Genetic markers and population history: Finland revisited.
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ABSTRACT:
SUBMITTER: Palo JU
PROVIDER: S-EPMC2986642 | biostudies-other | 2009 Oct
REPOSITORIES: biostudies-other
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Project description:Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery.
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Project description:Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.
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Project description:BackgroundOur current understanding of archaic admixture in humans relies on statistical methods with large biases, whose magnitudes depend on the sizes and separation times of ancestral populations. To avoid these biases, it is necessary to estimate these parameters simultaneously with those describing admixture. Genetic estimates of population histories also confront problems of statistical identifiability: different models or different combinations of parameter values may fit the data equally well. To deal with this problem, we need methods of model selection and model averaging, which are lacking from most existing software.ResultsThe Legofit software package allows simultaneous estimation of parameters describing admixture, and the sizes and separation times of ancestral populations. It includes facilities for data manipulation, estimation, analysis of residuals, model selection, and model averaging.ConclusionsLegofit uses genetic data to study the history of a subdivided population. It is unaffected by recent history and can therefore focus on the deep history of population size, subdivision, and admixture. It outperforms several statistical methods that have been widely used to study population history and should be useful in any species for which DNA sequence data is available from several populations.
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