folds. Recently, they have been the base for reconciling the neutralist and selectionist views on evolution. Here, we adapted this concept to the study of population genetics data. Specifically, we applied genotype networks to the human 1000 genomes dataset, and analyzed networks composed of short haplotypes of Single Nucleotide Variants (SNV). The result is a scan of how properties related to genetic heterogeneity and stability to mutations are distributed along the human genome. We found that genes involved in acquired immunity, such as some HLA and MHC genes, tend to have the most heterogeneous and connected networks, and that coding regions tend to be more heterogeneous and stable to mutations than non-coding regions. We also found, using coalescent simulations, that regions under selection have more extended and connected networks. The application of the concept of genotype networks can provide a new opportunity to understand the evolutionary processes that shaped our genome. Learning how the genotype space of each region of our genome has been explored during the evolutionary history of the human species can lead to a better understanding on how selective pressures and neutral factors have shaped genetic diversity within populations and among individuals. Combined with the availability of larger datasets of sequencing data, genotype networks represent a new approach to the study of human genetic diversity that looks to the whole genome, and goes beyond the classical division between selection and neutrality methods. © 2014 Dall'Olio et al., This work was supported by grants BFU2010-19443 (subprogram BMC) awarded to JB by Ministerio de Ciencia y Tecnología (Spain) and by the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101). GMD is supported by a FPI fellowship BES-2009-017731. AW would like to acknowledge support by the Swiss National Science Foundation and by the URPP Evolutionary Biology at the University of Zurich.

The search for a method that utilizes biological information to predict humans’ place of origin has occupied scientists for millennia. Over the past four decades, scientists have employed genetic data in an effort to achieve this goal but with limited success. While biogeographical algorithms using next-generation sequencing data have achieved an accuracy of 700 km in Europe, they were inaccurate elsewhere. Here we describe the Geographic Population Structure (GPS) algorithm and demonstrate its accuracy with three data sets using 40,000–130,000 SNPs. GPS placed 83% of worldwide individuals in their country of origin. Applied to over 200 Sardinians villagers, GPS placed a quarter of them in their villages and most of the rest within 50 km of their villages. GPS’s accuracy and power to infer the biogeography of worldwide individuals down to their country or, in some cases, village, of origin, underscores the promise of admixture-based methods for biogeography and has ramifications for genetic ancestry testing., Current methods to identify the geographical origin of humans based on DNA data present limited accuracy. Here, the authors develop a new algorithm, the Genographic Population Structure (GPS), and demonstrate its ability to place worldwide individuals within their country or, in some cases, village of origin.

[cat] La diversitat observada en els grups humans ha estat àmpliament documentada per antropòlegs segons els coneixements i tècniques disponibles en cada moment. Actualment, un dels aspectes en els quals s’està invertint molt d’esforç és en la modelització dels fenotips anomenats complexos, fruit de la interacció d’un elevat nombre de components genètics i ambientals, on hi trobem moltes malalties. Alguns d’aquests fenotips presenten grans diferències entre les poblacions humanes, i per tant, també els seus factors causants. Per tal d’entendre la distribució observada d’aquests fenotips i els seus factors determinants, és necessari fer una ullada a la història demogràfica de les poblacions. En aquest context, aquesta tesi és un estudi antropogenètic de diferents gens, el gen del factor de coagulació XIII (F13A1) i els gens de les sintases d’òxid nítric (NOS), implicats en un fenotip complex amb variació poblacional com són les malalties cardiovasculars. Les nostres poblacions d’estudi es situen al voltant de la Mediterrània i al continent europeu, on, tot i tractar-se d’una àrea geogràfica no molt extensa, la variació en la presència de les malalties cardiovasculars és considerable. En un primer article, polimorfismes del gen F13A1 són analitzats en una mostra de 101 famílies de l’àrea de Barcelona. L’anàlisi de transmissió al•lèlica entre pares/mares i fills afectats d’infart de miocardi va mostrar una interacció intra-gènica degut a la sobretransmissió de la variant al•lèlica Pro564 de rs5982 en el subgrup de mostra on els fills afectats presentaven el genotip Val34-Val34 per rs5985, donant un paper pro-trombòtic del FXIII. Alhora, es va observar que l’al•lel més curt (3.2 repeticions) de F13A1-STR es trobava infratransmès, mentre que l’al•lel més llarg, d’entre els de més freqüència poblacional (7 repeticions), s’observava sobretransmès, apuntant cap a un paper regulador de F13A1-STR en l’expressió del gen F13A1 i, per tant, en la disponibilitat en sang del FXIII. En un segon article, un conjunt de 61 SNPs presents als tres gens NOS (NOS3, NOS1 i NOS2A) van ser analitzats per associació amb l’infart de miocardi en 2165 casos i 2153 controls D’aquests, 4 SNPs independents van presentar indicis d’associació amb la malaltia. El score de risc genètic a partir d’aquests 4 SNPs va explicar una contribució a l’infart de miocardi inferior al 1%. Per contra, en un conjunt de 34 mostres poblacionals, la mitjana poblacional del score es correlaciona positivament amb la incidència coronària registrada en 10 poblacions del projecte MONICA i n’explica fins a un 67% en dones i un 86% en homes, fruit de la colinearitat del score amb molts altres factors de risc amb la mateixa distribució poblacional. Aquest fet ens indica que l’estudi de la distribució genètica de risc ens pot ser molt útil per elaborar estratègies de prevenció en salut pública. Finalment, en un tercer article, mitjançant l’anàlisi de 114 SNPs i 17 STRs, es va determinar que les principals estructures de variació genètica en les poblacions eren gradients de continuïtat genètica distribuïts seguint eixos similars a nord-sud i est-oest. L’estimació de components genètics “ancestrals” va indicar l’existència de 3 components interpretats com d’origen Paleolític europeu, Paleolític nord africà i Neolític europeu. Aquests resultats s’ajusten a simulacions computacionals on aquesta distribució s’explicaria per un doble procés de Neolització: una expansió neolítica al continent europeu lligada a la cultura ceràmica Linearbandkeramik i una expansió neolítica a la Mediterrània lligada a la cultura ceràmica Cardial. Alhora, aquestes estimacions genètiques van explicar altes contribucions a la incidència coronària en 11 poblacions del projecte MONICA (36-98%), fet que indica que la predisposició poblacional a la malaltia és fruit de la demografia històrica de les poblacions i no a efectes d’adaptació al medi., [eng] Human diversity has been widely documented by anthropologists. Nowadays, modelling complex phenotypes is one of the top research areas. Complex phenotypes show different distribution among populations, as well as the factors that cause them. In this context, this thesis assessed the role of some polymorphisms of coagulation factor XIII gene (F13A1) and Nitric Oxide Synthase genes (NOS) in coronary artery diseases (CAD), and their distribution among European and Mediterranean populations in relation with coronary incidence. In the first article, F13A1 gene polymorphisms were tested in a sample of 101 families from the area of Barcelona. The analysis of allele transmission from parents to affected children showed an allele-allele interaction between Pro564 and Val34 allele variants of rs5982 and rs5985 polymorphisms. At the same time, an under-transmission of the shorter allele in size (3.2 repeats) and an over-transmission of the largest allele in size among common alleles (7 repeats) of F13A1-STR pointed to a regulatory role in F13A1 gene expression and, therefore , bloodstream FXIII availability. In the second study, for the first time, we proposed to estimate the genetic CAD predisposition at population level using genetic risk scores (GRS). A GRS, composed by 4 risk markers from NOS genes, explained less than 1% of CAD phenotype, but the mean value of GRS per population clearly correlated with CAD incidence explaining a 86% of coronary event rates in men and 67% in women. This phenomenon was explained by the colineal effect of several risk variants showing the same geographic distribution. Population GRS is a promising approach in public health interventions. Finally, in the third article, the analyses 114 SNPs and 17 microsatellites from NOS gene regions revealed a genetic structure among populations in genetic gradients distributed resembling north-south and east-west axes. Three ancestral components were estimated and interpreted as Palaeolithic European, Palaeolithic North African and Neolithic European genetic components. These results fitted a process of dual Neolithisation: one expansion in the European continent leaded by the Linearbandkeramk culture and another in the Mediterranean Basin linked to the Cardial ceramic culture. At the same time, the population structure estimates explained a large proportion of coronary events rates (36-98%), indicating that population predisposition to coronary disease is the result of demography instead of an adaptation to the environment.

Gómez-Sánchez, Daniel et al., Previous mitochondrial DNA analyses on ancient European remains have suggested that the current distribution of haplogroup H was modeled by the expansion of the Bell Beaker culture (ca 4,500-4,050 years BP) out of Iberia during the Chalcolithic period. However, little is known on the genetic composition of contemporaneous Iberian populations that do not carry the archaeological tool kit defining this culture. Here we have retrieved mitochondrial DNA (mtDNA) sequences from 19 individuals from a Chalcolithic sample from El Mirador cave in Spain, dated to 4,760-4,200 years BP and we have analyzed the haplogroup composition in the context of modern and ancient populations. Regarding extant African, Asian and European populations, El Mirador shows affinities with Near Eastern groups. In different analyses with other ancient samples, El Mirador clusters with Middle and Late Neolithic populations from Germany, belonging to the Rössen, the Salzmünde and the Baalberge archaeological cultures but not with contemporaneous Bell Beakers. Our analyses support the existence of a common genetic signal between Western and Central Europe during the Middle and Late Neolithic and points to a heterogeneous genetic landscape among Chalcolithic groups. © 2014 Gómez-Sánchez et al., This work is supported by FEDER and Spanish Government Grant BFU2012-34157.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited., Searching for Darwinian selection in natural populations has been the focus of a multitude of studies over the last decades. Here we present the 1000 Genomes Selection Browser 1.0 (http://hsb.upf.edu) as a resource for signatures of recent natural selection in modern humans. We have implemented and applied a large number of neutrality tests as well as summary statistics informative for the action of selection such as Tajima's D, CLR, Fay and Wu's H, Fu and Li's F* and D*, XPEHH, ΔiHH, iHS, FST, ΔDAF and XPCLR among others to low coverage sequencing data from the 1000 genomes project (Phase 1; release April 2012). We have implemented a publicly available genome-wide browser to communicate the results from three different populations of West African, Northern European and East Asian ancestry (YRI, CEU, CHB). Information is provided in UCSC-style format to facilitate the integration with the rich UCSC browser tracks and an access page is provided with instructions and for convenient visualization. We believe that this expandable resource will facilitate the interpretation of signals of selection on different temporal, geographical and genomic scales. © 2013 The Author(s). Published by Oxford University Press., Ministerio de Ciencia y Tecnología (Spain); Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101); Subprogram BMC [BFU2010-19443 awarded to J.B.]; Post-doctoral scholarship from the Volkswagenstiftung [Az: I/85 198 to J.E.]; Spanish government [BFU-2008-01046; SAF2011-29239]; The Spanish government FPI scholarships [BES-2009-017731 and BES-2011-04502 to G.M.D. and M.P., respectively]; PhD fellowship from ‘Acción Estratégica de Salud, en el marco del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011’ from Instituto de Salud Carlos III (to P.L.). Funding for open access charge: Prof. Jaume Bertranpetit.

Ballantyne, Kaye N. et al.-- This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, >99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y-STRs in identifying and separating unrelated and related males and provides a reference database. The value of 13 rapidly-mutating (RM) Y-STRs for differentiating male individuals is investigated in 14,644 related and unrelated men sampled from 111 worldwide populations. Over 99% of the 12,272 unrelated men were completely individualized. Of the 2,378 father-son pairs, 27% were separated. Figure: blue lines represent Y-STR haplotypes shared between population pairs in a subset of 7,784 males from 65 populations. Almost all shared haplotypes defined by conventional 17 Yfiler Y-STRs (above) are resolved with the 13 RM Y-STRs (below). © 2014 Wiley Periodicals, Inc.

The genetic basis of phenotypes that have contributed to the adaptation of species and organisms to new environments is a central question in evolutionary genetics. The recent accumulation of genetic variability data has allowed a genome-wide search for different signatures of positive selection which has led to the discovery of hundreds of putative candidate genes that may have played a role in adaptation. However, such hypothesis-free approaches do not reveal either causal variants or the actual biological mechanisms that have made each adaptation possible. Furthermore, the detection of molecular signatures is limited both by the complex architecture of the genome and by the possible polygenic nature of the selected trait. In this thesis, through different evolutionary and functional approaches, we have disentangled the adaptive role of two non-synonymous variants in two different candidate genes encoding for a lymphocyte receptor and a zinc transporter, respectively. In past human adaptation, they were most likely selected as more effective means to fight pathogens. We have also revealed differences in the action of natural selection between different pathways and different coding and non-coding genomic elements in the chimpanzee lineage by analyzing polymorphisms and divergence data together. Thus, the results of this PhD thesis have contributed to detect new instances of genetic adaptation and provide biological explanation to them., La base genética de los carácteres que han contribuido a la adaptación de los organismos y las especies ha sido siempre una pregunta central en biología evolutiva. Gracias a la acumulación masiva de datos de variabilidad genética, en los últimos años se ha podido detectar en el genoma diferentes señales de selección positiva y también localizar cientos de genes candidatos que han podido tener un papel en la adaptación de las poblaciones a diferentes ambientes. Sin embargo en estos estudios, donde no hay una hipótesis a priori, se desconoce qué variantes dentro de estos genes fueron realmente las que proporcionaron una ventaja selectiva y por qué. Además, la compleja arquitectura del genoma y la naturaleza poligénica de muchos carácteres hace que sea difícil detectar casos más complejos de adaptación. En esta tesis se intenta resolver algunos de estos problemas. En primer lugar, mediante un enfoque evolutivo y funcional, hemos descifrado el rol adaptativo de dos variantes genéticas, una en un receptor linfocitario y la otra en un transportador de zinc, que probablemente fueron seleccionadas por conferir resistencia a patógenos. En segundo lugar, mediante el análisis de datos de polimorfismo y divergencia conjuntamente, también hemos detectado distintos mecanismos de acción de la selección natural en distintos pathways y entre elementos codificantes y elementos no codificantes reguladores en chimpancé.

Antisocial and criminal behaviors are multifactorial traits whose interpretation relies on multiple disciplines. Since these interpretations may have social, moral and legal implications, a constant review of the evidence is necessary before any scientific claim is considered as truth. A recent study proposed that men with wider faces relative to facial height (fWHR) are more likely to develop unethical behaviour mediated by a psychological sense of power. This research was based on reports suggesting that sexual dimorphism and selection would be responsible for a correlation between fWHR and aggression. Here we show that 4,960 individuals from 94 modern human populations belonging to a vast array of genetic and cultural contexts do not display significant amounts of fWHR sexual dimorphism. Further analyses using populations with associated ethnographical records as well as samples of male prisoners of the Mexico City Federal Penitentiary condemned by crimes of variable level of inter-personal aggression (homicide, robbery, and minor faults) did not show significant evidence, suggesting that populations/individuals with higher levels of bellicosity, aggressive behaviour, or power-mediated behaviour display greater fWHR. Finally, a regression analysis of fWHR on individual's fitness showed no significant correlation between this facial trait and reproductive success. Overall, our results suggest that facial attributes are poor predictors of aggressive behaviour, or at least, that sexual selection was weak enough to leave a signal on patterns of between- and within-sex and population facial variation., Facultad de Ciencias Naturales y Museo

Numerous studies of human populations in Europe and Asia have revealed a concordance between their extant genetic structure and the prevailing regional pattern of geography and language. For native South Americans, however, such evidence has been lacking so far. Therefore, we examined the relationship between Y-chromosomal genotype on the one hand, and male geographic origin and linguistic affiliation on the other, in the largest study of South American natives to date in terms of sampled individuals and populations. A total of 1,011 individuals, representing 50 tribal populations from 81 settlements, were genotyped for up to 17 short tandem repeat (STR) markers and 16 single nucleotide polymorphisms (Y-SNPs), the latter resolving phylogenetic lineages Q and C. Virtually no structure became apparent for the extant Y-chromosomal genetic variation of South American males that could sensibly be related to their inter-tribal geographic and linguistic relationships. This continent-wide decoupling is consistent with a rapid peopling of the continent followed by long periods of isolation in small groups. Furthermore, for the first time, we identified a distinct geographical cluster of Y-SNP lineages C-M217 (C3*) in South America. Such haplotypes are virtually absent from North and Central America, but occur at high frequency in Asia. Together with the locally confined Y-STR autocorrelation observed in our study as a whole, the available data therefore suggest a late introduction of C3* into South America no more than 6,000 years ago, perhaps via coastal or trans-Pacific routes. Extensive simulations revealed that the observed lack of haplogroup C3* among extant North and Central American natives is only compatible with low levels of migration between the ancestor populations of C3* carriers and non-carriers. In summary, our data highlight the fact that a pronounced correlation between genetic and geographic/cultural structure can only be expected under very specific conditions, most of which are likely not to have been met by the ancestors of native South Americans., Author Summary In the largest population genetic study of South Americans to date, we analyzed the Y-chromosomal makeup of more than 1,000 male natives. We found that the male-specific genetic variation of Native Americans lacks any clear structure that could sensibly be related to their geographic and/or linguistic relationships. This finding is consistent with a rapid initial peopling of South America, followed by long periods of isolation in small tribal groups. The observed continent-wide decoupling of geography, spoken language, and genetics contrasts strikingly with previous reports of such correlation from many parts of Europe and Asia. Moreover, we identified a cluster of Native American founding lineages of Y chromosomes, called C-M217 (C3*), within a restricted area of Ecuador in North-Western South America. The same haplogroup occurs at high frequency in Central, East, and North East Asia, but is virtually absent from North (except Alaska) and Central America. Possible scenarios for the introduction of C-M217 (C3*) into Ecuador may thus include a coastal or trans-Pacific route, an idea also supported by occasional archeological evidence and the recent coalescence of the C3* haplotypes, estimated from our data to have occurred some 6,000 years ago.

[Background] Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints., [Results] Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1., [Conclusions] These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway., This work was funded by grant BFU2010-19443 (subprogram BMC) awarded to JB by Ministerio de Ciencia y Tecnología (Spain), and the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101). GMD is supported by a FPI fellowship (BES-2009-017731) from the Ministerio de Ciencia y Tecnología, (Spain). PL is supported by a PhD fellowship from “Acción Estratégica de Salud, 2008-2011” from Instituto de Salud Carlos III and LM is supported by a postdoctoral fellowship from the Juan de la Cierva Program of the Spanish Ministry of Science and Innovation (MICINN).

Henn, Brenna M. et al., [Abstract] North African populations are distinct from sub-Saharan Africans based on cultural, linguistic, and phenotypic attributes; however, the time and the extent of genetic divergence between populations north and south of the Sahara remain poorly understood. Here, we interrogate the multilayered history of North Africa by characterizing the effect of hypothesized migrations from the Near East, Europe, and sub-Saharan Africa on current genetic diversity. We present dense, genome-wide SNP genotyping array data (730,000 sites) from seven North African populations, spanning from Egypt to Morocco, and one Spanish population. We identify a gradient of likely autochthonous Maghrebi ancestry that increases from east to west across northern Africa; this ancestry is likely derived from >back-to-Africa> gene flow more than 12,000 years ago (ya), prior to the Holocene. The indigenous North African ancestry is more frequent in populations with historical Berber ethnicity. In most North African populations we also see substantial shared ancestry with the Near East, and to a lesser extent sub-Saharan Africa and Europe. To estimate the time of migration from sub-Saharan populations into North Africa, we implement a maximum likelihood dating method based on the distribution of migrant tracts. In order to first identify migrant tracts, we assign local ancestry to haplotypes using a novel, principal component-based analysis of three ancestral populations. We estimate that a migration of western African origin into Morocco began about 40 generations ago (approximately 1,200 ya); a migration of individuals with Nilotic ancestry into Egypt occurred about 25 generations ago (approximately 750 ya). Our genomic data reveal an extraordinarily complex history of migrations, involving at least five ancestral populations, into North Africa. © 2012 Henn et al., [Author Summary] Proposed migrations between North Africa and neighboring regions have included Paleolithic gene flow from the Near East, an Arabic migration across the whole of North Africa 1,400 years ago (ya), and trans-Saharan transport of slaves from sub-Saharan Africa. Historical records, archaeology, and mitochondrial and Y-chromosome DNA have been marshaled in support of one theory or another, but there is little consensus regarding the overall genetic background of North African populations or their origin and expansion. We characterize the patterns of genetic variation in North Africa using ~730,000 single nucleotide polymorphisms from across the genome for seven populations. We observe two distinct, opposite gradients of ancestry: an east-to-west increase in likely autochthonous North African ancestry and an east-to-west decrease in likely Near Eastern Arabic ancestry. The indigenous North African ancestry may have been more common in Berber populations and appears most closely related to populations outside of Africa, but divergence between Maghrebi peoples and Near Eastern/Europeans likely precedes the Holocene (>12,000 ya). We also find significant signatures of sub-Saharan African ancestry that vary substantially among populations. These sub-Saharan ancestries appear to be a recent introduction into North African populations, dating to about 1,200 years ago in southern Morocco and about 750 years ago into Egypt, possibly reflecting the patterns of the trans-Saharan slave trade that occurred during this period., BMH, SG, and CDB were supported by NIH grant 3R01HG003229. LRB and DC were supported by MCINN grant CGL2010-14944/BOS and Generalitat de Catalunya grant 2009SGR1101. AM-E and AB were supported by NIH grant R01GM083606.

Martínez-Cruz, Begoña et al.-- The Genographic Consortium, Vlad III The Impaler, also known as Dracula, descended from the dynasty of Basarab, the first rulers of independent Wallachia, in present Romania. Whether this dynasty is of Cuman (an admixed Turkic people that reached Wallachia from the East in the 11 th century) or of local Romanian (Vlach) origin is debated among historians. Earlier studies have demonstrated the value of investigating the Y chromosome of men bearing a historical name, in order to identify their genetic origin. We sampled 29 Romanian men carrying the surname Basarab, in addition to four Romanian populations (from counties Dolj, N = 38; Mehedinti, N = 11; Cluj, N = 50; and Brasov, N = 50), and compared the data with the surrounding populations. We typed 131 SNPs and 19 STRs in the non-recombinant part of the Y-chromosome in all the individuals. We computed a PCA to situate the Basarab individuals in the context of Romania and its neighboring populations. Different Y-chromosome haplogroups were found within the individuals bearing the Basarab name. All haplogroups are common in Romania and other Central and Eastern European populations. In a PCA, the Basarab group clusters within other Romanian populations. We found several clusters of Basarab individuals having a common ancestor within the period of the last 600 years. The diversity of haplogroups found shows that not all individuals carrying the surname Basarab can be direct biological descendants of the Basarab dynasty. The absence of Eastern Asian lineages in the Basarab men can be interpreted as a lack of evidence for a Cuman origin of the Basarab dynasty, although it cannot be positively ruled out. It can be therefore concluded that the Basarab dynasty was successful in spreading its name beyond the spread of its genes. © 2012 Martinez-Cruz et al., The present study was supported by the Ministerio de Ciencia e Innovación, Spain (CGL2010-14944), Direcció General de Recerca, Generalitat de Catalunya (2009SGR1101) (both to DC), and a Vici Grant of the Netherlands Organization for Scientific Research (to MGN).

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R2>0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region., Author Summary Individuals from Latin America are descendants of multiple ancestral populations, primarily Native American, European, and African ancestors. The relative proportions of these ancestries can be estimated using genetic markers, known as ancestry informative markers (AIMs), whose allele frequency varies between the ancestral groups. Once determined, these ancestral proportions can be correlated with normal phenotypes, can be associated with disease, can be used to control for confounding due to population stratification, or can inform on the history of admixture in a population. In this study, we identified a panel of AIMs relevant to Latin American populations, validated the panel by comparing estimates of ancestry using the panel to ancestry determined from genome-wide data, and tested the panel in a diverse set of populations from the Americas. The panel of AIMs produces ancestry estimates that are highly accurate and appropriately controlled for population stratification, and it was used to genotype 18 populations from throughout Latin America. We have made the panel of AIMs available to any researcher interested in estimating ancestral proportions for populations from the Americas.

Background Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. Methods The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. Results Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. Conclusions The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives. This action has been supported in part by grants from the Generalitat Valenciana in Spain (AP140/08) and the Biomedical Research Foundation from the Hospital of Elche, Spain (FIBElx0902). CG, AMC, CEl and LPC are recipients of fellowships from the Conselleria de Educació (Generalitat Valenciana); Fundacion Juan Peran-Pikolinos; Fundacion Carolina-BBVA and Fondo Investigación Sanitaria (FI07/00303), respectively. RJ is receptor of a grant from Instituto de Salud Carlos III (INT09/208) SI

[spa] La tesis trata de definir algunos aspectos de la situación demográfica y describir la genética poblacional a partir del estudio de haplogrupos del ADN mitocondrial (ADNmt), secuenciación de la región de control d-loop del ADNmt (HVRI), de microsatélites autosómicos, short tandem repeats (STR´s) y microsatélites del cromosoma Y de un grupo de etnias asentadas en el Piedemonte del Departamento del Beni de Bolivia. Las poblaciones Mosetén y Chimane son autóctonas de la zona mientras que las poblaciones Aymará y Quechua deben considerarse colonas en la región ya que su área de poblamiento original se halla en otros departamentos, mayoritariamente andinos. Las poblaciones autóctonas, si bien presentan una cultura común, pertenecen a grupos lingüísticos claramente diferenciados. Las etnias Mosetén y Chimane son de habla Ge-Pano-Caribe, mientras que las poblaciones Aymará y Quechua pertenecen al stock de lenguas Andinas. Las poblaciones del Piedemonte andino boliviano son potencialmente muy interesantes en el contexto de la biología y la evolución humana dada su ubicación geográfica a medio camino de la zona andina y la amazónica y por el contexto de su historia. El piedemonte es una ruta natural de paso entre las dos áreas que presenta una historia demográfica compleja con llegadas migratorias primitivas, influencias incaicas y reducciones franciscanas y jesuíticas que influyeron en la dinámica poblacional de los grupos que allí habitaban y que, en la actualidad, si bien mantienen sus peculiaridades culturales y lingüísticas, poseen un reducido efectivo poblacional. Por otro lado, los movimientos migratorios más recientes de otras poblaciones hacen de la región del Piedemonte una zona excelente para estudiar la diversidad y microdiferenciación de las poblaciones humanas en el continente americano., [eng] The thesis attempts to define the demographic situation of a group of Macro-Panoan linguistic populations living in the Piedmont foothills of the Beni Department (Bolivia) and describe the population genetics of these populations using mitochondrial DNA haplogroups, mtDNA hipervariable region I (HVRI) of the control region, autosomal microsatellites (STR's) and Y-chromosome microsatellites (Y-STR’s). Moseten and Chimane populations are autochthonous indigenous of the area while Aymara and Quechua populations should be considered new settlers in the region since their original settlements are the Andean Departments. These two groups of populations belong to distinct linguistic clusters. Chimane Moseten belong to Ge-Pano-Carib speaking group while the Aymara and Quechua populations belong to the Andean language stock. Populations of the Bolivian piedmont are potentially interesting in the context of biology and human evolution because of its location halfway between the Andes and the Amazon areas and the context of its history. The piedmont is a natural passage between the two areas with a complex demographic history with primitive migratory arrivals, Inca influences and Franciscan and Jesuit reductions that influenced the population dynamics of the groups who lived in this territory in the past. Populations who live in piedmont nowadays, maintain their linguistic and genetic diversity although they have a reduced effective population. On the other hand, more recent migration of other populations make the region an excellent location to study the diversity and microdifferentiation of human population in the Americas.

Previous genetic, anthropological and linguistic studies have shown that Roma (Gypsies) constitute a founder population dispersed throughout Europe whose origins might be traced to the Indian subcontinent. Linguistic and anthropological evidence point to Indo-Aryan ethnic groups from North-western India as the ancestral parental population of Roma. Recently, a strong genetic hint supporting this theory came from a study of a private mutation causing primary congenital glaucoma. In the present study, complete mitochondrial control sequences of Iberian Roma and previously published maternal lineages of other European Roma were analyzed in order to establish the genetic affinities among Roma groups, determine the degree of admixture with neighbouring populations, infer the migration routes followed since the first arrival to Europe, and survey the origin of Roma within the Indian subcontinent., Our results show that the maternal lineage composition in the Roma groups follows a pattern of different migration routes, with several founder effects, and low effective population sizes along their dispersal. Our data allowed the confirmation of a North/West migration route shared by Polish, Lithuanian and Iberian Roma. Additionally, eleven Roma founder lineages were identified and degrees of admixture with host populations were estimated. Finally, the comparison with an extensive database of Indian sequences allowed us to identify the Punjab state, in North-western India, as the putative ancestral homeland of the European Roma, in agreement with previous linguistic and anthropological studies., Trabajo parcialmente financiado por la Fundación de Ciencia y Tecnología, a través del proyecto PTDC/ANT/70413/2006 y POCI 2010, Programa Operacional Ciencia e Inovación; Dirección General de Investigación, Ministerio de Educación y Ciencia, España (CGL2009-14944/BOS); Direcció General de Recerca, Generalitat de Catalunya (2009SGR1101) y la Austrian Science Fund (FWF): TR397.

8 páginas, 3 figuras, 4 tablas., Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humans., This research was funded by grants BFU2007-63657, BFU2009-13409-C02-02 and SAF-2007-63171 awarded by Ministerio de Educación y Ciencia (Spain), by the Direcció General de Recerca of Generalitat de Catalunya (Grup de Recerca Consolidat 2005SGR/00608 and 2009 SGR 1101), and by the National Institute for Bioinformatics (www.inab.org), a platform of Genoma España.

Studies of large sets of single nucleotide polymorphism (SNP) data have proven to be a powerful tool in the analysis of the genetic structure of human populations. In this work, we analyze genotyping data for 2841 SNPs in 12 sub-Saharan African populations, including a previously unsampled region of southeastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1000 SNPs. Our main results both confirm the results of previous studies, and show new and interesting features in sub-Saharan African genetic complexity. There is a strong differentiation of Nilo-Saharans, much beyond what would be expected by geography. Hunter-gatherer populations (Khoisan and Pygmies) show a clear distinctiveness with very intrinsic Pygmy (and not only Khoisan) genetic features. Populations of the West Africa present an unexpected similarity among them, possibly the result of a population expansion. Finally, we find a strong differentiation of the southeastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region., Esta investigación ha sido financiada por la Dirección General de Investigación, Ministerio de Ciencia y Tecnología, España (becas SAF2007-63.171, BFU2007-63657) y la Direcció General de Recerca de la Generalitat de Catalunya (2009 SGR 1101). MS fue financiado por una beca de doctorado del Programa de becas FPU del Ministerio de Educación y Ciencia, España (AP2005-3982).

Background Genetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias. Results In this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts. Conclusions In general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community. This work was supported in part by Agencia IDEA, Consejería de Innovación, Ciencia y Empresa (830882); Corporación Tecnológica de Andalucía (07/124); Ministerio de Educación y Ciencia (PCT-A41502790-2007 and PCT-010000-2007-18); Programa de Ayudas Torres Quevedo del Ministerio de Ciencia en Innovación (PTQ2002-0206, PTQ2003-0549, PTQ2003-0546, PTQ2003-0782, PTQ2003-0783, PTQ2004-0838, PTQ04-1-0006, PTQ04-3-0718, PTQ06-1-0002). CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an ISCIII project.

[spa] En esta tesis se ha analizado la variación que presentan (i) los polimorfismos Alu del cromosoma X y (ii) unos SNPs y microsatélites dentro y en torno a las regiones genómicas de los genes que codifican para los factores de coagulación VII y XII (F7 y F12 respectivamente) en distintas poblaciones humanas procedentes mayoritariamente del mediterráneo además de otras regiones geográficas. Los polimorfismos Alu son muy útiles para los estudios antropológicos que investigan el origen y las relaciones genéticas entre diversas poblaciones humanas. Asimismo, en los genes F7 y F12 se sitúan unas mutaciones que determinan los niveles plasmáticos de los factores de coagulación VII y XII y el desarrollo de enfermedades cardiovasculares, teniendo su distribución poblacional un alto interés epidemiológico. Las principales conclusiones de la tesis son las siguientes: 1. La diferenciación genética entre poblaciones del norte de África y sur de Europa es baja pero significativa. 2. Para del mismo rango de distancias geográficas en el mediterráneo, las distancias genéticas entre poblaciones procedentes de costas opuestas son más largas que entre poblaciones de la misma costa, indicando que el mar mediterráneo puede haber actuado como una barrera al flujo génico entre el norte de África y sur Europa. 3. El análisis de haplotipos de las regiones F7 y F12 ha proporcionado evidencias de un flujo génico subsahariano más elevado hacia el norte de África que el sur de Europa. Esta observación podría ser el resultado de la existencia de una barrera genética en el Mediterráneo. 4. Como han mostrado los análisis de componentes principales, la diferenciación genética interpoblacional en la parte europea del mediterráneo es menos pronunciada que en la parte Africana. 5. A diferencia de estudios anteriores, la variación genética estudiada en este trabajo mostró que los vascos no presentaron ninguna posición genética especial con respecto a otras poblaciones del sur de Europa. 6. Según los polimorfismos Alu del cromosoma X, los bereberes egipcios del Oasis de Siwa aparecen como la población más diferenciada dentro del norte de África y con una fuerte influencia subsahariana. 7. Todos los datos afirman que, de todas las poblaciones del norte de África, la población de Monastir en Túnez es la más cercana genéticamente a Europa, posiblemente debido a los antecedentes históricos de la región y a un aislamiento geográfico menos pronunciado en comparación con otros países del norte de África. 8. La variación genética del cromosoma X, pero sobretodo de los marcadores autosómicos, mostró que los bereberes procedentes del Magreb (Asni y Khenifra) son notablemente los más diferenciados en el conjunto de las poblaciones norteafricanas examinadas. 9. La distribución poblacional de la variación en la región promotora del gen F7 no presenta rasgos de selección positiva en la región mediterránea. En cambio, hay evidencias sólidas de una la selección positiva en la población indígena de Bolivia. 10. La falta de asociación entre el polimorfismo FXII 46C>T y la cardiopatía isquémica en el estudio caso-control de Túnez sugiere que dicho polimorfismo no es un factor de riesgo universal de la cardiopatía isquémica., [eng] In this work we have analyzed the variation of (i) several X chromosome polymorphic Alu insertions and (ii) several SNPs and microsatellites within and around the genomic regions of the genes coding for coagulation factors VII and XII (F7 and F12 respectively) in different human populations - mainly Mediterranean, but also from other geographic regions. Alu polymorphisms are very useful for anthropological studies to investigate the origin and genetic relationships between different human populations. In addition, there are certain mutations in the F7 and F12 genes that affect plasma levels of coagulation factors VII and XII, as well as the risk of cardiovascular diseases, with a high epidemiological relevance. The main conclusions of the thesis are the following: 1. Genetic differentiation among populations of northern Africa and southern Europe is low but significant. 2. For the same range of geographical distances in the Mediterranean, the genetic distances between populations from opposite coasts are longer than those between populations of the same coast, indicating that the Mediterranean may have acted as a barrier to gene flow between northern Africa and southern Europe. 3. Haplotype analysis of the F7 and F12 genomic regions has provided evidence of a higher sub-Saharan gene flow to northern Africa than to Southern Europe. This observation may be the result of the existence of a genetic barrier in the Mediterranean. 4. As shown by the principal component analysis, genetic differentiation between the studied populations in southern Europe is less pronounced than that in Africa. 5. Unlike previous studies, the genetic variation studied in this work showed that the Basques present no special genetic characteristics compared to other southern European populations. 6. According to the X chromosome Alu polymorphisms, the Egyptian Berbers from the Siwa Oasis appear as the most differentiated population within North African with a strong sub-Saharan influence. 7. The data indicate that, of all North African populations, the population of Monastir in Tunisia is genetically closest to Europe, possibly due to the historical background of the region and a less pronounced geographic isolation compared to other countries of northern Africa. 8. The genetic variation of both the X chromosome and, for the most part, the autosomal markers showed that the Berbers from the Maghreb (Asni and Khenifra) are significantly more differentiated among all North African populations. 9. The population distribution of the variation in the F7 gene promoter region shows no traits of positive selection in the Mediterranean region. On the contrary, there is strong evidence of positive selection in the indigenous population of Bolivia. 10. The lack of association between polymorphism FXII 46C> T and ischemic heart disease in the case-control study of Tunisia suggests that this polymorphism is not a universal risk factor for ischemic heart disease

Natural selection has played an important role in shaping human genetic variation, thus, finding variants that have been targeted by positive selection can provide insights about which genes influence human phenotypic variability. In this work we conduct a genome-wide survey of protein-coding genes comparing humans, chimpanzees, and closely related species in order to detect the fraction of genes undergoing positive selection on the human lineage, and further investigate intraspecific variation in a subset of candidate genes in the search of recent selective events in worldwide human populations. Our results suggest that most of the genes implicated in selective events during early human evolution differ from those involved in recent human adaptations, implying distinct selective pressures during varying stages of human evolutionary history. We also found three genome regions with evidence of recent positive selection, which were dissected to propose targets of selection and discuss on the possible underlying selective pressures in each case., La selección natural ha moldeado de forma importante la variación genética humana, por lo que encontrar variantes que hayan sido seleccionadas positivamente puede dar indicios acerca de los genes que determinan la diversidad fenotípica humana. En este trabajo comparamos los genes del genoma humano, del chimpancé y de varias especies cercanamente emparentadas para detectar aquellos genes bajo selección positiva en el linaje humano, y posteriormente evaluar la variación intraespecífica en un subconjunto de genes con la intención de buscar eventos de selección reciente en poblaciones humanas de todo el mundo. Nuestros resultados sugieren que la mayoría de genes implicados en eventos selectivos durante la evolución temprana del hombre no son los mismos que aquellos involucrados en adaptaciones humanas recientes, lo que implica la existencia de diferentes presiones selectivas a lo largo de las distintas etapas de la historia evolutiva humana. También encontramos tres regiones genómicas con evidencias de selección positiva reciente, las cuales fueron analizadas en profundidad para proponer posibles dianas de selección y discutir las presiones selectivas subyacentes en cada caso.

La família d'elements genètics Alu recents són insercions polimòrfiques disperses pel genoma humà. Les seves propietats com a marcadors neutres, amb estat ancestral conegut i identitat per descendència permeten, conjuntament amb la seva variació genètica associada en forma d'haplotips, ésser emprades com una eina útil en l'estudi de la genètica de les poblacions humanes. Aquest treball ha utilitzat una bateria de 20 polimorfismes Alu i tres sistemes haplotípics Alu/STR (CD4, DM, FXIIIB) en l'estudi de dos sistemes poblacionals humans amb històries particulars: la conca mediterrània i el poblament humà de l'Illa de Pasqua i el Pacífic. En el primer cas -el gruix principal d'aquesta tesi- s'han analitzat 2.291 individus d'un total de 24 poblacions antropològicament ben caracteritzades per discernir les relacions entre grups humans mediterranis, el paper dels grups berbers en la conformació d'una particularitat biològica ancestral a la regió, l'empremta de la invasió islàmica a la península Ibèrica, i el rol de les grans illes mediterrànies en l'expansió de nombroses civilitzacions i el seu impacte en la constitució genètica de les poblacions humanes actuals de la conca mediterrània. En el segon cas, s'han estudiat dos llinatges humans a Illa de Pasqua per tal de caracteritzar a partir de la variació genètica d'elements Alu el grau d'interacció d'aquesta població, durant els darrers dos segles, amb altres poblacions humanes i per discernir possibles escenaris de poblament humà recent al Pacífic i a la Polinèsia remota.Els principals resultats de d'aquesta investigació es resumeixen a continuació:1) La caracterització genètica dels grups berbers actuals mostra una certa diferenciació respecte dels grups arabòfons nord-africans, en part associada també a una major proximitat genètica dels primers amb les poblacions humanes del sud de la península Ibèrica i amb algunes de les grans illes mediterrànies.2) Les poblacions berbers presenten una elevada diversitat genètica, amb un marcat gradient de flux gènic provinent de l'Àfrica sub-sahariana i amb variants genètiques pròpies (p.e. CD4 75(+) i CD4 80(-)) i/o compartides amb altres poblacions de la conca mediterrània (p.e. DM 107(-) i CD4 110(-)) i suggerents d'un fons genètic comú ancestral pre-neolític a la regió.3) L'anàlisi del elements Alu i els sistemes haplotípics permet confirmar la permeabilitat -en diferents moments del passat- de les barreres naturals del Desert del Sàhara i de l'Estret de Gibraltar i de Messina al Mediterrani.4) La deriva genètica i l'aïllament poblacional han exercit un important paper en la conformació biològica de la població sarda, mentre que a la part occidental de Sicília el flux gènic africà hauria tingut un efecte destacable. Mallorca, Còrsega i la Sicília més oriental haurien viscut unes relacions històriques més contínues amb l'Europa continental.5) Els registres genealògics disponibles per a la població de l'Illa de Pasqua i la seva caracterització genètica han permès inferir patrons biodemogràfics i històrics particulars per a la població nativa, amb aportacions molt significatives -durant tot el segle XX- provinents de colonitzadors europeus i d'un pool gènic extern amerindi. 6) L'estudi comparatiu amb altres poblacions del Pacífic i asiàtiques demostra que els ancestres polinèsics provindrien de la regió del sud-est asiàtic i les seves grans illes, amb una certa influència de poblacions melanèsiques (15%) i que no estarien directament associades a l'expansió de la cultura neolítica de l'arròs des de Xina, Taiwan i Filipines., PhD SUMMARY:"Alu" elements are polymorphic insertions within the human genome. Its properties as neutral markers with known ancestral state and descend identity, along with their associated genetic variation, allow their use as a tool for the study of human populations. This work analyze a complete set of 20 Alu polymorphisms and 3 Alu/STR compound systems (CD4, DM, FXIIIB) for the study of two particular human systems: the Mediterranean basin and the human settlement of Easter Island and Polynesia.In the first case, the analysis try to discern the role of Berbers in the shaping of a particular biological and ancestral background in the region, the impact of the Islamic occupation and the function of large Mediterranean islands in the expansion of many civilizations biologically affecting today Mediterranean people. In the second case, the study assesses the interaction of Easter Island with other human groups and discerns possible scenarios of recent human settlement of Polynesia.Results of this research shown:1) The genetic differentiation of Berber groups with respect to North African Arabs, partly associated with greater genetic similarity with the Iberian Peninsula and with Mediterranean islands.2) A high Berber genetic diversity, with gradients of gene flow from sub-Saharan Africa, and mainly associated with particular genetic variants (CD4 75(+) and CD4 80 (-)), and shared with other populations in western Mediterranean basin (DM 107(-) and CD4 110(-)).3) Alu elements and compound systems confirms the permeability, at different past times, of natural barriers like the Sahara Desert and the Straits of Gibraltar.4) Population genetic drift and isolation have shaped the biological composition of Sardinians, whereas in western Sicily the African gene flow has had a remarkable effect.5) Genealogical records available for Easter Island inhabitants and their genetic characterization allow the reconstruction of historical biodemographic patterns and the origin of the native population, with recent significant contributions from Europeans and Amerindians.6) The comparative study shows that Polynesian ancestors came mainly from SE Asia and its major islands, with some Melanesian influence (15%) and are not associated with the Neolithic expansion of rice cultures from E China.

[eng] This thesis is the final outcome of the project "Quantitative genetics of craniofacial traits: a functional approach to heritability", which received support from the Wenner-Gren Foundation for Anthropological Research in 2004. The main goal is to integrate geometric morphometric with quantitative genetics in order to estimate the genetic variation underlying skull morphology and to assess its capability to evolve. The analyses herein are based on a sample of human skulls from Hallstatt, an Austrian village from the Alps. The uniqueness of this sample for evolutionary anthropological studies is the availability of associated genealogical data. The results show that substantial amounts of genetic variation underlying both size and shape and pervasive genetic integration are the two main aspects that characterize the genetic architecture of the human skull. The main developmental regions of the human skull (namely the face, the neurocranium and the basicranium) have similar amounts of genetic variation. There is evidence for genetic constraints, which reduce the evolutionary potential of the human skull. These correspond to shape features that can not evolve because they do not have sufficient genetic variation. The ability to evolve is restricted by complex patterns of covariation among cranial regions which direct evolution towards certain trajectories of morphological change that would maintain an operational and functional skull shape. Simulation analyses suggest a re-interpretation of the selective scenarios for human evolution. The origin of any one of the derived characters of modern humans may have facilitated the evolution of the others. The morphological changes associated with bipedalism may have enhanced the evolution of a more globular and expanded neurocranial shape, which could be favoured afterwards by selection for bigger and more complex brains. Natural selection has significantly acted over the last 200 years, since strong directional selection on skull shape and weak stabilizing selection on skull size has been detected at Hallstatt's population. However, other microevolutionary forces contributed to the evolution of skull morphology but in opposite directions, causing a non correspondence between secular trends and the response to selection patterns. The skull responds to these pressures through complex and widespread networks of genetic and epigenetic interactions., [cat] Aquesta tesi és el resultat final d'un projecte titulat "Quantitative genetics of craniofacial traits: a functional approach to heritability", que va rebre finançament per part de la Wenner Gren Foundation for Anthropological Research l'any 2004. El principal objectiu d'aquest projecte és integrar els mètodes de Morfometria Geomètrica i de Genètica Quantitativa per quantificar la variació genètica que determina la morfologia del crani humà i estimar la seva capacitat d'evolucionar. Les anàlisis realitzades estan basades en una mostra de cranis moderns de Hallstatt, una localitat dels Alps austríacs. Aquesta és una mostra única per a estudis d'antropologia evolutiva perquè els cranis tenen informació demogràfica i genealògica associada. Altres objectius específics de la tesi es detallen a continuació: 1) Quantificar els patrons de variació-covariació genètica, fenotípica i ambiental de la morfologia craniofacial humana, a través de caràcters craneomètrics univariats i multivariats. 2) Analitzar els patrons d'integració morfològica del crani humà, tant a nivell fenotípic com genètic. 3) Estimar la capacitat evolutiva del crani humà. 4) Simular l'evolució dels caràcters derivats de la morfologia craniofacial dels humans moderns. 5) Detectar l'acció de la selecció natural en el crani humà, combinant dades demogràfiques d'èxit reproductiu amb dades morfològiques. Els resultats obtinguts evidencien que els dos aspectes que caracteritzen l'arquitectura genètica del crani humà són, d'una banda, els elevats nivells de variació genètica que determinen tant la forma com la grandària del crani humà; i per l'altra, els patrons dominants d'integració morfològica. Les tres regions principals del crani (la cara, el neurocrani i el basicrani) presenten nivells similars de variació genètica, però la base del crani és la que mostra una major integració. Les anàlisis de Genètica Quantitativa indiquen l'existència de límits genètics al canvi morfològic, que redueixen la capacitat de resposta a la selecció. Aquests límits corresponen a característiques morfològiques que no poden evolucionar perquè no tenen suficient variació genètica heretable. La capacitat evolutiva del crani humana està restringida i dirigida cap a determinades trajectòries de canvi morfològic que mantindrien una forma cranial operativa i funcional. Les anàlisis de simulació de la selecció mostren que l'origen de qualsevol dels caràcters derivats dels humans moderns pot haver facilitat l'evolució dels altres, fet que suggereix una reinterpretació dels escenaris selectius de l'evolució humana. Concretament, els resultats indiquen que l'evolució del bipedisme podria haver estimulat l'evolució d'una volta cranial més gran i més globular, que posteriorment podria haver estat afavorida per la selecció per un cervell de major grandària i més complex, tal com indiquen les evidències moleculars. Finalment, s'ha detectat que la selecció natural ha operat en l'evolució de la forma del crani de la població de Hallstatt durant els últims 200 anys. Els resultats mostren una acció significativa de selecció direccional en la forma del crani i de selecció estabilitzadora en la grandària del crani. No obstant això, es detecta que altres forces microevolutives (flux gènic, mestissatge, variació ambiental) han participat en aquest procés evolutiu, però en direccions oposades a les seleccionades. La conclusió general d'aquesta tesi posa de manifest que el crani humà es troba sota l'acció de nombroses forces evolutives, que actuen simultàniament i dirigint el canvi morfològic. El crani respon a aquestes pressions a través de complexes xarxes d'interacció genètica i epigenètica.

Les malalties complexes conformen en l'actualitat la principal causa de mortalitat en les societats occidentals. D'entre elles, destaquen les malalties cardiovasculars per la seva elevada incidència tot i mostrar diferències poblacionals, com a la Mediterrània, on la mortalitat és inferior a la d'altres països europeus. Els factors genètics semblen jugar un paper important en la predisposició a patir aquestes malalties, actuant a diferents nivells i sobre diferents mecanismes de regulació fisiològica. L'òxid nítric (NO) és un dels elements implicats en aquesta regulació mitjançant els seus efectes tan directes com indirectes. El present treball ha analitzat la variació de 14 polimorfismes de DNA en els gens de les sintases d'òxid nítric NOS1, NOS2 i NOS3 en 9 poblacions humanes de la Península Ibèrica, Sardenya, Sud de França, berbers del Nord d'Àfrica i Alemanya, per avaluar-ne la seva variabilitat a la Mediterrània i la seva utilitat per reconstruir la història de les poblacions humanes. Alhora, s'ha analitzat la implicació d'aquests polimorfismes en la predisposició a la cardiopatia isquèmica (CAI) mitjançant el test de desequilibri de la transmissió (TDT) en una mostra de 101 famílies nuclears (n=302) amb un fill afectat per CAI. Per tal d'establir un significat funcional de les possibles associacions detectades s'han analitzat els nivells de nitrats i nitrits (NOx), indicadors de la producció d'òxid nítric. Totes tres regions gèniques han presentat un elevat grau de desequilibri de lligament al llarg de tota la seqüència, inclús entre parelles de polimorfismes separats més de 140 Kb. La variació observada a nivell poblacional evidencia una variabilitat interpoblacional significativa estructurada en tres grups (Europa continental, Sardenya i Berbers del Marroc) amb una variabilitat més gran entre els grups que dins dels grups. Aquesta variabilitat s'ha mostrat equivalent a la d'altres polimorfismes en regions no funcionals que s'utilitzen en estudis de genètics de poblacions, tot i que la variabilitat al gen NOS3 semblaria menys adequada per detectar relacions interpoblacionals. Les poblacions sardes analitzades es mostren com les més diferenciades de la resta i les de menor variabilitat. D'altra banda, les poblacions berbers mostren la major variabilitat del conjunt i una relativa heterogeneïtat entre si, diferenciant-se de la resta de poblacions analitzades. L'al·lel T del polimorfisme C3391T del gen NOS1 s'ha associat, sol o en haplotips que l'inclouen, amb un risc incrementat per la CAI (RR=1.8-2.0), així com també amb nivells disminuits de nitrats i nitrits en plasma en els fills amb hipertensió. La manca de funcionalitat d'aquest polimorfisme fa suposar que un altre polimorfisme (possiblement a la regió codificant pel domini reductasa de la proteïna) sigui el veritable causant d'aquesta associació. L'al·lel de 9 repeticions del pentanucleòtid (CCTTT)n de la regió promotora del gen NOS2 ha presentat associació significativa amb la malaltia (p=0.008) conferint un risc menor per la CAI (RR=0.027). L'estudi de la regió promotora d'aquest gen podria proporcionar informació important sobre la implicació del gen NOS2 en la malaltia cardiovascular. Al gen NOS3, els al·lels de ≥38 repeticions del dinucleòtid (CA)n de l'intró 13 es mostren significativament associats a un menor risc (RR=0.17) per la CAI. Estudis in vivo i in vitro indiquen que l'associació podria estar relacionada amb una major eficiència en els processos de splicing, tot i que els resultats discrepen totalment amb els d'alguns treballs previs., EXTRACTE EN ANGLÈS - SUMMARY: Cardiovascular diseases are a leading cause of mortality in western countries, although their incidence is not equally distributed among them, showing Mediterranean countries the lowest mortalities in Europe. Genetic risk factors play an important role in the pathophysiology of cardiovascular disorders, where nitric oxide (NO) mediates vasoprotective processes through reactions with its target molecules. The present work has analyzed the variation of 14 polymorphisms in the nitric oxide synthase (NOS1, NOS2 and NOS3) in 9 human populations from Iberian Peninsula, Sardinia, South France, berbers from North Africa, and Germany in order to evaluate their variation and their usefulness to reconstruct human populations history. Furthermore, an association study between these markers and ischaemic heart disease (IHD) has been performed in a 101 families sample (n=302) through transmission disequilibrium test (TDT). Aditionally, nitrate and nitrite (NOx) levels (indicators of NO production) have been quantified in the families sample to stablish a functional explanation for the detected associations. NOS variability has been useful to assess population relationships, being the most reliable estructuration that constituted by three groups: continental Europe, Sardinia, and North-Africa. Sardinian samples have shown the lower levels of intrapopulation variation and the Berber samples the highest heterogeneity. The T-allele of C3391T polymorphism in NOS1 gene has been associated with a lower risk for IHD (RR=1.8-2.0) together with lower NOx levels among hypertensive affected offspring. This polymorphism has not a functional role, and the association is probably related with an unidentified polymorphism in the NOS1 sequence. 9-repeats allele of the pentanucleotide (CCTTT)n in NOS2 promoter region plays a protective role (RR=0.27) in IHD, and the analysis of this promoter region could provide information on NOS2 implication in cardiovascular disease. In NOS3 gene, ≥38-repeats alleles of intron 13 (CA)n dinucleotide show a reduced risk (RR=0.17) for IHD. In vivo and in vitro models indicate that this association could be related to a greater efficacy in splicing processes, although there are discrepancies with previous association studies.

Las enfermedades genéticas se clasifican típicamente en dos grandes grupos: las enfermedades mendelianas y las enfermedades complejas. Mientras que las enfermedades mendelianas se caracterizan por ser de baja frecuencia en la población y estar causadas por mutaciones en un gen particular, las enfermedades complejas son el principal problema sanitario en los países desarrollados y se encuentran producidas por la interacción de factores ambientales y factores genéticos. En este caso no se puede hablar de mutación en un determinado gen, sino de polimorfismo que incrementa en una pequeña fracción el riesgo a padecer la enfermedad. En la presente tesis se ha estudiado la distribución espacial de la variabilidad genética tanto en enfermedades mendelianas (en concreto la fibrosis quística, la fenilcetonuria y la b-talasemia) como en una enfermedad compleja (la enfermedad coronaria) en poblaciones europeas y de todo el mundo. Los resultados obtenidos sugieren que la distribución geográfica de la variabilidad genética de las enfermedades mendelianas depende principalmente de factores demográficos y de la historia de las poblaciones. Ahora bien, este efecto no es independiente de factores selectivos. En particular, fenómenos de selección equilibradora pueden incrementar o disminuir la variabilidad genética en una población dependiendo de el momento en el que se dio el evento selectivo. En el caso de la enfermedad compleja estudiada, la enfermedad coronaria, nuestros resultados indican que la distribución espacial de los polimorfismos de riesgo en poblaciones europeas depende, al igual que sucede con otros marcadores genéticos, principalmente de la historia de poblaciones, especialmente del poblamiento del continente europeo, la posterior reexpansión después del último periodo glacial y de las gran expansión poblacional de los agricultores durante el neolítico.

El trabajo realizado trata de estudiar la diversidad del genoma mitocondrial humano en poblaciones humanas de diferentes áreas geográficas que habían sido hasta ahora poco o nada estudiadas. Los grupos de poblaciones humanos estudiados en este trabajo esta formado por las poblaciones del oeste del Mediterráneo, de l'África sub-Sahariana, de la Isla de La Reunión, y de l'Asia. Cada una de estas poblaciones pertenecen a un entorno geográfico diferente y han padecido diferentes y numerosos movimientos de poblaciones que han modulado su composición genética. El análisis de diferentes polimorfismos del genoma mitocondrial han permitido entender los factores poblacionales, tal como la migración, la mezcla genética, la deriva genética, los efectos fundadores, y inferir la historia d la poblaciones bajo estudio, La metodología utilizada incluye diferentes tipos de técnicas adaptadas a los diferentes tipos de polimorfismos estudiados. La técnica aplicadas fueron la secuenciación, el análisis de fragmentos y la técnica de SNaPshot. Los resultados obtenidos han aportado un conocimiento nuevo de las poblaciones que han modulado la diversidad genética de los grandes grupos humanos a nivel continental pero también a un nivel mas regional.

S'ha dut a terme un estudi biodemogràfic complert de la població del Delta de l'Ebre (Tarragona) a partir dels matrimonis registrats a quatre de les seves parròquies: la Cava, Jesús i Maria, Amposta i St.Jaume d'Enveja, durant els segles XIX i XX. Va ser precisament durant aquests segles quan va tenir lloc la colonització massiva del Delta gràcies a la canalització de les seves terres i a la conseqüent extensió dels cultius, especialment del cultiu de l'arròs. En un primer moment la població colonitzadora arribava des de les terres de secà del voltant, però, ràpidament les immigracions es van estendre a individus provinents del País Valencià i l'Aragó i, més endavant, del sud de la Península Ibèrica.Entre els aspectes analitzats en aquesta tesi, destaquen l'estacionalitat matrimonial, els nivells d'endogàmia i consanguinitat de la població, les distàncies interparroquials obtingudes a partir dels matrimonis i un exhaustiu estudi dels cognoms dels cònjuges (diversitat, isonímia, consanguinitat, etc). Prèviament, però s'ha dut a terme una descripció de la població utilitzant els paràmetres biodemogràfics habituals.Els diversos resultats obtinguts mostren que es tracta d'una zona amb una elevada endogàmia (de les més altes de Catalunya) i un comportament força aïllat respecte altres poblacions de la comarca i de les comarques veïnes. L'economia, basada de manera majoritària en el cultiu de l'arròs té una enorme influència en els cicles matrimonials dels habitants del Delta, tal i com ho demostra la marcada estacionalitat matrimonial observada durant la primera meitat del segle XX, amb màxims entre octubre i març, coincidint amb l'època de menor activitat agrícola en aquest tipus de cultiu.Alhora, en la població deltaica s'observa una estructura interna força peculiar. En primer lloc destaca la clara diferenciació dels matrimonis registrats a Amposta respecte els de la resta de parròquies, especialment a causa d'una major presència d'individus nascuts fora del Delta en els matrimonis ampostins. Així doncs, la població d'Amposta, ja sigui degut a la seva situació geogràfica, més perifèrica respecte la resta de parròquies analitzades o bé degut a la seva condició de capital de comarca, ha actuat com un focus d'atracció de la població immigrant i, per tant, té un comportament molt menys endògam que la resta de parròquies.Per altra banda, si només es tenen en compte els matrimonis entre individus nascuts al Delta de l'Ebre, s'observa una clara diferenciació entre les parròquies d'una i altra banda del riu. Aquest fet subratlla la importància d'aquest com a barrera entre les poblacions, potser no tan geogràfica com històrica, ja que precisament el riu hauria marcat la frontera entre les dues etapes del procés de canalització: una primera a la riba sud cap al 1860 i una segona als voltants de 1912 a la riba nord. Aquesta asincronia es veu clarament reflectida en les distàncies genètiques calculades entre les poblacions d'una i altra riba del riu, tant a partir del nombre de matrimonis com a partir de les freqüències dels cognoms.ENGLISH ABSTRACT, A biodemographic analysis of the Ebro Delta (Tarragona) population has been done using the marriages recorded in four of its parishes: La Cava and Jesús i Maria, both on the north side of the river, and Amposta and St.Jaume d'Enveja, on the south side. These marriages are dated on the 19th and 20th centuries, the period when the the river was canalized allowing the extension of the crops (particularly rice) on the region and, consequently, the settlement of the land. The first immigrants arrived from the neighbouring dry land, later came from Valencia and Aragon and finally from the south of the Iberian Peninsula.The parameters analysed are: marriage seasonality, levels of endogamy and inbreeding, distances between parishes as taken from marriages and an exhaustive surname analysis. Previously, a population's description has been done using the usual biodemographic parameters.Obtained results show that the Ebro Delta has high endogamy levels (one of the highest in Catalonia) and an isolated behaviour relative to the neighbouring populations. Economy is based on rice culture, and has a great influence on the marriage cycle, as can be observed by the clear marriage seasonality on the first half of the 20th century, with maximums between October and March, when the activity decreases.An apparent internal structure emerges on the Delta population. First of all, there is a clear differentiation of Amposta with respect to the rest of the locations, with a lesser influence of the agrarian cycle over nuptiality and a greater incidence of marriages to individuals born outside the delta. If only the marriages between people born on the Ebro Delta are taken into account, a separation from parishes from both banks of the river can be observed, fact that can be related with the different colonizing processes of both hemideltas.

Se ha analizado la variabilidad de 16 polimorfismos hemáticos en la población de la isla de Menorca. Con ello se pretende la caracterización antropogenética de dicha población en relación a otros grupos de la Península Ibérica, de la Cuenca Mediterránea y del Centro y Norte de Europa. Los datos aportados en Menorca representan asimismo una contribución para ampliar el conocimiento de estos marcadores en las poblaciones españolas.Si se tiene en cuenta la posición geográfica y la historia de Menorca, dos factores parecen haber tenido un papel esencial en la configuración de las características de esta población. En efecto, la condición de insularidad, por un lado, puede haber favorecido un cierto aislamiento ya que constituye una relativa barrera geográfica, y por otro lado, supone un lugar de paso en el tráfico marítimo por donde han podido llegar influencias de grupos poblacionales diversos. Así pues, el interés antropológico del estudio de la población de Menorca radica en su carácter autóctono y en su peculiar situación dentro de las rutas marítimas del Mediterráneo Occidental, por lo que puede considerarse mediterráneo particular del que se carece de datos relativos a sus características hematológicas.Para llevar a cabo el análisis experimental se recogieron muestras de sangre en distintas campañas, que fueron procesadas convenientemente en función de los caracteres a estudiar. Todas las muestras analizadas proceden de individuos de ambos sexos, naturales del área de Ciutadella y con ascendencia menorquina al menos en dos generaciones, por lo que pueden considerarse representativas de la población autóctona.Los polimorfismos estudiados son los sistemas de grupos sanguíneos ABO, Lewis, Rh (CDE), MNSs, Kel1, P y Duffy; los enzimas eritrocitarios Adenosindeaminasa(ADA; EC 3.5.4.4), 6-Fosfogluconato deshidrogenasa (6-PGD; EC 1.1.1.44), Esterasa D (EsD; EC 3.1.1.1), Fosfatasa ácida (ACP-l; EC 3.1.3.2) y Glioxalasa 1 (GLO 1; EC 4.4.1.5), y las proteínas séricas Haptoglobina (Hp), Transferrina (Tf), Componente grupal específico (Gc) y Alfa-1-antitripsina (sistema Pi).Los antígenos de los grupos sanguíneos fueron detectados utilizando muestras de sangre conservadas a + 4 ºC, en un período de tiempo no superior a los 5 días después de la extracción. Para ello los hematíes fueron sometidos a reacciones de aglutinación usando los anticuerpos anti-A(1); -A, -B, -(A + B), -Le(a), -Le(b), -D, -(C + C(W)), -C(w), -c, -E, -e, -M, -N, -S, -s. -K, -k, -PI Y -Fy(a), siguiendo las técnicas habituales.Los fenotipos isoenzimáticos fueron identificados mediante electroforesis horizontal en gel de almidón a partir de sedimentos de hematíes congelados a -40 ºC. Una vez finalizada la electroforesis, las zonas de actividad enzimática fueron reveladas mediante la tinción de los geles utilizando sustratos específicos.La determinación de las variantes proteicas fue llevada a cabo a partir de muestras de suero conservadas a -40 ºC, mediante técnicas de electroforesis vertical e isoelectroenfoque en geles de poliacrilamida. La sensibilidad de estos métodos ha permitido la identificación de tipos y subtipos de las proteínas estudiadas.Los valores fenotípicos obtenidos en el análisis experimental han sido sometidos a un tratamiento estadístico que incluye el cálculo de las frecuencias génicas según el método de "máxima verosimilitud" y el estado de equilibrio Hardy-Weinberg mediante la prueba de la (X)2. De este modo, la población de Menorca queda caracterizada por las frecuencias de 54 alelos y de 12 combinaciones haplotípicas.Asimismo, a partir de las frecuencias obtenidas se ha estudiado comparativamente el grado de afinidad entre Menorca y otros grupos de ámbito mediterráneo y europeo. Este análisis se ha llevado a cabo atendiendo, en primer lugar, a cada sistema por separado, utilizando la prueba de la X(2) , el tratamiento de las tablas 2 x 2 de Fisher y el método gráfico del triángulo equilátero cuando ha sido factible. También se han realizado comparaciones considerando simultáneamente varios loci mediante el análisis .de las distancias genéticas según los coeficientes de Nei (1972),Prevosti (1974) y Edwards (1971).Los cálculos de las distancias y la construcción de los dendrogramas correspondientes aplicando el algoritmo UPGMA han sido efectuados utilizando el programa BIOSYS.Los resultados encontrados ponen de manifiesto la utilidad general de los polimorfismos hemáticos y en particular la de los subtipos proteicos para la descripción de las poblaciones humanas. En este sentido, las frecuencias alélicas de todos los marcadores analizados en Menorca permiten la identificación antropogenética de dicha población. Las comparaciones efectuadas para los distintos sistemas indican que la posición de Menorca con respecto a los grupos comparados queda definida por presentar las siguientes características:a) Frecuencias bajas para los genes B, C(W) y Fy(a), que se ajustan a los gradientes descritos para estos alelos, según los cuales disminuyen en sentido E-O en la región mediterránea y también de NE a SO en el Centro y Norte de Europa.b) Un valor de P(I) claramente diferenciado de los del Mediterráneo Oriental y de otras poblaciones de la Península Ibérica.c) Unas frecuencias de Ms, NS, ACP(A) y ACP(B) que, si bien quedan dentro de la variabilidad mediterránea, son extremas con respecto a los grupos norte y centroeuropeos.d) Un valor de PGC(C) similar a los más bajos del Mediterráneo y del mismo orden que los más elevados del Centro y Norte de Europa.e) Unas frecuencias elevadas de ADA(I) y GLO(I) de acuerdo con el aumento en sentido este-oeste que presentan ambos alelas en la región circunmediterránea.f) Unos valores para los marcadores proteicos muy similares a los de la Península Ibérica y que resultan extremos (máximos para Hp(I), Pi(S) y Pi(M3) , y mínimos para Gc(IF), Gc(IS), Pi(M)y Pi(MI)) con respecto a la variabilidad descrita en otros grupos del Mediterráneo y del Centro y Norte de Europa.Los análisis de las distancias genéticas revelan que la población menorquina presenta mayor afinidad genética con otros grupos mediterráneos que con los del Centro y Norte de Europa. Asimismo, dentro del ámbito mediterráneo, Menorca muestra mayor semejanza con las poblaciones de la parte central y noroccidental que con otros grupos de esta área geográfica. Por último, dentro de la Península Ibérica, la población estudiada es más afín con las series de la costa nororiental que con las de otras zonas peninsulares. Esto podría estar en relación con la influencia del área catalana sobre Menorca a lo largo de su historia, sin embargo no se excluyen diferencias importantes para algunos de los "loci" considerados.En conclusión, los resultados del presente estudio ponen de manifiesto la similitud de la población actual de la isla de Menorca con el conjunto de poblaciones de su entorno geográfico, aunque manteniendo unas características diferenciales que le confieren una personalidad propia desde el punto de vista genético. Estas diferencias podrían explicarse, por un lado, como consecuencia de los aportes génicos externos que ha ido recibiendo a lo largo de su historia por parte de distintos grupos poblacionales.Por otro lado, la condición de insularidad podría haber contribuido asimismo a su diferenciación., Genetic polymorphism of seven blood group systems (ABO, Lewis, Rh-CDE, MNSs, Kell, P and Duffy), five red cell enzymes (ADA, 6-PGD, ESD, ACP-l and GLO 1), and four serum proteins (Hp, Tf, Gc and alpha-lantitrypsin) has been investigated in Minorcan Island population. Blood samples were collected from unrelated individuals of both sexes living in the northwest part (Ciutadella) of the Island, and whose ancestors (parents and grandparents) were autochthonous. Using specific antisera the blood specimens were tested for the following blood group antigens: A, A(1), B, Le(a), Le(b), D, D(u), C, C(w), c, E, e, M, N, S, s, K, k, PI and Fy(a). Typing in each enzyme system was performed on erythrocyte lysates by horizontal starch gel electrophoresis. The haptoglobin alpha and alpha(2)-peptides were studied by vertical polyacrylamide gel electrophoresis while the Tf, Gc and alpha1-antitrypsin subtypes were determined using isoelectric focusing techniques. The frequencies of 54 alleles and 12 haplotypes obtained have made possible the genetic characterization of Minorcan population in relation to different population sets: Iberian Peninsula, Mediterranean area, and North and Central Europe. Genetic distance analysis have been performed according to the coefficients of Nei (1972), Prevosti (1974) and Edwards (1971) using the BIOSYS program. The results of distances were clustered by the application of the UPGMA algorithm to construct the dendrograms. Genetically, Minorca is closer to the northwest Mediterranean populations than to others from North and Central Europe. In the Iberian Peninsula, Minorca is genetically more similar to the northeast coast groups, possibly according to the greater Catalan influence over the Island in the past. Nevertheless, we do not exclude important differences with these populations for some of the studied characters. In conclusion, for the genetic markers considered it is evident the integration of the Minorcan population into the Spanish and northwest Mediterranean ambit, although showing a particular features which make it different from neighbouring groups. This differentiation could be due to the contributions of different population groups which has undergone along the history. On the other hand, these differences could also have been preserved thanks to the insularity of the studied population.

ACKGROUND: In recent years, several genomic regions have been robustly associated with coronary artery disease (CAD) in different genome-wide association studies (GWASs) conducted mainly in people of European descent. These kinds of data are lacking in African populations, even though heart diseases are a major cause of premature death and disability. METHODS: Here, 384 single nucleotide polymorphisms (SNPs) in the top four CAD risk regions (1p13, 1q41, 9p21, and 10q11) were genotyped in 274 case-control samples from Morocco and Tunisia, with the aim of analyzing for the first time if the associations found in European populations were transferable to North Africans. RESULTS: The results indicate that, as in Europe, these four genetic regions are also important for CAD risk in North Africa. However, the individual SNPs associated with CAD in Africa are different from those identified in Europe in most cases (1p13, 1q41, and 9p21). Moreover, the seven risk variants identified in North Africans are efficient in discriminating between cases and controls in North African populations, but not in European populations. CONCLUSIONS: This study indicates a disparity in markers associated to CAD susceptibility between North Africans and Europeans that may be related to population differences in the chromosomal architecture of these risk regions.

It is well known that the Neolithic transition spread across Europe at a speed of about 1 km/yr. This result has been previously interpreted as a range expansion of the Neolithic driven mainly by demic diffusion (whereas cultural diffusion played a secondary role). However, a long-standing problem is whether this value (1 km/yr) and its interpretation (mainly demic diffusion) are characteristic only of Europe or universal (i.e. intrinsic features of Neolithic transitions all over the world). So far Neolithic spread rates outside Europe have been barely measured, and Neolithic spread rates substantially faster than 1 km/yr have not been previously reported. Here we show that the transition from hunting and gathering into herding in southern Africa spread at a rate of about 2.4 km/yr, i.e. about twice faster than the European Neolithic transition. Thus the value 1 km/yr is not a universal feature of Neolithic transitions in the world. Resorting to a recent demic-cultural wave-of-advance model, we also find that the main mechanism at work in the southern African Neolithic spread was cultural diffusion (whereas demic diffusion played a secondary role). This is in sharp contrast to the European Neolithic. Our results further suggest that Neolithic spread rates could be mainly driven by cultural diffusion in cases where the final state of this transition is herding/pastoralism (such as in southern Africa) rather than farming and stockbreeding (as in Europe).

9 pages, 2 figures, 4 additional files., [Background] It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8., [Results] Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates., [Conclusion] The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology., This research was supported by "Fundación Genoma España" (proyectos piloto CEGEN 2004–2005), Dirección General de Investigación, Ministerio de Educación y Ciencia of Spain (grants BFU2005-00243, BFU2006-01235, BFU2006-15413-CO2-01, SEJ2006-13537) and Direcció General de Recerca, Generalitat de Catalunya (2005SGR00608). SNP genotyping services were provided by the Spanish "Centro Nacional de Genotipado"