Methods for the Selection of Tagging Snps: a Comparison of Tagging Efficiency and Performance
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Haplotype Block Definition and Its Application X. Zhu, S. Zhang, D
Haplotype Block Definition and Its Application X. Zhu, S. Zhang, D. Kan, and R. Cooper Pacific Symposium on Biocomputing 9:152-163(2004) HAPLOTYPE BLOCK DEFINITION AND ITS APPLICATION X. ZHU1, S. ZHANG2,3, D. KAN1, R. COOPER1 1 Department of Preventive Medicine and Epidemiology, Loyola University Stritch School of Medicine, Maywood, IL 60153, 2 Department of Mathematical Science, Michigan Technological University, Houghton, MI and 3Department of Mathematics, Heilongjiang University, Harbin, China We present a simple two-stage procedure to define haplotype blocks and construct a statistic to test whether a polymorphism belongs to a block. Applying this method to the data of Gabriel et al. [2002] yielded longer haplotype blocks than were originally reported with a similar average percentage of common haplotypes in blocks. Furthermore, across regions of the genome and among the four populations that were studied, we found that linkage disequilibrium between a given single nucleotide polymorphism (SNP) and the haplotype block was a monotonic function of distance. This correlation was essentially independent of the minor allele frequency of the putative causal SNP when it fell outside of the block, however it was strongly dependent on the minor allele frequency when the SNP was internal to the block. These results have direct application to the design of candidate gene or region-wide association studies. 1 Introduction Since SNPs occur about every 300bp they provide much more information than other types of sequence variants in mapping complex diseases. Because the evolutionary history of common diseases is not known, one promising approach is to comprehensively test common genetic variants for association with the trait being studied [1,2]. -
Linkage Disequilibrium
Linkage Disequilibrium Biostatistics 666 Logistics: Office Hours Office hours on Mondays at 4 pm. Room 4614 School of Public Health Tower Previously … Basic properties of a locus • Allele Frequencies • Genotype Frequencies Hardy-Weinberg Equilibrium • Relationship between allele and genotype frequencies that holds for most genetic markers Exact Tests for Hardy-Weinberg Equilibrium Today … We’ll consider properties of pairs of alleles Haplotype frequencies Linkage equilibrium Linkage disequilibrium Let’s consider the history of two neighboring alleles… Alleles that exist today arose through ancient mutation events… Before Mutation A C G T A A G T A C G T A C G T G T A C G A C G After Mutation A C G T A A G T A C G T A C G T G T A C G A C G A C G T A C G T A CMutation G T A C G T G T A C G A C G Alleles that exist today arose through ancient mutation events… Before Mutation A After Mutation A C Mutation One allele arose first, and then the other… Before Mutation A G C G After Mutation A G C G C C Mutation Recombination generates new arrangements for ancestral alleles Before Recombination A G C G C C After Recombination A G C G C C A C Recombinant Haplotype Linkage Disequilibrium Chromosomes are mosaics Ancestor Extent and conservation of mosaic pieces depends on Present-day • Recombination rate • Mutation rate • Population size • Natural selection Combinations of alleles at very close markers reflect ancestral haplotypes Why is linkage disequilibrium important for gene mapping? Association Studies and Linkage Disequilibrium -
The Role of Haplotypes in Candidate Gene Studies
Genetic Epidemiology 27: 321–333 (2004) The Role of Haplotypes in Candidate Gene Studies Andrew G. Clarkn Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York Human geneticists working on systems for which it is possible to make a strong case for a set of candidate genes face the problem of whether it is necessary to consider the variation in those genes as phased haplotypes, or whether the one-SNP- at-a-time approach might perform as well. There are three reasons why the phased haplotype route should be an improvement. First, the protein products of the candidate genes occur in polypeptide chains whose folding and other properties may depend on particular combinations of amino acids. Second, population genetic principles show us that variation in populations is inherently structured into haplotypes. Third, the statistical power of association tests with phased data is likely to be improved because of the reduction in dimension. However, in reality it takes a great deal of extra work to obtain valid haplotype phase information, and inferred phase information may simply compound the errors. In addition, if the causal connection between SNPs and a phenotype is truly driven by just a single SNP, then the haplotype- based approach may perform worse than the one-SNP-at-a-time approach. Here we examine some of the factors that affect haplotype patterns in genes, how haplotypes may be inferred, and how haplotypes have been useful in the context of testing association between candidate genes and complex traits. Genet. Epidemiol. & 2004 Wiley-Liss, Inc. Key words: haplotype inference; haplotype association testing; candidate genes; linkage equilibrium Grant sponsor: NIH; Grant numbers: GM65509, HL072904. -
Creation of Subgroup-Specific Haplotype Blocks and Libraries
HIGHLIGHTED ARTICLE | INVESTIGATION HaploBlocker: Creation of Subgroup-Specific Haplotype Blocks and Libraries Torsten Pook,*,†,1 Martin Schlather,†,‡ Gustavo de los Campos,§ Manfred Mayer,** Chris Carolin Schoen,** and Henner Simianer*,† *Department of Animal Sciences, Animal Breeding and Genetics Group, University of Goettingen, 37075, Germany, †Center for Integrated Breeding Research, University of Goettingen, 37075, Germany, ‡Stochastics and Its Applications Group, University of Mannheim, 68159, Germany, §Departments of Epidemiology and Biostatistics and Statistics and Probability, Institute for Quantitative Health Science and Engineering, Michigan State University, Michigan 48824, and **Plant Breeding, Technical University of Munich School of Life Sciences Weihenstephan, 85354 Freising, Germany ORCID IDs: 0000-0001-7874-8500 (T.P.); 0000-0001-5692-7129 (G.d.l.C.); 0000-0003-2687-8316 (M.M.) ABSTRACT The concept of haplotype blocks has been shown to be useful in genetics. Fields of application range from the detection of regions under positive selection to statistical methods that make use of dimension reduction. We propose a novel approach (“HaploBlocker”) for defining and inferring haplotype blocks that focuses on linkage instead of the commonly used population-wide measures of linkage disequilibrium. We define a haplotype block as a sequence of genetic markers that has a predefined minimum frequency in the population, and only haplotypes with a similar sequence of markers are considered to carry that block, effectively screening a dataset for group-wise identity-by-descent. From these haplotype blocks, we construct a haplotype library that represents a large proportion of genetic variability with a limited number of blocks. Our method is implemented in the associated R-package HaploBlocker, and provides flexibility not only to optimize the structure of the obtained haplotype library for subsequent analyses, but also to handle datasets of different marker density and genetic diversity. -
1 DRUG DISCOVERY TARGETING GENOMIC APPROACH Submitted
DRUG DISCOVERY TARGETING GENOMIC APPROACH A Dissertation submitted to the Department of Pharmacy, East West University, in partial fulfillment of the requirements for the degree of Master of Pharmacy. Submitted By Mst. Tania Ashraf ID: 2014-3-79-006 Department Of Pharmacy East West University 1 This thesis paper is dedicated to my beloved Parents… 2 DECLARATION BY THE CANDIDATE I, Mst.Tania Ashraf, hereby declare that this dissertation, entitled “Drug discovery targeting genomic approach” submitted to the Department of Pharmacy, East West University, in the partial fulfillment of the requirement for the degree of Master of Pharmacy, is a genuine & authentic research work carried out by me under the guidance of Dr. Repon Kumer Saha, Assistant Professor, Department of Pharmacy, East West University, Dhaka. The contents of this dissertation, in full or in parts, have not been submitted to any other Institute or University for the award of any Degree or Diploma of Fellowship. ---------------------------------- Mst. Tania Ashraf ID: 2014-3-79-006 Department of Pharmacy East West University Jaharul Islam city, Aftabnagar, Dhaka 3 CERTIFICATION BY THE SUPERVISOR This is to certify that the desertion, entitled “Drug discovery targeting genomic approach” is a benefice research work done, under our guidance and supervision by Mst. Tania Ashraf (ID: 2014-3-79-006), in partial fulfillment of the requirement for the degree of Master of Pharmacy. ------------------------------------- Dr. Repon Kumer Saha Assistant Professor Department of Pharmacy East West University Jaharul Islam city, Aftabnagar, Dhaka 4 ENDORSEMENT BY THE CHAIRPERSON This is to certify that the dissertation, entitled “Drug discovery targeting proteomic approach” is a bonafide research work done by Mst.Tania Ashraf (ID: 2014-3-79-006), in partial fulfillment of the requirements for the degree of Master of Pharmacy. -
Transferability of Tag Snps to Capture Common Genetic Variation in DNA Repair Genes Across Multiple Populations Paul I.W. De
Transferability of Tag SNPs to Capture Common Genetic Variation in DNA Repair Genes Across Multiple Populations Paul I.W. De Bakker, Robert R. Graham, David Altshuler, Brian E. Henderson, and Christopher A. Haiman Pacific Symposium on Biocomputing 11:478-486(2006) TRANSFERABILITY OF TAG SNPS TO CAPTURE COMMON GENETIC VARIATION IN DNA REPAIR GENES ACROSS MULTIPLE POPULATIONS PAUL I.W. DE BAKKER, ROBERT R. GRAHAM, DAVID ALTSHULER Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA BRIAN E. HENDERSON, CHRISTOPHER A. HAIMAN Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA Genetic association studies can be made more cost-effective by exploiting linkage disequilibrium patterns between nearby single-nucleotide polymorphisms (SNPs). The International HapMap Project now offers a dense SNP map across the human genome in four population samples. One question is how well tag SNPs chosen from a resource like HapMap can capture common variation in independent disease samples. To address the issue of tag SNP transferability, we genotyped 2,783 SNPs across 61 genes (with a total span of 6 Mb) involved in DNA repair in 466 individuals from multiple populations. We picked tag SNPs in samples with European ancestry from the Centre d’Etude du Polymorphisme Humain, and evaluated coverage of common variation in the other samples. Our comparative analysis shows that common variation in non- African samples can be captured robustly with only marginal loss in terms of the maximum r2. We also evaluated the transferability of specified multi-marker haplotypes as predictors for untyped SNPs, and demonstrate that they provide equivalent coverage compared to single-marker tests (pairwise tags) while requiring fewer SNPs for genotyping. -
The Definition of Multilocus Haplotype
Aus der Arbeitsgruppe Bioinformatik des Max-Delbruck-Centrums¨ fur¨ Molekulare Medizin (MDC), Berlin-Buch, in Kooperation mit der Medizinischen Fakult¨at der Charit´e- Universit¨atsmedizin Berlin The Definition of Multilocus Haplotype Blocks and Common Diseases Dissertation zur Erlangung des akademischen Grades Doctor rerum medicarum (Dr. rer. medic.) im Fach Medizin vorgelegt der Medizinischen Fakult¨at der Charit´e– Universit¨atsmedizin Berlin Humboldt-Universit¨at zu Berlin von Herrn Dipl.-Math. Michael Nothnagel geboren am 22.07.1971 in Berlin Pr¨asident der Humboldt-Universit¨at zu Berlin: Prof. Dr. Jurgen¨ Mlynek Dekan der Medizinischen Fakult¨at der Charit´e– Universit¨atsmedizin Berlin: Prof. Dr. med. Martin Paul Gutachter: 1. Univ.Prof. Dr. em. Jens G. Reich 2. Suzanne M. Leal, Ph.D., Associate Professor 3. Prof. Dr. Andreas Ziegler eingereicht am: 03. M¨arz 2004 Datum der Promotion (Tag der mundlichen¨ Prufung):¨ 13. Dezember 2004 Abstract Current approaches to haplotype block definition target either absent recom- bination events or the efficient description of genomic variation. This thesis aims to define blocks of single nucleotide polymorphisms (SNP) as areas of elevated linkage disequilibrium (LD). To this end, a new entropy-based measure for LD between multiple markers/loci, the Normalized Entropy Dif- ference, is developed and is characterized as a multilocus extension of the pairwise measure r2. A corresponding algorithm for the block definition is proposed. Its evaluation on a data set of human chromosome 12 from the International Haplotype Map project proves the usefulness of the derived blocks with respect to several features, including their chromosomal cover- age and the number and portion of common block haplotypes. -
Efficient Design and Analysis of Genome-Wide
UNIVERSITY OF CALIFORNIA Los Angeles Efficient Design and Analysis of Genome-wide Association Studies A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Computer Science by Emrah Kostem 2013 c Copyright by Emrah Kostem 2013 ABSTRACT OF THE DISSERTATION Efficient Design and Analysis of Genome-wide Association Studies by Emrah Kostem Doctor of Philosophy in Computer Science University of California, Los Angeles, 2013 Professor Eleazar Eskin, Chair The recent advances in genomic technologies, have made it possible to collect large- scale information on genetic variation across a diverse biological landscape. This has resulted in an exponential influx of genetic information and the field of genetics has be- come data-rich in a relatively short amount of time. These developments have opened new avenues to elucidate the genetic basis of complex diseases, where the traditional disease study approaches had little success. In recent years, the genome-wide association study (GWAS) approach has gained widespread popularity for its ease of use and effectiveness, and is now the standard approach to study complex diseases. In GWAS, information on millions of single- nucleotide polymorphisms (SNPs) is collected from case and control individuals. SNP genotyping is cost-effective and due to their abundance in the genome, SNPs are cor- related to their neighboring genetic variation, which makes them tags for genomic regions. Typically, each SNP is statistically tested for association to disease, and the genomic regions tagged by the significant SNPs are believed to be harboring the func- tional variants contributing to disease. In order to reduce the cost of GWAS and the redundancy in the information col- ii lected, an informative subset of the SNPs, or tag SNPs, are genotyped. -
Large-Scale Evolutionary Analysis of Polymorphic Inversions in the Human Genome
ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Doctoral thesis Large-scale evolutionary analysis of polymorphic inversions in the human genome Author Carla Giner Delgado Director Mario Caceres´ Aguilar Departament de Gen`eticai de Microbiologia Facultat de Bioci`encies Universitat Aut`onomade Barcelona 2017 Large-scale evolutionary analysis of polymorphic inversions in the human genome Mem`oriapresentada per Carla Giner Delgado per a optar al grau de Doctora en Gen`etica per la Universitat Aut`onomade Barcelona Autora Director Carla Giner Delgado Mario Caceres´ Aguilar Bellaterra, 28 de Setembre de 2017 Abstract Chromosomal inversions are structural variants that invert a fragment of the genome without usually modifying its content, and their subtle but powerful effects in natural populations have fascinated evolutionary biologists for a long time. Discovered a century ago in fruit flies, their association with dif- ferent evolutionary processes, such as local adaptation and speciation, was soon evident in several species. However, in the current era of genomics and big data, inversions frequently escape the grasp of current technologies and remain largely overlooked in humans. -
A Primary Assembly of a Bovine Haplotype Block Map Based On
Genetics: Published Articles Ahead of Print, published on April 15, 2007 as 10.1534/genetics.106.069369 A primary assembly of a bovine haplotype block map based on a 15k SNP panel genotyped in Holstein-Friesian cattle Mehar S. Khatkar*,§,1, Kyall R. Zenger*,§, Matthew Hobbs*,§, Rachel J. Hawken†,§, Julie A. L. Cavanagh*,§, Wes Barris†,§, Alexander E. McClintock*,§, Sara McClintock‡,§, Peter C. Thomson*,§, Bruce Tier§, Frank W. Nicholas*,§ and Herman W. Raadsma*,§ * Centre for Advanced Technologies in Animal Genetics and Reproduction (ReproGen), University of Sydney, Camden NSW 2570, Australia † CSIRO Livestock Industries, St Lucia QLD 4067, Australia. ‡ Animal Genetics and Breeding Unit*, University of New England, NSW 2351, Australia. § CRC for Innovative Dairy Products, William Street, Melbourne, Vic, 3000, Australia. 1 Running title: Haplotype blocks in bovine genome Keywords: Linkage disequilibrium, haplotype blocks, tag SNPs, bovine, genome- wide, maps 1Corresponding author: Centre for Advanced Technologies in Animal Genetics and Reproduction (ReproGen), University of Sydney, PMB 3, Camden NSW 2570, Australia. E-mail: [email protected] FAX: +61-2-9351 1693 Tele: +61-2-9351 1687 2 ABSTRACT Analysis of data on 1,000 Holstein-Friesian bulls genotyped for 15,036 SNPs has enabled genome-wide identification of haplotype blocks and tag SNPs. A final subset of 9,195 SNPs in Hardy-Weinberg equilibrium and mapped on autosomes on the bovine sequence assembly (release Btau 3.1) were used in the present study. The average inter-marker spacing was 251.8 kb. The average MAF was 0.29 (0.05-0.5). Following recent precedents in human HapMap studies, a haplotype block was defined where 95 % of combinations of SNPs within a region are in very high linkage disequilibrium. -
Single Nucleotide Polymorphism Facilitated Downregulation of The
Volume 20 Number 3 March 2018 pp. 289–294 289 www.neoplasia.com Single Nucleotide Polymorphism Somenath Datta*, Richard M. Sherva†, Mart De La Cruz*, Michelle T. Long*, Priya Roy*, Facilitated Down-Regulation of the Vadim Backman‡, Sanjib Chowdhury*,1 and ,1 Cohesin Stromal Antigen-1: Hemant K. Roy* Implications for Colorectal *Department of Medicine, Section of Gastroenterology, Boston University Medical Center, Boston, MA 02118, USA; Cancer Racial Disparities †Department of Medicine, Section of Biomedical Genetics, Boston University Medical Center, Boston, MA 02118, USA; ‡Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA Abstract The biological underpinnings for racial disparities in colorectal cancer (CRC) incidence remain to be elucidated. We have previously reported that the cohesin SA-1 down-regulation is an early event in colon carcinogenesis which is dramatically accentuated in African-Americans. In order to investigate the mechanism, we evaluated single nucleotide polymorphisms (SNPs) for association with SA-1-related outcomes followed by gene editing of candidate SNP. We observed that rs34149860 SNP was significantly associated with a lower colonic mucosal SA-1 expression and evaluation of public databases showed striking racial discordance. Given that the predicted SNP would alter miR-29b binding site, we used CRISPR knock-in in CRC cells and demonstrated that the SNP but not wild-type had profound alterations in SA-1 expression with miR-29b inhibitor. This is the first demonstration of high-order chromatin regulators as a modulator of racial differences, risk alteration with SNPs and finally specific modulation by microRNAs. Neoplasia (2018) 20, 289–294 Introduction Since many SNPs have a racial predilection, this provides a Colorectal cancer (CRC) remains the second leading causes of cancer potential mechanism for racial disparities in CRC. -
A Primary Assembly of a Bovine Haplotype Block Map Based on a 15,036-Single-Nucleotide Polymorphism Panel Genotyped in Holstein–Friesian Cattle
Copyright Ó 2007 by the Genetics Society of America DOI: 10.1534/genetics.106.069369 A Primary Assembly of a Bovine Haplotype Block Map Based on a 15,036-Single-Nucleotide Polymorphism Panel Genotyped in Holstein–Friesian Cattle Mehar S. Khatkar,*,†,1 Kyall R. Zenger,*,† Matthew Hobbs,*,† Rachel J. Hawken,†,‡ Julie A. L. Cavanagh,*,† Wes Barris,†,‡ Alexander E. McClintock,*,† Sara McClintock,†,§ Peter C. Thomson,*,† Bruce Tier,† Frank W. Nicholas*,† and Herman W. Raadsma*,† *Centre for Advanced Technologies in Animal Genetics and Reproduction (ReproGen), University of Sydney, Camden NSW 2570, Australia, ‡CSIRO Livestock Industries, St. Lucia QLD 4067, Australia, §Animal Genetics and Breeding Unit, University of New England, Armidale NSW 2351, Australia and †CRC for Innovative Dairy Products, Melbourne, Vic 3000, Australia Manuscript received December 6, 2006 Accepted for publication April 3, 2007 ABSTRACT Analysis of data on 1000 Holstein–Friesian bulls genotyped for 15,036 single-nucleotide polymorphisms (SNPs) has enabled genomewide identification of haplotype blocks and tag SNPs. A final subset of 9195 SNPs in Hardy–Weinberg equilibrium and mapped on autosomes on the bovine sequence assembly (release Btau 3.1) was used in this study. The average intermarker spacing was 251.8 kb. The average minor allele frequency (MAF) was 0.29 (0.05–0.5). Following recent precedents in human HapMap studies, a haplotype block was defined where 95% of combinations of SNPs within a region are in very high linkage dis- equilibrium. A total of 727 haplotype blocks consisting of $3 SNPs were identified. The average block length was 69.7 6 7.7 kb, which is 5–10 times larger than in humans.