The French Canadian founder population : lessons and insights for genetic epidemiological research

La population canadienne-française a une histoire démographique unique faisant d’elle une population d’intérêt pour l’épidémiologie et la génétique. Cette thèse vise à mettre en valeur les caractéristiques de la population québécoise qui peuvent être utilisées afin d’améliorer la conception et l’analyse d’études d’épidémiologie génétique. Dans un premier temps, nous profitons de la présence d’information généalogique détaillée concernant les Canadiens français pour estimer leur degré d’apparentement et le comparer au degré d’apparentement génétique. L’apparentement génétique calculé à partir du partage génétique identique par ascendance est corrélé à l’apparentement généalogique, ce qui démontre l'utilité de la détection des segments identiques par ascendance pour capturer l’apparentement complexe, impliquant entre autres de la consanguinité. Les conclusions de cette première étude pourront guider l'interprétation des résultats dans d’autres populations ne disposant pas d’information généalogique. Dans un deuxième temps, afin de tirer profit pleinement du potentiel des généalogies canadienne-françaises profondes, bien conservées et quasi complètes, nous présentons le package R GENLIB, développé pour étudier de grands ensembles de données généalogiques. Nous étudions également le partage identique par ascendance à l’aide de simulations et nous mettons en évidence le fait que la structure des populations régionales peut faciliter l'identification de fondateurs importants, qui auraient pu introduire des mutations pathologiques, ce qui ouvre la porte à la prévention et au dépistage de maladies héréditaires liées à certains fondateurs. Finalement, puisque nous savons que les Canadiens français ont accumulé des segments homozygotes, à cause de la présence de consanguinité lointaine, nous estimons la consanguinité chez les individus canadiens-français et nous étudions son impact sur plusieurs traits de santé. Nous montrons comment la dépression endogamique influence des traits complexes tels que la grandeur et des traits hématologiques. Nos résultats ne sont que quelques exemples de ce que nous pouvons apprendre de la population canadienne-française. Ils nous aideront à mieux comprendre les caractéristiques des autres populations de même qu’ils pourront aider la recherche en épidémiologie génétique au sein de la population canadienne-française.The French Canadian founder population has a demographic history that makes it an important population for epidemiology and genetics. This work aims to explain what features can be used to improve the design and analysis of genetic epidemiological studies in the Quebec population. First we take advantage of the presence of extended genealogical records among French Canadians to estimate relatedness from those records and compare it to the genetic kinship. The kinship based on identical-by-descent sharing correlates well with the genealogical kinship, further demonstrating the usefulness of genomic identical-by-descent detection to capture complex relatedness involving inbreeding and our findings can guide the interpretation of results in other population without genealogical data. Second to optimally exploit the full potential of these well preserved, exhaustive and detailed French Canadian genealogical data we present the GENLIB R package developed to study large genealogies. We also investigate identical-by-descent sharing with simulations and highlight the fact that regional population structure can facilitate the identification of notable founders that could have introduced disease mutations, opening the door to prevention and screening of founder-related diseases. Third, knowing that French Canadians have accumulated segments of homozygous genotypes, as a result of inbreeding due to distant ancestors, we estimate the inbreeding in French Canadian individuals and investigate its impact on multiple health traits. We show how inbreeding depression influences complex traits such as height and blood-related traits. Those results are a few examples of what we can learn from the French Canadian population and will help to gain insight on other populations’ characteristics as well as help the genetic epidemiological research within the French Canadian population

Population genetics of identity by descent

Recent improvements in high-throughput genotyping and sequencing technologies have afforded the collection of massive, genome-wide datasets of DNA information from hundreds of thousands of individuals. These datasets, in turn, provide unprecedented opportunities to reconstruct the history of human populations and detect genotype-phenotype association. Recently developed computational methods can identify long-range chromosomal segments that are identical across samples, and have been transmitted from common ancestors that lived tens to hundreds of generations in the past. These segments reveal genealogical relationships that are typically unknown to the carrying individuals. In this work, we demonstrate that such identical-by-descent (IBD) segments are informative about a number of relevant population genetics features: they enable the inference of details about past population size fluctuations, migration events, and they carry the genomic signature of natural selection. We derive a mathematical model, based on coalescent theory, that allows for a quantitative description of IBD sharing across purportedly unrelated individuals, and develop inference procedures for the reconstruction of recent demographic events, where classical methodologies are statistically underpowered. We analyze IBD sharing in several contemporary human populations, including representative communities of the Jewish Diaspora, Kenyan Maasai samples, and individuals from several Dutch provinces, in all cases retrieving evidence of fine-scale demographic events from recent history. Finally, we expand the presented model to describe distributions for those sites in IBD shared segments that harbor mutation events, showing how these may be used for the inference of mutation rates in humans and other species.Comment: Ph.D. thesi

Prediction and estimation of effective population size

Effective population size (Ne) is a key parameter in population genetics. It has important applications in evolutionary biology, conservation genetics, and plant and animal breeding, because it measures the rates of genetic drift and inbreeding and affects the efficacy of systematic evolutionary forces such as mutation, selection and migration. We review the developments in predictive equations and estimation methodologies of effective size. In the prediction part, we focus on the equations for populations with different modes of reproduction, for populations under selection for unlinked or linked loci, and for the specific applications to conservation genetics. In the estimation part, we focus on methods developed for estimating the current or recent effective size from molecular marker or sequence data. We discuss some underdeveloped areas in predicting and estimating Ne for future research

Induse jõe oru inimeste, parside, India juutide ja Tharu hõimu geneetilise põlvnemise piiritlemine

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKäesolev on viies Tartu Ülikoolis valminud väitekiri Lõuna-Aasia rahvaste geneetilisest ajaloost. Asustatud kaasaegse inimese poolt märksa enne viimase jääaja maksimumi, elab tänapäeval selles regioonis üle 1.8 miljardi inimese – pea veerand inimkonnast. Seega ei ole võimalik süvitsi mõista kaasaegse inimese geneetise varieeruvuse kujunemist, sh eriti väljapool Sahara-alust Aafrikat, omamata detailsemat teadmist Lõuna-Aasia rahvaste geneetikast Väitekiri põhineb neljal ilmunud artiklil. Neist esimeses uurisime Kirde-Indiat asustavaid rahvaid seoses võimaliku pärinevusega Induse oru kultuurist ja järgnenud vedade ajastust. Teine ja kolmas artikkel on pühendatud migratsioonidele, mis tõid Indiasse religioosses mõttes uusi rahvagruppe: parsid Iraanist alates 7. sajandi lõpupoolelt ja juudid, kelle saabumine Indiasse on toimunud mitme lainena. Neljandas artiklis on vaatluse all Nepaalis, kuid ka India põhjapoolsetes osariikides elutsev rahvarohke tharu hõim. Esimes artikli huvitavamaks leiuks on usutavasti juba vedade ajastust tuntud Rori populatsiooni genoomis väljenduv suurem geneetiline afiinsus põhjapoolse stepivööndi rahvastega, samuti ka lääne-eurooplastega, mis räägib põhja-lõunasuunalistest migratsiooni(de)st eelajaloolisel ajal. Parside saabumist Lõuna-Aasiasse seostatakse Iraani islamiseerumisega 7. sajandil. Võrreldes parside genoome nende ajaloolises kontekstis leidsime ulatusliku segunemise Lõuna-Aasia rahvastega, sealjuures asümeetriliselt isa ja emaliinides. Sama saab väita ka Indias judaistliku traditsiooni elemente säilitanud erinevate kogukondade kohta, kelle genoomis on siiski selgelt säilunud Lähis- ja Kesk-Ida pärandit. Puudutavalt aga geneetiliselt ulatuslikult varieeruvat tharu hõimu, kelle hulgas on selgesti eristatav ka Ida-Aasia komponent, segunenuna Lõuna-Aasia pärandiga, paistab õigustatud olevat neid vaadelda esmajoones mitte sedavõrd deemilise, kuivõrd just kultuurilise konstruktsioonina.Presented hereby is the 5th in a series of PhD theses prepared in Tartu University, addressing genetics of population history of the South Asian peoples. Inhabited considerably before the Last Glacial Maximum, the region harbors by now about 1.8 billion humans – almost a quarter of the global population. Therefore, understanding of present-day variation of the latter, in particular outside sub-Saharan Africa, is not possible without deeper knowledge about genetics of South Asian populations. This thesis is based on four published papers. The first one is focused on selected populations inhabiting northeastern Indus Valley, bearing, in particular, in mind ancient Indus Valley civilization and following it Vedic period. The second and the third paper address historically somewhat better known migrations, bringing to India religiously distinct Parsi and Jewish peoples. The fourth paper analyses the genetic variation of a populous Tharu tribe, living predominantly in Nepal, but also in northern provinces of India. Perhaps the most interesting finding of the first paper is that the presumably identified already in Vedic texts, Ror population exhibits significant genetic affinity with northern Steppe and West European peoples, testifying about prehistoric north to south migration(s). The arrival of Parsis to South Asia in 7th century was a consequence of the Islamization of Iran. Comparing Parsi genomes in their historic contexts, we observed their extensive admixture with South Asians, in particular, asymmetrically in paternal and maternal lineages. Nearly the same can be said about different Indian communities that preserved Judaist traditions: their genomes show affinities to peoples living in the Near and Middle East. As far as the genetically highly diverse Tharu tribe is concerned, a clearly distinct East Asian contribution can be seen, admixed with South Asian genetic heritage. It seems justified to identify the Tharu as cultural, rather than demic phenomenon.https://www.ester.ee/record=b542949

HaploBlocks : Efficient Detection of Positive Selection in Large Population Genomic Datasets

Genomic regions under positive selection harbor variation linked for example to adaptation. Most tools for detecting positively selected variants have computational resource requirements rendering them impractical on population genomic datasets with hundreds of thousands of individuals or more. We have developed and implemented an efficient haplotype-based approach able to scan large datasets and accurately detect positive selection. We achieve this by combining a pattern matching approach based on the positional Burrows-Wheeler transform with model-based inference which only requires the evaluation of closed-form expressions. We evaluate our approach with simulations, and find it to be both sensitive and specific. The computational resource requirements quantified using UK Biobank data indicate that our implementation is scalable to population genomic datasets with millions of individuals. Our approach may serve as an algorithmic blueprint for the era of "big data" genomics: a combinatorial core coupled with statistical inference in closed form.Peer reviewe

Implementing parasite genotyping into national surveillance frameworks: Feedback from control programmes and researchers in the Asia-pacific region

The Asia-Pacific region faces formidable challenges in achieving malaria elimination by the proposed target in 2030. Molecular surveillance of Plasmodium parasites can provide important information on malaria transmission and adaptation, which can inform national malaria control programmes (NMCPs) in decision-making processes. In November 2019 a parasite genotyping workshop was held in Jakarta, Indonesia, to review molecular approaches for parasite surveillance and explore ways in which these tools can be integrated into public health systems and inform policy. The meeting was attended by 70 participants from 8 malaria-endemic countries and partners of the Asia Pacific Malaria Elimination Network. The participants acknowledged the utility of multiple use cases for parasite genotyping including: quantifying the prevalence of drug resistant parasites, predicting risks of treatment failure, identifying major routes and reservoirs of infection, monitoring imported malaria and its contribution to local transmission, characterizing the origins and dynamics of malaria outbreaks, and estimating the frequency of Plasmodium vivax relapses. However, the priority of each use case varies with different endemic settings. Although a one-size-fits-all approach to molecular surveillance is unlikely to be applicable across the Asia-Pacific region, consensus on the spectrum of added-value activities will help support data sharing across national boundaries. Knowledge exchange is needed to establish local expertise in different laboratory-based methodologies and bioinformatics processes. Collaborative research involving local and international teams will help maximize the impact of analytical outputs on the operational needs of NMCPs. Research is also needed to explore the cost-effectiveness of genetic epidemiology for different use cases to help to leverage funding for wide-scale implementation. Engagement between NMCPs and local researchers will be critical throughout this process

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes

Uurali rahvaste geneetiline ajalugu läbi isaliini N ja autosoomse varieeruvuse prisma

Väitekirja elektrooniline versioon ei sisalda publikatsiooneEuroopast Lääne-Siberini levinud uurali keelkond postuleeriti enam kui saja aasta eest. Mitme põlvkonna eri teadusvaldkondade teadlaste töö tulemusena on kogutud aukartustäratav andmestik selle keelkonna rahvaste kohta, kuid erilise huvi objektiks on jäänud küsimus nende ühisest päritolust, võimalikust algkodust ja rändeteedest, mille kohta on välja pakutud arvukalt huvitavaid hüpoteese. Eelkõige geograafiast sõltuvas isalt pojale päranduvate Y-kromosoomi variantide ehk isaliinide jaotusmustris eristub selgelt haplogrupp N, mis seob nii Euroopa kui Aasia põhjaaladel elavaid rahvaid ning iseloomustab ka suurt osa uurali keeli kõnelevatest meestest. Käesoleva doktoritöö eesmärgiks oli esiteks rakendada kaasaegseid DNA järjestustehnoloogiaid hindamaks haplogrupi N fülogeneetilise puu sisestruktuuri ja alamklaadide ekspansiooniaegu ning levikut Põhja-Euraasias. Teiseks testida uusimate statistiliste meetoditega võimaliku geneetilise ühisosa olemasolu uurali keelesugulaste vahel, tuginedes ülegenoomsetele genotüpiseerimisandmetele. Selgus, et haplogrupp N on tõenäoliselt algselt pärit Põhja-Hiinast või mandrilisest Kagu-Aasiast ning haplogrupi sisemine struktuur koosneb mitmest piiritletud geograafilise levikuga alamklaadist. Ühel neist, haplogrupi N3 alamklaad N3a3’6, mille levikuaja algus jääb umbes 5000 aasta tagusesse aega, on tähelepanuväärselt lai geograafiline levik, mis ulatub Läänemere idakaldalt kuni Mongoolia ja Vene Beringiani ning hõlmab märkimisväärse osa kõikidesse suurematesse Põhja-Euraasia keelkondadesse kuuluvatest meestest. Ülegenoomsete andmete põhjal on enamusel uurali keeli kõnelejatest piiratud, kuid tuvastatav hiljutine tõenäoliselt Siberi päritolu geneetiline ühisosa, mis vihjab keelte levikuga kaasas käinud inimeste rändele. Samas on see ühine geneetiline komponent seotud ulatuslikumate ida poolt lähtunud mõjutustega Kirde-Euroopa kaasaegsete rahvaste geenifondile, mis tõenäoliselt ei piirdunud ainult uurali keeli rääkinud inimeste sisserändega.The Uralic linguistic family has been postulated for more than a hundred years with a current distribution area spanning from Europe to West Siberia. The prehistory of Uralic languages and their speakers has been under scrutiny of several generations of scientists from a variety of scientific fields. Numerous hypotheses have been proposed regarding their common origin, dispersal routes and possible homeland, but these questions continue to remain scientifically disputable. A clear disruptor in the pattern of geography-dependent distribution of Y-chromosomal paternal lineages is haplogroup N that unites populations across entire north Eurasia and describes a fair share of Uralic-speaking males in both northeastern Europe and west Siberia. First aim of this thesis was to apply novel DNA re-sequencing approach to resolve the inner phylogenetic structure of haplogroup N and estimate coalescent ages along with geographic distribution of its inner subclades. Second aim was to test for a common autosomal genetic substrate between Uralic speakers using novel statistical methods. The results suggest hg N to initially originate from North China or Mainland Southeast Asia and contain several novel subclades with distinct phylogeographic spread. One such subclade, N3a3’6 within subhaplogroup N3, displays an expansion time of 5000 years, but has a remarkably wide geographic distribution ranging from the eastern shores of the Baltic Sea to Mongolia and Pacific Russian Beringia, encompassing a considerate fraction of men from all major linguistic families in north Eurasia. Whole genome data shows a small, yet significant autosomal genetic component of possible Siberian ancestry shared between most of the Uralic-speaking populations, suggesting a migratory contribution to the dispersal of the languages. This component is part of a broader eastern influence on the genepool of modern northern Europe and was probably not limited to the spread of extant Uralic languages.https://www.ester.ee/record=b526783