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We have used targeted genomic sequencing of high-complexity DNA pools based on long-range PCR and deep DNA sequencing by the SOLiD technology. The method was used for sequencing of 286 kb from four chromosomal regions with quantitative trait loci (QTL) influencing blood plasma lipid and uric acid levels in DNA pools of 500 individuals from each of five European populations. The method shows very good precision in estimating allele frequencies as compared with individual genotyping of SNPs (r(2) = 0.95, P < 10(-16)). Validation shows that the method is able to identify novel SNPs and estimate their frequency in high-complexity DNA pools. In our five populations, 17% of all SNPs and 61% of structural variants are not available in the public databases. A large fraction of the novel variants show a limited geographic distribution, with 62% of the novel SNPs and 59% of novel structural variants being detected in only one of the populations. The large number of population-specific novel SNPs underscores the need for comprehensive sequencing of local populations in order to identify the causal variants of human traits.

Original publication

DOI

10.1038/ejhg.2011.138

Type

Journal article

Journal

European journal of human genetics : EJHG

Publication Date

01/2012

Volume

20

Pages

77 - 83

Addresses

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SciLifeLab Uppsala, Uppsala University, Uppsala, Sweden.

Keywords

EUROSPAN Consortium, Chromosomes, Human, Humans, Lipase, Sensitivity and Specificity, Cohort Studies, Sequence Alignment, Sequence Analysis, DNA, Computational Biology, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Glucose Transport Proteins, Facilitative, INDEL Mutation, Genetic Testing, Genomic Structural Variation