Frazer, K., Ballinger, D., Cox, D., Hinds, D., Stuve, L., Gibbs, R. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851-861

University of Cambridge, Cambridge, England, United Kingdom
Nature (Impact Factor: 41.46). 11/2007; 449(7164):851-61. DOI: 10.1038/nature06258
Source: PubMed

ABSTRACT We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

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    • "Large-scale trans-ethnic meta-analysis of GWAS was undertaken in 26,488 T2D cases and 83,964 controls from populations of European, East Asian, South Asian and Hispanic ancestry [10••], each imputed up to reference panels from the HapMap Project Consortium (Phase II/III) [14, 15]. The study validated previous observations that allelic effects on T2D at lead GWAS SNPs are predominantly homogeneous across ancestry groups [46], suggesting that susceptibility loci would be amenable to trans-ethnic fine mapping. "
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    ABSTRACT: Genome-wide association studies of type 2 diabetes have been extremely successful in discovering loci that contribute genetic effects to susceptibility to the disease. However, at the vast majority of these loci, the variants and transcripts through which these effects on type 2 diabetes are mediated are unknown, limiting progress in defining the pathophysiological basis of the disease. In this review, we will describe available approaches for assaying genetic variation across loci and discuss statistical methods to determine the most likely causal variants in the region. We will consider the utility of trans-ethnic meta-analysis for fine mapping by leveraging the differences in the structure of linkage disequilibrium between diverse populations. Finally, we will discuss progress in fine-mapping type 2 diabetes susceptibility loci to date and consider the prospects for future efforts to localise causal variants for the disease.
    Current Diabetes Reports 11/2014; 14(11):549. DOI:10.1007/s11892-014-0549-2 · 3.08 Impact Factor
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    • "The use of lymphoblastoid cell lines (LCLs) in human genetics studies has been controversial for some time. On the one hand, LCLs are a renewable resource that provides investigators with the nearly unique opportunity to perform in-depth studies of molecular and complex phenotypes using the same collection of samples [1]–[4]. On the other hand, the transformation that immortalizes the LCLs, through the infection of primary B cells with EBV, is known to result in certain artifacts [2], [5]. "
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    ABSTRACT: Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines (LCLs) are a widely used renewable resource for functional genomic studies in humans. The ability to accumulate multidimensional data pertaining to the same individual cell lines, from complete genomic sequences to detailed gene regulatory profiles, further enhances the utility of LCLs as a model system. However, the extent to which LCLs are a faithful model system is relatively unknown. We have previously shown that gene expression profiles of newly established LCLs maintain a strong individual component. Here, we extend our study to investigate the effect of freeze-thaw cycles on gene expression patterns in mature LCLs, especially in the context of inter-individual variation in gene expression. We report a profound difference in the gene expression profiles of newly established and mature LCLs. Once newly established LCLs undergo a freeze-thaw cycle, the individual specific gene expression signatures become much less pronounced as the gene expression levels in LCLs from different individuals converge to a more uniform profile, which reflects a mature transformed B cell phenotype. We found that previously identified eQTLs are enriched among the relatively few genes whose regulations in mature LCLs maintain marked individual signatures. We thus conclude that while insight drawn from gene regulatory studies in mature LCLs may generally not be affected by the artificial nature of the LCL model system, many aspects of primary B cell biology cannot be observed and studied in mature LCL cultures.
    PLoS ONE 09/2014; 9(9):e107166. DOI:10.1371/journal.pone.0107166 · 3.23 Impact Factor
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    • "Based on these findings, we decided to expand current knowledge of potentially damaging SNVs within the KLKs (as predicted by the functional SNV class and its impact on KLK structure) and investigate their frequencies in certain populations and their potential to result in clinical phenotypes. Single nucleotide polymorphisms (SNPs) are variations at a single nucleotide position and are considered to be the most frequent type of variation within the human genome, comprising about 0.1% of the human genome (Collins et al., 1998; International HapMap et al., 2007). Rare SNPs are present at a frequency above 1% in the general population, whereas common SNPs are present at a frequency above 5–10% (Kruglyak and Nickerson, 2001; Ladiges et al., 2004). "
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    ABSTRACT: Abstract Kallikreins (KLKs) are a group of 15 serine proteases encoded by the KLK locus on chromosome 19. Certain single nucleotide variants (SNVs) within the KLK locus have been linked to human disease. Next-generation sequencing of large human cohorts enables reexamination of genomic variation at the KLK locus. We aimed to identify all KLK-related SNVs and examine their impact on gene regulation and function. To this end, we mined KLK SNVs across Ensembl and Exome Variant Server, with exome-sequencing data from 6503 individuals. PolyPhen-2-based prediction of damaging SNVs and population frequencies of these SNVs were examined. Damaging SNVs were plotted on protein sequence and structure. We identified 4866 SNVs, the largest number of KLK-related SNVs reported. Fourteen percent of noncoding SNVs overlapped with transcription factor binding sites. We identified 602 missense coding SNVs, among which 148 were predicted to be damaging. Nine missense SNVs were common (>1% frequency) and displayed significantly different frequencies between European-American and African-American populations. SNVs predicted to be damaging appeared to alter tertiary structure of KLK1 and KLK6. Similarly, these missense SNVs may affect KLK function, resulting in disease phenotypes. Our study represents a mine of information for those studying KLK-related SNVs and their associations with diseases.
    Biological Chemistry 09/2014; 395(9):1037-1050. DOI:10.1515/hsz-2014-0136 · 3.27 Impact Factor
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