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219
A first-generation linkage disequilibrium map of human chromosome 22
- Nature
, 2002
"... A collection of DNA sequence variants across the genome may be used to test specific genes or regions of the human genome for association with a variety of phenotypes such as disease risk or variable drug response. Detecting association relies on the non-random correlation (“linkage disequilibrium”, ..."
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Cited by 95 (7 self)
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A collection of DNA sequence variants across the genome may be used to test specific genes or regions of the human genome for association with a variety of phenotypes such as disease risk or variable drug response. Detecting association relies on the non-random correlation (“linkage disequilibrium”, LD) of one of the marker alleles with a trait-related variant. We have measured LD along the complete sequence of human chromosome 22. Duplicate genotyping and analysis of 1,504 markers in CEPH reference families at a median spacing of 15kb reveals a highly variable pattern of LD along the chromosome, in which extensive regions of virtually complete LD up to 758 kb in length are interspersed with regions of little or no detectable LD. The LD patterns are replicated in 1,286 overlapping markers genotyped on a panel of unrelated U.K. Caucasians. There is a strong correlation between high LD and low recombination frequency in the extant genetic map, reflecting patterns of historic recombination between ancestral chromosomes that yield conserved blocks of LD in present-day chromosomes. This study demonstrates the feasibility for developing genome-wide maps of LD.
Haplotypes and informative SNP selection algorithms: don’t block out information
- Proceedings of the Seventh International Conference on Research in Computational Molecular Biology
, 2003
"... It is widely hoped that variation in the human genome will provide a means of predicting risk of a variety of complex, chronic diseases. A major stumbling block to the successful identification of association between human DNA polymorphisms (SNPs) and variability in risk of complex diseases is the e ..."
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Cited by 40 (5 self)
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It is widely hoped that variation in the human genome will provide a means of predicting risk of a variety of complex, chronic diseases. A major stumbling block to the successful identification of association between human DNA polymorphisms (SNPs) and variability in risk of complex diseases is the enormous number of SNPs in the human genome (4,9). The large number of SNPs results in unacceptably high costs for exhaustive genotyping, and so there is a broad effort to determine ways to select SNPs so as to maximize the informativeness of a subset. In this paper we contrast two methods for reducing the complexity of SNP variation: haplotype tagging, i.e. typing a subset of SNPs to identify segments of the genome that appear to be nearly unrecombined (haplotype blocks), and a new block-free model that we develop in this report. We present a statistic for comparing haplotype blocks and show that while the concept of haplotype blocks is reasonably robust there is substantial variability among block partitions. We develop a measure for selecting an informative subset of SNPs in a block free model. We show that the general version of this problem is NP-hard and give efficient algorithms for two important special cases of this problem.
Characterization of multilocus linkage disequilibrium,
- Genet. Epidemiol.
, 2005
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Evidence of a Large-Scale Functional Organization of Mammalian Chromosomes
- PLoS Genet
, 2005
"... Evidence from inbred strains of mice indicates that a quarter or more of the mammalian genome consists of chromosome regions containing clusters of functionally related genes. The intense selection pressures during inbreeding favor the coinheritance of optimal sets of alleles among these genetically ..."
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Cited by 15 (0 self)
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Evidence from inbred strains of mice indicates that a quarter or more of the mammalian genome consists of chromosome regions containing clusters of functionally related genes. The intense selection pressures during inbreeding favor the coinheritance of optimal sets of alleles among these genetically linked, functionally related genes, resulting in extensive domains of linkage disequilibrium (LD) among a set of 60 genetically diverse inbred strains. Recombination that disrupts the preferred combinations of alleles reduces the ability of offspring to survive further inbreeding. LD is also seen between markers on separate chromosomes, forming networks with scale-free architecture. Combining LD data with pathway and genome annotation databases, we have been able to identify the biological functions underlying several domains and networks. Given the strong conservation of gene order among mammals, the domains and networks we find in mice probably characterize all mammals, including humans.
A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4 � Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population
, 2004
"... Variants in hepatocyte nuclear factor-4 � (HNF4�), a transcription factor that influences the expression of glucose metabolic genes, have been correlated with maturityonset diabetes of the young, a monogenic form of diabetes. Previously, in a genome scan of Ashkenazi Jewish type 2 diabetic families, ..."
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Variants in hepatocyte nuclear factor-4 � (HNF4�), a transcription factor that influences the expression of glucose metabolic genes, have been correlated with maturityonset diabetes of the young, a monogenic form of diabetes. Previously, in a genome scan of Ashkenazi Jewish type 2 diabetic families, we observed linkage to the chromosome 20q region encompassing HNF4�. Here, haplotype-tag single nucleotide polymorphisms (htSNPs) were identified across a 78-kb region around HNF4 � and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetic (n � 275) and control (n � 342) subjects. We found that two of nine htSNPs were associated with type 2 diabetes: a3 � intronic SNP, rs3818247 (29.2 % case subjects vs. 21.7 % control subjects; P � 0.0028, odds ratio [OR] 1.49) anda5 � htSNP located �3.9 kb upstream of P2, rs1884614
Comprehensive identification and characterization of diallelic insertiondeletion polymorphisms in 330 human candidate genes
, 2005
"... Despite being the second most frequent type of polymorphism in the genome, diallelic insertion–deletion polymorphisms (indels) have received far less attention in the study of sequence variation. In this report, we describe an approach that can detect indels in the heterozygous state and can compreh ..."
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Cited by 13 (1 self)
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Despite being the second most frequent type of polymorphism in the genome, diallelic insertion–deletion polymorphisms (indels) have received far less attention in the study of sequence variation. In this report, we describe an approach that can detect indels in the heterozygous state and can comprehensively identify indels in the target sequence. Using this approach, we identified 2393 indels in a set of 330 candidate genes, i.e. an average of seven indels per gene with about two indels per gene being common (minor allele fre-quency 0.1). We compared the population genetic characteristics of indels with substitutions in this data. Our data supported the findings that deletions occur more frequently in the human genome. 5 0-UTR and coding regions of the genes showed a significantly lower diversity for indels compared with other regions, suggesting differences in effects of selection on indels and substitutions. Sequence diversity and pairwise linkage disequilibrium (LD) findings of the different populations were similar to earlier results and included a greater skew towards low-frequency variants and a faster rate of LD decay in the African-descent population compared with the non-African populations. Within populations, the allele frequency spectra and LD-decay profiles for indels were similar to substitutions. Overall, the findings suggest that, although the mechanisms giving rise to indels may be different from those causing substitutions, the evolutionary his-tories of indels and substitutions are similar, and that indels can play a valuable role in association studies and marker selection strategies.
Understanding Human DNA Sequence Variation at Pennsylvania State U niversity on M arch 1, 2014 http://jhered.oxfordjournals.org/ D ow nloaded from
, 1991
"... Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different po ..."
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Cited by 12 (3 self)
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Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different populations and the species as a whole, among other studies. With the advent of DNA-based markers in the last quarter century, these studies have accelerated. One of the challenges for the next century is to understand that variation. One component of that understanding will be population genetics. We present here examples of many of the ways these new data can be analyzed from a population perspective using results from our laboratory on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support an ‘‘out of Africa’ ’ hypothesis for human dispersal around the world and begin to refine the understanding of population structures and genetic relationships. We are also developing baseline information against which we can compare findings at different loci to aid in the identification of loci subject, now and in the past, to selection (directional or balancing). We do not yet have a comprehensive understanding of the extensive variation in the human genome, but some of that understanding is coming from population genetics.
Review Characterizing Linkage Disequilibrium in Pig Populations
"... Knowledge of the extent and range of linkage disequilibrium (LD), defined as non-random association of alleles at two or more loci, in animal populations is extremely valuable in localizing genes affecting quantitative traits, identifying chromosomal regions under selection, studying population hist ..."
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Cited by 11 (0 self)
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Knowledge of the extent and range of linkage disequilibrium (LD), defined as non-random association of alleles at two or more loci, in animal populations is extremely valuable in localizing genes affecting quantitative traits, identifying chromosomal regions under selection, studying population history, and characterizing/managing genetic resources and diversity. Two commonly used LD measures, r2 and D’, and their permutation based adjustments, were evaluated using genotypes of more than 6,000 pigs from six commercial lines (two terminal sire lines and four maternal lines) at ~4,500 autosomal SNPs (single nucleotide polymorphisms). The results indicated that permutation only partially removed the dependency of D ’ on allele frequency and that r2 is a considerably more robust LD measure. The maximum r2 was derived as a function of allele frequency. Using the same genotype dataset, the extent of LD in these pig populations was estimated for all possible syntenic SNP pairs using r2 and the ratio of r2 over its theoretical maximum. As expected, the extent of LD highest for SNP pairs was found in tightest linkage and decreased as their map distance increased. The level of LD found in these pig populations appears to be lower than previously implied in several other studies using microsatellite genotype data. For all pairs of SNPs approximately 3 centiMorgan (cM) apart, the average r2 was equal to 0.1. Based on the average population-wise LD found in these six commercial pig lines, we recommend a spacing of 0.1 to 1 cM for a whole genome association study in pig populations. Key words: LD, LD measure, pigs 1.
SNPAnalyzer: a web-based integrated workbench for singlenucleotide polymorphism analysis. Nucleic Acids Res 2005; 33(Web Server issue
"... SNPAnalyzer is a software that performs four essen-tial statistical analyses of SNPs in a common compu-tational environment. It is composed of three main modules: (i) data manipulation, (ii) analysis and (iii) visualization. The data manipulation module is responsible for data input and output, and ..."
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Cited by 10 (0 self)
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SNPAnalyzer is a software that performs four essen-tial statistical analyses of SNPs in a common compu-tational environment. It is composed of three main modules: (i) data manipulation, (ii) analysis and (iii) visualization. The data manipulation module is responsible for data input and output, and handles genotype, phenotype and genetic distance data. To ensure user convenience, the data format is simple. The analysis module performs statistical calculations and consists of four subcomponents: (i) Hardy– Weinberg equilibrium, (ii) Haplotype Estimation, (iii) linkage disequilibrium (LD) and (iv) quantitative trait locus analysis. The main feature of the analysis module is multiple implementations of different algorithms and indices for haplotype estimation and for LD analysis. This enables users to compare separate results generated by different algorithms, which help to avoid biased results acquired by apply-ing a single statistical algorithm. The performance of all implemented algorithms has been validated using experimentally proven datasets. The visualization module presents most of the analyzed results as figures, rather than as simple text, which aids in the intuitive understanding of complex data. The SNPAnalyzer has been developed using C and C11 and is available at
Successful design and conduct of genome-wide association studies
- Hum Mol Genet
"... Genome wide association studies are becoming an increasingly effective tool for identifying genetic factors contributing to complex diseases. In this review, I discuss two sets of genome-wide association studies that identified novel genetic factors for age-related macular degeneration and genetic f ..."
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Genome wide association studies are becoming an increasingly effective tool for identifying genetic factors contributing to complex diseases. In this review, I discuss two sets of genome-wide association studies that identified novel genetic factors for age-related macular degeneration and genetic factors for type II diabetes. In reviewing these sets of studies, my goal is to identify factors that contributed to the success of these studies. Design related factors include the selection of traits that show strong familiality, the selection of clinically homogeneous populations, and selecting cases that have a family history. Ethnic stratification within the study sample can lead to biases and methods to control for stratification are briefly reviewed. Finally, the impact of SNP selection on the power of a study and procedures for improving power by inferring genotypes, by combining data across studies and by performing multistage analyses are discussed. The continuing success of genome-wide association studies depends upon careful selection of populations for study and on collaborative analytical approaches.
