Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: The South African abalone, Haliotis midae, commonly known as perlemoen, is an economically important gastropod mollusc. Historically, this species maintained a lucrative fisheries sector; however with increasingly lower landings there has now been a shift to aquaculture. Efforts to conserve natural populations and to improve abalone aquaculture production are thus running in parallel. Previous studies reported significant disparities in parental contributions in aquaculture populations that could explain the rapid divergence of commercial stocks from wild populations. Furthermore, subtle, but significant, population differentiation has also been reported for wild populations on the west-, south-, and east coast of the South African coastline. This study therefore aimed to investigate the evolutionary forces, in particularly selection, facilitating population divergence in wild and cultured H. midae populations using a population genomics approach. By using both microsatellite- and single nucleotide polymorphism (SNP) markers it was found that approximately 10% to 27% of the H. midae genome may be influenced by selection. When incorporating these loci into analyses of population differentiation (e.g. AMOVA, factorial correspondence analysis and estimates of genetic distance) there was a marked increase in genetic divergence between wild and cultured populations (especially when using microsatellite loci) and amongst populations from different geographic regions (particularly supported by the SNP loci). The differences in population clustering as highlighted by microsatellite- and SNP markers can most likely be attributed to the genomic distribution of the respective loci: The SNP markers were developed from EST sequences and therefore mostly represents protein structural variation; whereas the microsatellite markers, found to be putatively under selection, were mainly located in regulatory motifs. The results of this study therefore confirmed previous observations of divergence amongst wild- and cultured populations, but more importantly demonstrated that selection is an important factor driving this divergence. In wild populations selection probably facilitates adaptation to local environmental conditions, whilst amongst aquaculture population adaptation to captivity, husbandry practices and artificial selection may be important determinants. There is evidence for population bottlenecks in wild- and cultured populations; nonetheless long-term effective population sizes seem to be large. Amongst the wild populations, however, short-term population sizes appear to be small most likely due to differential spawning rates amongst reproductively active animals leading to temporal fluctuation in genetic diversity. The results indicate that contact between wild and cultured abalone should be minimised to prevent any adverse effects due to outbreeding depression. With regards to conservation, an emphasis on maintaining adaptive diversity of the wild stocks might be warranted. Continued genetic monitoring is advisable for both wild and cultured abalone populations as to optimally manage the abalone resource for both conservation and commercial viability and sustainability. / AFRIKAANSE OPSOMMING: Die Suid-Afrikaanse perlemoen, Haliotis midae, is 'n ekonomies belangrike buikpotige weekdier. Histories het hierdie spesie 'n winsgewende vissery gehandhaaf, maar met steeds dalende vangste is daar nou 'n verskuiwing na akwakultuur. Pogings om natuurlike populasies te bewaar en perlemoen te verbeter vir verhoogde akwakultuur produksie loop dus in parallel. Vorige studies het bevind dat beduidende verskille in ouerlike bydraes tot die nageslag, in akwakultuur populasies, kan verduidelik hoekom die populasies so vinnig divergeer van die wilde voorouers. Verder, is subtiele, maar betekenisvolle genetiese differensiasie tussen wilde populasies aan die wes-, suid-en ooskus van die land gevind. Hierdie studie is dus daarop gemik om ondersoek in te stel na die mate waartoe verskeie evolusionêre prosesse, in besonder seleksie, die populasie divergensie in beide wilde en gekweekte H. midae teweegbring deur gebruik te maak van ‘n populasie genomika benadering. Deur gebruik te maak van beide mikrosatelliet- en enkel nukleotied polimorfisme (ENP) merkers is dit bevind dat ongeveer 10% tot 27% van die H. midae genoom moontlik beïnvloed word deur seleksie. Met die gebruik van loki onder seleksie tydens die ontleding van populasie differensiasie (bv. AMOVA, faktoriaal korrespondensie analise en genetiese afstand ramings) was daar 'n merkbare toename in genetiese divergensie tussen wilde- en gekweekte populasies (veral wanneer mikrosatelliet loki gebruik is) en onder die populasies vanuit verskillende geografiese gebiede (veral ondersteun deur die ENP loki). Die verskille in die populasie groeperings soos uitgelig deur die mikrosatelliet- en ENP-merkers kan waarskynlik toegeskryf word aan die genomiese verspreiding van die onderskeie loki: Die ENP-merkers is ontwikkel vanaf uitgedrukte volgorde merker (UVM) volgordes en daarom verteenwoordig dit meestal proteïen strukturele veranderinge, terwyl mikrosatelliet merkers eerder in regulatoriese motiewe geleë is. Die resultate van hierdie studie steun dus vorige waarnemings, maar meer belangrik, het dit getoon dat seleksie ‘n betekenisvolle faktor in populasie divergensie in beide wilde en gekweekte populasies is. In wilde populasies fasiliteer seleksie waarskynlik die aanpassing tot plaaslike omgewingstoestande terwyl seleksie onder die gekweekte populasies teweeggebring kan word as gevolg van aanpassing tot aanhouding, boerdery praktyke en kunsmatige seleksie. Daar is bewyse vir populasie bottelnekke in wilde- en gekweekte populasies; tog blyk langtermyn effektiewe populasiegroottes om redelik groot te wees. Onder die wilde populasies is egter gevind dat kort-termyn populasiegroottes klein kan wees, waarskynlik as gevolg van differensiële broeikoerse onder reproduktiewe diere. Dit het tot gevolg dat daar beduidende fluktuasies is in temporale genetiese diversiteit. Die resultate dui daarop dat kontak tussen wilde en gekweekte perlemoen tot 'n minimum beperk moet word om enige nadelige effekte weens uitteling depressie te voorkom. Verder, met betrekking tot bewaring, is ‘n klem op die handhawing van aangepaste genetiese diversitiet dalk geregverdig. Voortgesette genetiese monitering word aanbeveel vir beide wilde- en gekweekte perlemoen populasies ter wille van die optimale bestuur van die perlemoen hulpbron vir beide bewaring en kommersiële lewensvatbaarheid en volhoubaarheid. / International Foundation for Science / National Research Foundation of South Africa / Stellenbosch University

This PhD seeks to explore the development of a bio-molecular (i.e., genomic) map as a sovereign resource in Mexico. The basic analytical thread of the dissertation is related to the circulation of genomic variability through the policy/legal and scientific social worlds that compose the Mexican medical-population genomics arena. It follows the construction of the Mexican Institute of Genomic Medicine (INMEGEN), the notion of genomic sovereignty, and the Mexican Genome Diversity Project (MGDP).The key argument for the construction of the INMEGEN relied in a nationalist policy framing, which considered the Mexican genome as a sovereign resource, coupling Mexican “uniqueness” to the very nature of genomic science. Nevertheless, the notion of genomic sovereignty was nothing similar to a paradigm, and was not based on shared visions of causality, since the very “nature” of the policy object —Mexican Genome— was, and still is, a disputed reality. It was through the rhetoric upon independence, emancipation and biopiracy: i.e. experiences of dispossession “in archaeology, botany or zoology” (IFS 2001: 25) that the novelty of population genomics became amenable to be understood as a sovereign matter. Therefore, the strategic reification of Mexicanhood fuelled the whole policy and the legal agenda of the INMEGEN as well, which permitted cooperation without consensus and opened the process of policy innovation. Conversely, scientists considered genomic sovereignty an unfounded exaggeration, but anyhow they cooperated and even created a new policy and scientific enterprise. Genomic sovereignty exemplifies the process of cooperation without consensus on its most extreme version .So, as the notion circulated and gradually became a law to protect Mexican genomic patrimony, the initial coalition of scientists, lawyers and policy makers disaggregated. Many of the original members of the coalition now think of genomic sovereignty as a strategy of the INMEGEN to monopolise genomic research in the country. This dissertation additionally explores the way in which the MGDP is constructed in mass media, in INMEGEN´s communication and in the laboratory practices. These different dimensions of the MGDP depict the difficulties that emerge between the probabilistic, relative and multiple constructions of population genomics and the rhetorical strategies to continually assert the existence of the unique “Mexican Genome”. I argue that the Mexican case study provides an entry point to what I and others (Benjamin 2009; Schwartz-Marin 2011) have identified as a postcolonial biopolitics in which the nation state is reasserted rather than diluted. However the relation between sovereignty, race and nation is not mediated by the biological purification of the nation (Agamben 1998; Foucault 2007), or the active participation of citizens looking to increase their vitality (Rose 2008, Rose & Rabinow 2006), but on an awareness of subalternity in the genomic arena and a collective desire to compete in the biomedical global economy.

A cana-de-açúcar (Saccharum ssp.) é uma cultura valiosa na produção de alimento, fibra e energia para o Brasil e, especialmente, para o estado de São Paulo. Com o advento da biotecnologia, alternativas de melhoramento genético têm despertado a atenção da comunidade científica, sendo etapas cruciais para tais avanços o sequenciamento e a caracterização do genoma das espécies cultivadas. Dada sua natureza poliploide, com frequente aneuploidia, a cana-de-açúcar apresenta dificuldades às práticas convencionais em genômica, de maneira que é vantajoso fazer uso de recursos de sequenciamento de nova geração e de espécies próximas para elucidar de forma mais efetiva o genoma da gramínea. Uma contribuição interessante, nesse sentido, é a caracterização funcional de polimorfismos genéticos existentes entre genótipos do gênero Saccharum, auxiliando investigações relacionadas à genômica de poliploides complexos, desenvolvendo um recurso a ser utilizado futuramente por melhoristas. Esse trabalho realizou a caracterização da variabilidade genômica a partir de dados genotípicos de indivíduos do Painel Brasileiro de Genótipos de Cana-de-Açúcar, obtidos via genotipagem-por-sequenciamento, utilizando como referência o genoma já sequenciado do sorgo. Os sítios variantes (sobretudo polimorfismos de nucleotídeo único) foram detectados com o software FreeBayes e suas possíveis funções e posições foram anotadas com o programa SnpEff. Utilizaram-se estatísticas de genética de populações, como a frequência alélica para várias classes de polimorfimo, o Teste de McDonald & Kreitman (busca de evidêcias de evolução adaptativa) e a heterozigosidade combinada (busca de regiões genômicas com assinatura de seleção), de modo a identificar regiões genômicas potencialmente envolvidas em eventos evolutivos. Os resultados demonstraram a perda de variabilidade entre os genótipos melhorados em relação aos ancestrais, com evidências de assinaturas de seleção, envolvendo questões sensíveis ao funcionamento da maquinaria celular (como respiração e fotossíntese) e a características valoradas para a cultura (destacando-se a resistência a patógenos e a biossíntese da sacarose). Tais indícios fornecem subsídios à compreensão do genoma e ao melhoramento genético desse poliploide. / Sugarcane (Saccharum ssp.) is a valuable crop for food, fiber and energy production in Brazil, especially to the São Paulo State. With the advent of biotechnology, alternatives to breeding have enticed attention of the scientific community, with genome sequencing and characterization being crucial steps to these advances. Because sugarcane is polyploid, with frequent aneuploidy, it presents difficulties to the application of standard practices in genomics, such that it is advantageous to make use of next generation sequencing alternatives and resources from related species to more effectively elucidate the genome of this grass. Thus, an interesting contribution is the functional characterization of genetic polymorphisms from the Saccharum genus, aiding investigations related to genomics of complex polyploids, developing a resource to be used in the future by breeders. Our goal was to perform this characterization with genotypic data from individuals of the Brazilian Panel of Sugarcane Genotypes, obtained by genotyping-by-sequencing (GBS), using as reference the previously sequenced sorghum genome. We called the variants (mainly single nucleotide polymorphisms) with FreeBayes and annotated their functions and positions with SnpEff. We used population genetics statistics, such as the allele frequency, the McDonald & Kreitman Test and the pooled heterozygosity, to identify genomic regions potentially involved in evolutionary events. The results showed a loss of variability between bred genotypes in relation to the ancestors, with evidences of selective sweeps, involving regions related to the cellular machinery (such as respiration and photosynthesis) and specific crop traits (especially disease resistance and sucrose biosynthesis). These results support understanding of the genome and breeding efforts in this polyploid grass.

Com a redução progressiva dos custos de sequenciamento completo do genoma humano, os estudos populacionais tornam-se viáveis. A interpretação dos dados e integração com informações clínicas, entretanto, apresentam-se como desafios crescentes. O conhecimento sobre a variabilidade genética e sua interação com fenótipos complexos podem ser ampliados com estudos de grande porte em populações miscigenadas, em particular de sociedades com heterogeneidades sociais, culturais e históricas, ainda pouco representadas globalmente na área da genômica. Este trabalho apresenta um conjunto de estudos colaborativos que se basearam em uma amostra de natureza representativa de idosos da cidade de São Paulo (amostra SABE, aproximadamente 1400 indivíduos) e em de octogenários cognitivamente saudáveis (amostra 80+, aproximadamente 130 indivíduos). Além de questionários e testes, DNA dos participantes foi obtido e exomas sequenciados para cerca de 600 indivíduos. Esta base permitiu a construção de grupos controles para diversos estudos de associação de variantes causais ou de suscetibilidade a doenças raras como distrofia muscular de cinturas, tumores do sistema endócrino e síndrome de Noonan, entre outras, além de integrar, como referência populacional local, o sistema de análise de variantes do serviço de diagnóstico molecular do Centro de Pesquisas sobre o Genoma Humano e Células-tronco da Universidade de São Paulo. Por ser uma amostra de idosos, além de permitir a construção de uma base eficiente para controles comparativos de doenças raras ou de início precoce, tornou-se possível a execução de projetos sobre envelhecimento cerebral através do recrutamento cerca de 580 indivíduos para ressonância magnética. Estudos com marcadores de demências, como polimorfismos do gene APOE (associado à doença de Alzheimer) indicaram que a população brasileira apresenta riscos diferenciais em relação a populações de outros países, provavelmente devido à estrutura populacional única do ponto de vista de ancestralidade genética e composição socio-econômica. Por fim, os estudos com ressonância magnética e genômica permitiram a investigação do fenótipo de lateralidade cerebral, que engloba dominâncias manual e de linguagem, que está presente de forma variável em seres humanos e está envolvida com distúrbios neuropsiquiátricos como dislexia e esquizofrenia. Foi possível detectar associação entre variantes do gene FOXP2, implicado no neurodesenvolvimento da linguagem, e endofenótipos assimétricos de tratos de substância branca envolvidos na produção da fala. O presente trabalho abre caminho para diversos novos projetos dada a escala de dados sociodemográficas, clínicos, funcionais e genômicos / Due to the progressive reduction of genome sequencing costs, population studies become feasible. Interpretation of subsequent data and integration with clinical information, however, impose a growing challenge. The knowledge about genetic variability and its interaction with complex phenotypes could be expanded with large scale admixed population studies, particularly in those samples that live in socially, culturally and historically heterogeneous communities, so far globally underrepresented in the genomics field. This thesis presents a collection of collaborative studies that were based on a population-representative sample of elderly from the city of São Paulo (SABE sample, approximately 1400 subjects) and a cognitively healthy octogenarians sample (80+ group, approximately 130 subjects). Comprehensive questionnaires and functional tests were obtained, along with DNA from all subjects and exome sequences from about 600 of them. This database allowed the assembly of control groups to several association studies with causal and susceptibility variants to rare disorders such as limb-girdle muscular dystrophy, endocrine system tumors and Noonan syndrome, among others, and, in addition, composed as a local population reference the analyses\' protocols in the molecular diagnosis service of the Human Genome and Stem-cell Research Center at the University of São Paulo. As this is an elderly sample, it was possible not only to build an efficient control group to compare with patients affected by rare or early onset disorders, but to promote projects on brain aging through recruitment of about 580 subjects to magnetic resonance imaging (MRI). Studies with markers of dementia, such as APOE gene polymorphisms (involved in Alzheimer\'s disease), suggested that the Brazilian population might present different risks compared to other countries, probably due to its unique population structure from the genetic ancestry standpoint and socioeconomic composition. As a final project, MRI and genomics studies were performed to investigate the phenotype of brain laterality, which comprises handedness and language dominance and it is variable among humans, with involvement with neuropsychiatric disorders such as dyslexia and schizophrenia. It was possible to detect an association between variants of FOXP2 gene, which is involved in neurodevelopmental processes of language, and asymmetry endophenotypes of white matter tracts that form the speech production circuitry. This effort opens several pathways to develop new projects due to the scale of sociodemographic, clinical, functional and genomic data

Evolution is an ubiquitous feature of living systems. The genetic composition of a population changes in response to the primary evolutionary forces: mutation, selection and genetic drift. Organisms undergoing rapid adaptation acquire multiple mutations that are physically linked in the genome, so their fates are mutually dependent and selection only acts on these loci in their entirety. This aspect has been largely overlooked in the study of asexual or somatic evolution and plays a major role in the evolution of bacterial and viral infections and cancer. In this thesis, we put forward a theoretical description for a minimal model of evolutionary dynamics to identify driver mutations, which carry a large positive fitness effect, among passenger mutations that hitchhike on successful genomes. We examine the effect this mode of selection has on genomic patterns of variation to infer the location of driver mutations and estimate their selection coefficient from time series of mutation frequencies. We then present a probabilistic model to reconstruct genotypically distinct lineages in mixed cell populations from DNA sequencing. This method uses Hidden Markov Models for the deconvolution of genetically diverse populations and can be applied to clonal admixtures of genomes in any asexual population, from evolving pathogens to the somatic evolution of cancer. To understand the effects of selection on rapidly adapting populations, we constructed sequence ensembles in a recombinant library of budding yeast (S. cerevisiae). Using DNA sequencing, we characterised the directed evolution of these populations under selective inhibition of rate-limiting steps of the cell cycle. We observed recurrent patterns of adaptive mutations and characterised common mutational processes, but the spectrum of mutations at the molecular level remained stochastic. Finally, we investigated the effect of genetic variation on the fate of new mutations, which gives rise to complex evolutionary dynamics. We demonstrate that the fitness variance of the population can set a selective threshold on new mutations, setting a limit to the efficiency of selection. In summary, we combined statistical analyses of genomic sequences, mathematical models of evolutionary dynamics and experiments in molecular evolution to advance our understanding of rapid adaptation. Our results open new avenues in our understanding of population dynamics that can be translated to a range of biological systems.

Comprendre l’émergence des maladies dans les agroécosystèmes nécessite d’étudier l’histoire évolutive des populations bactériennes associées aux plantes. L’objectif de ce travail était de déterminer les évènements évolutifsconduisant à l’émergence des lignées pathogènes ou pathovars dans l’espèce Xanthomonas arboricola. Une analyse de génétique des populations a été menée sur un panel de souches phytopathogènes et commensales et complétée par l’inférence des gains et pertes de facteurs de virulence. Cette espèce possède une structure de population épidémique ; les clones épidémiques ont émergé suite à l’acquisition de facteurs de virulence à partir d’un fond recombinant de souches commensales. Une analyse de génomique des populations et la reconstruction de scénarios de divergence entre ces clones et le réseau de souches recombinantes, a montré la persistance d’un flux de gènes asymétrique entre ces deux groupes, dans le sens souches pathogènes vers souches commensales. Enfin, l’histoire évolutive du principal facteur de virulence des Xanthomonas, le système de sécrétion de type 3, a été retracée au sein du genre, et a montré que celui-ci avait été acquis ancestralement puis perdu dans certaines souches commensales. En conclusion, l’ancêtre commun de X. arboricola possédait des facteurs de virulence et au sein des souches commensales, certaines ont perdu ces facteurs, tandis que d’autres ont conservé le répertoire ancestral. Ces dernières diffèrent peu de certains agents pathogènes, et pourraient représenter un risque pour de nouvelles émergences. Des travaux de génomique fonctionnelle permettraient de valider ces hypothèses. / Deciphering the evolutionary history of bacterial populations associated to plants is necessary to understand diseaseemergence in agroecosystems. The aim of this study is to unveil the evolutionary events responsible for pathogeniclineages or pathovar emergences in Xanthomonas arboricola. This species is composed of both plant pathogenic andcommensal strains Population genetics analyses and gain and loss inferences of virulence factors showed that X. arboricola exhibits an epidemic population structure, within which epidemic clones emerged from a recombinogenic background population following virulence factor acquisition. Population genomics and inference of divergence scenarii between epidemic clones and the network of recombinant strains showed persistence of homologous recombination along divergence of these two groups, with an asymmetric gene flux from pathogenic strains to commensal ones. Finally, evolutionary history of the type three secretion system (T3SS), the main virulence factor in Xanthomonas genus, was studied at genus scale and showed that T3SS was ancestrally acquired and lost in commensal strains. Altogether these analyses allowed us to show that the common ancestor of X.arboricola had virulence factors, and that within commensal strains, some lost these virulence factors whereas others kept the ancestral repertoire. These latter strains have a similar repertoire to that of some pathogenic strains, and could represent a risk for new disease emergence. Functional genomics could allow us to validate these hypotheses.

The last century, humans have been altering almost all natural environments at an accelerating rate, including the Baltic Sea that has highly eutrophicated areas and many coastal industries such as Pulp-mills. For animals living in a habitat that changes there are basically two alternatives, either to cope with the change or become locally extinct. This thesis aims to investigate if recent anthropogenic disturbance in the Baltic Sea can affect natural populations on a genetic level through natural selection. First, we found a fine-scale genetic structure in three-spine sticklebacks (Gasterosteus aculeatus) populations along the Swedish coast (paper I), indicating limited gene-flow between populations in geographic proximity. Different genetic markers, specifically Amplified Fragment Lenght Polymorpism (AFLP, and microsatellites,  gave different results, highlighting the heterogeneous character of genomes which demonstrates that it is important to choose a genetic marker that is relevant for the question at hand. With a population genomic approach, and a multilocus genetic marker (AFLP), we detected convergent evolution in genotype composition in stickleback populations living in environments affected by pulp-mill effluent (paper II) and in highly eutrophicated environments (paper III), compared to adjacent reference populations. We found loci, in both studies (paper II, III), that were different from a neutral distribution and thus probably under divergent selection for the habitat differences investigated. The selective effect from pulp-mill effluents were more pronounced, but the two different habitats had mutual characters (AFLP loci). In paper IV, we converted five anonymous AFLP loci to sequenced markers and aligned them to the stickleback genome. Four out of five loci aligned within, or close to, coding regions on chromosome I, chromosome VIII, chromosome XIX and chromosome XX. One of the loci, located on chromosome VIII and identified as under divergent selection in both paper II and III, has been identified in other studies as to be under selection for fresh water adaptation, including Baltic Sea stickleback populations. In conclusion, anthropogenic alterations of natural environments can have evolutionary consequences, probably adaptive, for the animals living there and the evolutionary response exhibited by natural populations can be very fast. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.</p>

No description available.

Infectious disease dynamics are inherently shaped by the distribution, ecology, and genetic variation of hosts. Conversely, pathogens exert powerful influences on hosts through demographic processes and natural selection. These tenets of disease ecology and evolutionary biology are illustrated in the case of white-nose syndrome (WNS), an emerging infectious disease of hibernating bats. WNS first emerged in 2006 and spread rapidly throughout eastern North America, causing massive declines in bat populations. To understand how host ecology and spatial distribution influence the spread of WNS, I evaluated risk models of colony-level correlates, including bat colony size, species composition, behavior, and gene flow. WNS was more likely to emerge in large colonies first, and species composition and behavior were also significant predictors of risk. Spatial spread was predicted by population genetics of little brown myotis (Myotis lucifugus), indicating coupling of host gene flow and pathogen dispersal, and potential for the application of landscape genetics to predict future spread. To guide management and evaluate pre-existing genetic diversity, I assessed population genetic structure of little brown myotis using restriction site-associated DNA sequencing (RAD-seq). RAD-seq data revealed two populations divided by the Rocky Mountains, with high gene flow between the distributions of putative subspecies. Demographic analyses and genome scans suggest adaptive genetic variation, variation that may be threatened by WNS in eastern North America. Drastic declines from WNS have likely imposed strong selection, and recent stabilization of populations near the disease epicenter suggests that resistance may have evolved in the host population. I generated whole genome sequence data for bats sampled before and after declines to test for demographic changes and natural selection. Average genomic differentiation and nucleotide diversity indicated little demographic change between the two periods, but preliminary analyses suggest genomic regions of differentiation combined with decreased nucleotide diversity in post-WNS relative to pre-WNS samples, hinting at a pattern of natural selection. Additional samples and in-depth analyses are necessary to robustly test these patterns; however, identification of signatures of selection in the bat genome would be an exciting indication of a rapid evolutionary response to an introduced disease.

Com a redução progressiva dos custos de sequenciamento completo do genoma humano, os estudos populacionais tornam-se viáveis. A interpretação dos dados e integração com informações clínicas, entretanto, apresentam-se como desafios crescentes. O conhecimento sobre a variabilidade genética e sua interação com fenótipos complexos podem ser ampliados com estudos de grande porte em populações miscigenadas, em particular de sociedades com heterogeneidades sociais, culturais e históricas, ainda pouco representadas globalmente na área da genômica. Este trabalho apresenta um conjunto de estudos colaborativos que se basearam em uma amostra de natureza representativa de idosos da cidade de São Paulo (amostra SABE, aproximadamente 1400 indivíduos) e em de octogenários cognitivamente saudáveis (amostra 80+, aproximadamente 130 indivíduos). Além de questionários e testes, DNA dos participantes foi obtido e exomas sequenciados para cerca de 600 indivíduos. Esta base permitiu a construção de grupos controles para diversos estudos de associação de variantes causais ou de suscetibilidade a doenças raras como distrofia muscular de cinturas, tumores do sistema endócrino e síndrome de Noonan, entre outras, além de integrar, como referência populacional local, o sistema de análise de variantes do serviço de diagnóstico molecular do Centro de Pesquisas sobre o Genoma Humano e Células-tronco da Universidade de São Paulo. Por ser uma amostra de idosos, além de permitir a construção de uma base eficiente para controles comparativos de doenças raras ou de início precoce, tornou-se possível a execução de projetos sobre envelhecimento cerebral através do recrutamento cerca de 580 indivíduos para ressonância magnética. Estudos com marcadores de demências, como polimorfismos do gene APOE (associado à doença de Alzheimer) indicaram que a população brasileira apresenta riscos diferenciais em relação a populações de outros países, provavelmente devido à estrutura populacional única do ponto de vista de ancestralidade genética e composição socio-econômica. Por fim, os estudos com ressonância magnética e genômica permitiram a investigação do fenótipo de lateralidade cerebral, que engloba dominâncias manual e de linguagem, que está presente de forma variável em seres humanos e está envolvida com distúrbios neuropsiquiátricos como dislexia e esquizofrenia. Foi possível detectar associação entre variantes do gene FOXP2, implicado no neurodesenvolvimento da linguagem, e endofenótipos assimétricos de tratos de substância branca envolvidos na produção da fala. O presente trabalho abre caminho para diversos novos projetos dada a escala de dados sociodemográficas, clínicos, funcionais e genômicos / Due to the progressive reduction of genome sequencing costs, population studies become feasible. Interpretation of subsequent data and integration with clinical information, however, impose a growing challenge. The knowledge about genetic variability and its interaction with complex phenotypes could be expanded with large scale admixed population studies, particularly in those samples that live in socially, culturally and historically heterogeneous communities, so far globally underrepresented in the genomics field. This thesis presents a collection of collaborative studies that were based on a population-representative sample of elderly from the city of São Paulo (SABE sample, approximately 1400 subjects) and a cognitively healthy octogenarians sample (80+ group, approximately 130 subjects). Comprehensive questionnaires and functional tests were obtained, along with DNA from all subjects and exome sequences from about 600 of them. This database allowed the assembly of control groups to several association studies with causal and susceptibility variants to rare disorders such as limb-girdle muscular dystrophy, endocrine system tumors and Noonan syndrome, among others, and, in addition, composed as a local population reference the analyses\' protocols in the molecular diagnosis service of the Human Genome and Stem-cell Research Center at the University of São Paulo. As this is an elderly sample, it was possible not only to build an efficient control group to compare with patients affected by rare or early onset disorders, but to promote projects on brain aging through recruitment of about 580 subjects to magnetic resonance imaging (MRI). Studies with markers of dementia, such as APOE gene polymorphisms (involved in Alzheimer\'s disease), suggested that the Brazilian population might present different risks compared to other countries, probably due to its unique population structure from the genetic ancestry standpoint and socioeconomic composition. As a final project, MRI and genomics studies were performed to investigate the phenotype of brain laterality, which comprises handedness and language dominance and it is variable among humans, with involvement with neuropsychiatric disorders such as dyslexia and schizophrenia. It was possible to detect an association between variants of FOXP2 gene, which is involved in neurodevelopmental processes of language, and asymmetry endophenotypes of white matter tracts that form the speech production circuitry. This effort opens several pathways to develop new projects due to the scale of sociodemographic, clinical, functional and genomic data