A User's Guide to the International HapMap Project Web Site
Contents
1. Examples Chr20 Chr9 660 000 760 000 SNP rs6870660 NM_153254 BRCA2 5q31 ENm010 Hide banner Bookmark this Link to Image High res Image Help 8 Search and specificity across different size scales See Mueller 2004 for a discussion of the practical application of these measurements The LOD metric used by this HapMap web site display is described in Daly et al 2001 Recipe 5 Generate a text listing of linkage disequilibrium values using the genome browser After selecting a region of interest and visually inspecting the extent of LD across the gene or genes of interest the researcher may wish to download a tab delimited numeric summary of the LD values in the selected region This information can be used to select a set of tag SNPs that will act as proxies for other SNPs that are in high LD with them l Starting at step 6 from recipe 1 navigate to the region of interest Locate the Reports and Analysis menu above the Detail panel and select the menu item Dump HapMap LD Data Next click the Configure button This will open a configuration page that allows you to select which HapMap population to dump data for and whether to save the data to disk or view it in the web browser gt 23 Search using a sequence name gene name locus or other landmark The wildcard character is allowed To center on a location click the ruler Use the Scroll Zoom buttons to change 3 Click2. as described in recipes 4 and 6 An alternative however is to activate a track that displays the phased haplotypes themselves The phased haplotype data described in this recipe was generated by the International HapMap Project Consortium using the program PHASE version 2 0 Stephens and Donnelly 2003 During phasing each allele in a genotype is assigned to one or the other parental chromosome using a maximum likelihood algorithm that uses trio lineage information in the HapMap population groups or if trio information is not available by fitting the data to a model that minimizes the number of implied historical crossovers in the population The phased haplotypes are displayed as a graphic in which each chromosome of the individuals sampled by the Landmark or Region chr1 172164403 172264402 Data Source Search Reset HapMap Data Rel 16c 1 phasel June05 on NCBI B34 assembly dbSNP b124 project is represented as a line one pixel high and each SNP allele is arbitrarily colored blue or yellow A region of high LD will appear as a region in which there are long runs of SNPs whose alleles are the same color indicating that there is little recombination among them A region of low LD will appear as an area where the runs are shorter and more fragmentary 1 Browse to a region of interest see Recipe 1 Locate the Results and Analysis menu above the Detail panel and select the menu item Annotate Phased Haplot
3. section provides bulk downloads of HapMap data and analysis sets as well as interactive access to the HapMap database This paper will be concerned almost exclusively with the Data section Recipe 1 Browse genotypes using the genome browser Research into the genetic contributions to a human disease is often centered around a small number of candidate genes In such a case the researcher will wish to know whether there are any common single nucleotide polymorphisms SNPs in the neighborhood of the candidate gene s what those SNPs alleles are and what are the relative frequencies of the alleles in the population The researcher will also be particularly interested in coding SNPs cSNPs SNPs whose alleles change the amino acid sequence of the gene product and therefore may represent functional variations The genome browser at the HapMap web site provides access to small to medium sized regions of the genome for this type of interactive exploration This basic recipe shows how to start using the genome browser 1 Using any modern web browser go to www hapmap org 2 Click the Browse Project Data link under the Project Data section of the hapmap org home page This page can also be reached directly at http www hapmap org cgi perl gbrowse gbrowse 3 This will take you to a genome browser based on the Thorisson et al GBrowse package Stein et al 2002 Figure 1 Depending on your computer languag
4. LD to use r 2 D or LOD and which populations to display The Box Size configuration option allows you to select whether the plot will show the distances between SNPs proportionate to their genomic position or to display the SNPs in the region as if there were a constant distance between them heavily because the allelic state of a genotyped SNP will be a poor predictor of the state of non genotyped SNPs The determination of patterns of LD in the four populations characterized by the HapMap project is in fact one of the major goals of this project The International HapMap Project has precalculated patterns of LD among the genotyped SNPs The data can be downloaded in bulk from the HapMap web site or browsed interactively using the HapMap genome browser The latter method allows researchers to see patterns of LD in context with the distribution of genes of interest 1 To view available LD data precalculated from HapMap genotypes first browse to a region of interest see Recipe 1 2 After browsing to a region of interest select the Annotate LD plot plugin from the Reports and Analysis menu and click the Configure button to bring up a configuration page that will allow you to adjust the display properties to your liking Key parameters on this page are the HapMap populations to display which measure of LD to use choice of D r or LOD whether the triangle plot should be oriented with the vertex poin
5. an exon but create a synonymous nucleotide substitution are pink and those that fall into a non coding region are cyan These colors can be customized by selecting the Highlight SNP Properties item in the Reports and Analysis menu 9 At higher magnifications the genotyped SNPs change to display the alleles associated with the SNP The allele shown in blue is the allele present in the reference genomic sequence at that location and the red allele is the other allele present in the SNP 10 When zoomed in still further the genotyped SNPs track changes to show pie charts representing the allele frequency for each genotyped population The blue wedge of the piechart indicates the frequency of the allele that appears in the reference genome sequence The red wedge is the frequency of the alternative allele 11 Click on the glyph for an individual SNP to see a text based page with detailed genotype and allele counts and assay information The piechart display that appears in step 9 provides the researcher with the ability to easily distinguish SNPs that are International HapMap Project Home About the Project Data Publications Conference Search using a sequence name gene name locus or other landmark The wildcard character is allowed To center on a location click the ruler Use the showing various types of data The two most useful tracks are the Genotyped SNPs track that provides information on th
6. he is satisified with the characteristics of the tag set This recipe describes how to generate a text dump of the SNPs in this set so that they can be used to create a screening set when combined with information from other HapMap generated reports 1 First browse to a region of interest see Recipe 1 2 Locate the Results and Analysis menu above the Detail panel and select the menu item Dump tag SNP Data Press Configure to set up the interactive options for tag SNP selection as described in Recipe 6 Options include selecting a population and an algorithm uploading a list of SNPs to necessarily be included as a tag SNP uploading a list of SNPs to be excluded from the tag SNP list and setting cut offs for LD and allele frequency values 3 Click the Go button to retrieve the data and produce a report Thorisson et al The generated report contains a tab delimited list of tag SNP names chromosome position and allele frequency in the region This is followed by a section that lists the tag SNPs the non tag SNPs that they capture and the strength of LD between each tag SNP and the non tag SNPs it captures Recipe 8 View phased haplotypes on the genome browser A researcher may wish to correlate the tag SNP set selected by the tag SNP picker algorithm with the underlying haplotype structure of the region One way to do this is to turn both the tag SNP and pairwise LD tracks on simultaneously
7. queries find all tag SNPs for this list of zinc finger genes Acknowledgements We wish to thank the four anonymous reviewers for their constructive comments during the preparation of this work This work was supported by grants from The SNP Consortium and the Genome Institute of the National Institutes of Health References Barrett JC Fry B Maller J and Daly MJ 2005 Haploview analysis and visualization of LD and haplotype maps Bioinformatics 21 263 265 Birney E T D Andrews P Bevan M Caccamo Y Chen L Clarke G Coates J Cuff V Curwen T Cutts et al 2004 An overview of Ensembl Genome Res 14 925 928 Daly MJ Rioux JD Schaffner SF Hudson TJ Lander ES 2001 High resolution haplotype structure in the human genome Nat Genet 29 229 232 de Bakker P 2005 Tagger http www broad mit edu mpg tagger Gibbs R A J W Belmont P Hardenbol T D Willis F Yu H Yang L Y Ch ang W Huang B Liu Y Shen et al 2003 The International HapMap Project Nature 426 789 796 Gilbert D 2003 Shopping in the genome market with EnsMart Brief Bioinform 4 292 296 International HapMap Consortium 2005 International HapMap Consortium Paper Nature in press Kent W J C W Sugnet T S Furey K M Roskin T H Pringle A M Zahler and D Haussler 2002 The human genome browser at UCSC Genome Res 12 996 1006 Mueller J C 2001 Linkage disequilibrium for different scales and applic
8. save the data to disk or view it in the web browser 3 Choose the desired options and click the Go button to retrieve the data and produce a report The format is the same as the bulk download files see below The dumper Symbols and colours used Configuration settings are stored in chr10 127086514 127116489 Search Reset Annotate LD Plot Configure Go a browser cookie so next time Data Source HapMap Data Rel 16c 1 phasel June05 on NCBI B34 assembly dbSNP b124 Population descriptors YRl Yoruba in Ibadan Nigeria JPT Japanese in Tokyo Japan CHB Han Chinese in Beijing China CEU CEPH Utah residents with ancestry from northern and western Europe B Overview Overview of chri SES ee Scroll Zoom Z show 29 98 kbp gt NN crip you can click the Go button on the main page and dump data directly without having to configure the dumper first on 10m zon The text dump format consists knoun genes 580Kb gt d SNPs 5 6Kb dbSNP SNPs 568Kb a Details of a set of rows containing each SNPs dbSNP ID the two reference and alternative allele the position of the SNP on the genome and the genotypes of the 127090k 127100k Genotyped SNPs rs10159992 rs3740206 rs3781058 gt A A G CEU CHB JPT YRI CEU CHB JPT YRI rs2185740 T f CEU CHB JPT YRI CEU CHB JPT YRI LocusLink genes BCCIP BRCAZ and CDKN1A interactin
9. the Go button to retrieve the data and produce a report The format is the same as S E the bulk download files see below northern and western Europe Overview of chr5 Help links Viewing LD data Retrieving genotype data Retrieving frequency data Landmark or Region Reports amp Analysis 1 1 chr5 88070197 88270196 Search Reset Annotate LD Plot Configure Go The dumper configuration settings Data Source 2 i 3 paa eel oa inion mde o NEBI B34 assam ADEN bi i ScrolZoom KI show 200 kbp BID Fip are stored in a browser cookie so Population descriptors YRI Yoruba in Ibadan Nigeria JPT Japanese in Tokyo Japan CHB Han Chinese in Beijing China CEU CEPH Utah residents with ancestry from the next time you wish to perform this operation you can simply click the Go button on the main page on don on SON OTT 60N 70M BOM 100M 110M 120M 130M 140M 150M 160M 170M 160 C EEE N E EN E EE and dump the data directly without having to go through the RefSeq nRNNo NN002397 D n LA ani 8070E6060k B80S0k S8100k BELLOk Gei20k 813k 8140k 681k 6160k 6170k Solo S6l90k B 200k 6S210k 8220k 6 230k 8240k 6250k 060k 8270k configuration step ot CEUzdprine OS Figure 4 LD viewer displayed on the Genome Browser This image shows 200 kbp on chr5 for the CEU samples positions 88 070 197 to 88 270 196 The the fourth and fi
10. Thorisson et al A User s Guide to the International HapMap Project Web Site Gudmundur A Thorisson Albert V Smith Lalitha Krishnan and Lincoln D Stein Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor NY 11724 1 To whom correspondence should be addressed Email mummi cshl edu These authors contributed equally to the work The HapMap website at http www hapmap org is the primary portal to genotype data produced as part of the International Haplotype Map Project Gibbs et al 2003 In phase of the project over 1 1 million SNPs were genotyped in 270 individuals from 4 worldwide populations Consortium 2005 The HapMap website provides researchers with a number of tools that allow them to analyze the data as well as to download data for local analyses This paper presents step by step guides to using those tools including guides for retrieving genotype and frequency data picking tag SNPs for use in association studies viewing haplotypes graphically and examining marker to marker LD patterns The goal of the International HapMap Project International HapMap Consortium 2005 is to map and understand the patterns of common genetic diversity in the human genome in order to accelerate the search for the genetic causes of human disease The first major milestone of the project was the genotyping of 1 1 million SNPs across four populations a goal reached in the spring of 2005 Another 4 6 million SNPs are being
11. a via the genome browser is limited to regions no more than 5 Mb wide Researchers who wish to obtain data for chromosome or genome wide data have two choices bulk download or HapMart access The former described in recipe 10 provides text dumps of the entire HapMap data set and while complete does not provide any filtermg or selection services HapMart described in this section allows researchers to select SNPs using diverse criteria and to display just those aspects of the data set that they are interested in 1 Open the MartView interface at http www hapmap org BioMart martview and click the next button to start a new query using the default database and dataset 2 On the filter page see Figure 8 select SNPs to be g retrieved on the basis of numerous criteria either individually or in combination You can apply filters in any order and revise existing filters by using the next and back buttons As you apply filters the number of SNPs selected are shown in the summary panel on the right Available filters include a b Lists of SNPs to be included or excluded The mininum minor allele frequency of the selected SNPs Limit SNPs to those in Intronic Regions mRNA UTR regions coding non synonymous SNPs or coding synonymous SNPs Limit SNPs to a specific genomic region Limit SNPs to those which overlap specific gene ID s After selecting and refining the appropriate filters click
12. ations Brief Bioinform 5 355 364 Stein L D C Mungall S Shu M Caudy M Mangone A Day E Nickerson J E Stajich T W Harris A Arva et al 2002 The generic genome browser a building block for a model organism system database Genome Res 12 1599 1610 Stephens M and P Donnelly 2003 A comparison of bayesian methods for haplotype reconstruction from population genotype data Am J Hum Genet 73 1162 1169 Wheeler DL Barrett T Benson DA Bryant SH Canese K Church DM DiCuccio M Edgar R Federhen S Helmberg W Kenton DL Khovayko O Lipman DJ Madden TL Maglott DR Ostell J Pontius JU Pruitt KD Schuler GD Schriml LM Sequeira E Sherry ST Sirotkin K Starchenko G Suzek TO Tatusov R Tatusova TA Wagner L Yaschenko E 2005 Database resources of the National Center for Biotechnology Information Nucleic Acids Res 33 D39 45 1
13. e position alleles and allele tandmark orRegion frequencies of each SNP characterized pata source by the HapMap project and the RefSeq Scroll Zoom buttons to change magnification and position Examples Chr20 Chr9 660 000 760 000 SNP rs6870660 NM_153254 BRCA2 5q31 ENm010 Help links Viewing LD data Retrieving genotype data Retrieving frequency data Symbols and colours used Reports amp Analysis _ Search Reset Annotate LD Plot E Configure Go HapMap Data Relit16c 1 phasel June05 on NCBI B34 assembly dbSNP b124 GFlip Population descriptors YRI Yoruba in Ibadan Nigeria JPT Japanese in Tokyo Japan CHB Han Chinese in Beijing China CEU CEPH Utah mRNAs track which shows the residents with ancestry from northern and western Europe positions and structures of human protein coding genes 1 For performing in depth LD and Haplotype analysis of genotype data install Haploview in your local machine Haploview ver3 12 is now available for download Use the controls at the top of the page to Tracks Display Settings scroll left right or to change the Asdyourowntracks magnification of the region You may also click anywhere on the Overview or Home About the Project Data Publications Conference Please send questions and comments on website to he p hapmap org Note This page uses cookies to save and restore preference information No information is shar
14. e settings this page may appear in one of several languages In this guide we assume English Locate the Landmark or Region search box and enter a search term Any of the following types of search term will work a Achromosome name e g Chr10 b A chromosomal position in the format Chromosome start stop e g Chr9 25000 300000 c The name ofa SNP using its dbSNP rs name e g rs4285800 d A gene using its NCBI Refseq accession number e g NM_214279 e A gene using its common name e g BRCA2 f A chromosomal band e g 10q23 1 After entering one of these landmarks press the Search button or hit Enter This will return a page showing the region surrounding the requested feature Figure 2 If multiple features match then the page will show you a graphical summary of all possible features and prompt you to choose one At the top of the returned page is an Overview section that shows the cytogenetic map of the selected chromosome A red box indicates the section of the chromosome in view Beneath this is a Detail section that has horizontal tracks Binsttuetions appearance in a manner appropriate to the scale of the image At low magnifications genotyped SNPs appear as equilateral triangles The background color of the triangle indicates its coding status SNPs that introduce non synonymous amino acid changes are yellow those that fall in
15. ed the scale at the top of the Detail section sss senone browser version 1 63 in order to center the view on this Figure 1 Start page for the HapMap Genome Browser os This image shows the HapMap Genome Browser before a region has been loaded Use position the Data Source menu to select whether to search the current release the default or The genotyped SNP track changes its previous releases Type a chromosome name genomic region gene name SNP name or other identifier into the Landmark or Region textbox to access the region of interest Thorisson et al highly polymorphic in all four of the HapMap populations and therefore more likely to be polymoprhic in other populations as well Alternatively the researcher can identify SNPs that are more polymorphic in a single population and are therefore suitable as markers in population specific genetic screens The detailed view that is obtained when the researcher clicks on a genotyped SNP step 10 provides the researcher with the information needed to generate an assay for the SNP including the left and right flanking sequences needed to create PCR primers A hypertext link to dbSNP Wheeler et al 2005 provides more information about how the SNP was first discovered and any other population genetic information that may exist for it outside the HapMap project while a link to Ensembl Birney et al 2004 leads the researcher to a site where the structural i
16. en developed as portals to high volume genome wide datasets The UCSC Genome Browser Kent et al 2002 and the EnsEMBL project Birney et al 2004 have developed multispecies genome browsers that display genomic annotations graphically and offer retrieval of the underlying data dbSNP Wheeler et al 2004 is a repository for information on single nucleotide polymorphisms but does not yet contain extensive information on the relationships among those SNPs The HapMap web site located at http www hapmap org has a distinct focus It aims to be a resource in the display retrieval and analysis of high throughput high quality genome wide human genetic data with an emphasis on the support of tools for facilitating disease association studies Although the resource is still in development it currently provides the basic tools for visualizing patterns of common polymorphism among the populations surveyed by the HapMap project selecting tag SNP sets based on a variety of criteria and generating customized extracts of the data set In the future the HapMap web site will evolve to provide more services to those designing and interpreting genetic association studies In the near future we will integrate the HapMap genome browser more tightly with other genome browsers for example by sharing tracks with the UCSC Genome Browser and Ensembl projects This will provide researchers with the ability to see HapMap data in the context of ma
17. enome browser In a similar fashion the researcher may wish to download a summary of the frequencies of alleles across a region of interest The researcher can then select from this set those SNPs that meet certain criteria for instance those that are most highly polymorphic in a particular population of interest This recipe describes how to create a tab delimited summary of HapMap allele frequency data across a particular genomic region l Starting at step 6 from recipe 1 navigate to the region of interest 2 Locate the Reports and Analysis menu above the Detail panel and select the menu item Dump SNP frequency data Next click the Configure button This will open a configuration page that allows you to select the desired HapMap population and whether to save the data to disk or view it in the web browser 3 Click the Go button to retrieve the data and produce a report The format is the same as the bulk download files see below The dumper configuration settings are stored in a browser cookie so next time you can click the Go button on the main page and dump data directly without having to configure the dumper first The report generated by this recipe contains one row for each SNP consisting of each SNP s dbSNP ID its genomic position the number of times each possible genotype was seen in the selected population and the heterozygosity of the population for that SNP Recipe 4 View
18. fth columns strength of the the linkage disequilibrium is shown in increasing shades of red for higher LD values indicate the dbSNP IDs for the This particular option is the LOD plot option The report generated by this recipe will show pairwise LD between all SNPs within 500 kb of each other this window may be reduced in size in future releases of the database Each row of the report corresponds to one pair of SNPs The first two columns indicate the positions of the SNPs on the chromosome the third column is the population for which the LD values were calculated and Thorisson et al SNP pair These are followed by the D r and LOD scores for LD between the two SNPs Recipe 6 Pick tag SNPs using the Genome Browser Tag SNPs are a reduced set of SNPs that capture much of the LD in regions they can be used in association studies to reduce the number of SNPs needed to detect LD based association between a trait of interest and a region of the genome For small regions it is possible to select tag SNPs by hand using the graphical and numeric displays of LD generated by the previous two recipes but for best results it is recommended that the researcher use an algorithm that chooses tag SNPs by formally maximizing the number of linked SNPs captured by the tag set There is no single set of tag SNPs that will satisfy the diverse requirements of every association study design Researchers may wish to select SNP
19. g protein isoform This gene produc BCCIP BRCAZ and COKN1A interacting protein isoform C This gene prod psi124466g CEU CHB JPT YRI 127110k SNP on each of the individuals in the selected HapMap population Because this format is identical to that used by the bulk downloadable files it can be easily loaded into the HaploView rs2366045 Ti A CEU CHB JPT YRI rs12356233 rs12570438 c Ti CEU CHB JPT YRI CEU CHB JPT YRI re12570453 iy CEU CHB JPT YRI BCCIP BRCAZ and COKNiA interacting protein isoform This gene produc program Barrett et al 2005 for DHX32 DEAD H Asp Glu Ala Asp His box polupeptide 32 DEAD box prot RefSeq MRNAS NM_016567 loa detailed analysis on the a in a 4 NM_078468 NM078469 o m T NM 018180 researcher s local computer Figure 2 HapMap Genome Browser displaying BRCA2 region After typing BRCA2 into the search box the genome browser will display information about the region of the genome surrounding this gene The Overview panel provides a birds eye display of the whole chromosome with the region of interest indicated by a vertical red line The Details panel shows the selected region Multiple horizontal tracks provide information about genes SNPs and genotypes in the region 3 Thorisson et al Recipe 3 Generate a text listing of genotype frequencies using the g
20. genotyped in the second phase of the project and are scheduled for completion in fall 2005 The project data is available for unrestricted public at the HapMap web site located at http www hapmap org This site offers bulk downloads of the data set as well as interactive data browsing and analysis tools that are not elsewhere available Since it was opened to the public in November 2003 the HapMap data set has been downloaded over 500 000 times by researchers in more than 100 countries The site currently serves more than 30 000 static page requests per month of which 14 000 are bulk download requests and more than 100 000 accesses month to the interactive HapMap browser This paper describes the website and the tools that have been developed for viewing retrieving and analyzing the project data We show readers how to perform several useful and popular tasks and give an overview of new tools under development or planned for the future The HapMap Web Site The HapMap web site at www hapmap org is organized into three main sections accessible from the banner at the top of the page The home page gives an overview of the project and lists project news The About the Project section describes the HapMap project in more detail and provides pointers to background information about genetic association mapping the ethical issues raised by the project protocols used within the project and project administration The Data
21. mpact of the SNP on coding sequence splice sites and other features of nearby genes can be examined Showing 29 98 kbp from chr10 positions 127 086 514 to 127 116 489 a Instructions Search using a sequence name gene name locus or other landmark The wildcard character is allowed To center on a location click the ruler Use the Scroll Zoom buttons to change magnification and position Examples Chr20 Chr9 660 000 760 000 SNP rs6870660 NM_153254 BRCA2 5431 ENm010 Hide banner Bookmark this Link to Image High res Image Help 5 Search Help links Viewing LD data Landmark or Region Retrieving genotype data Retrieving frequency data Reports amp Analysis Recipe 2 Generate a text listing of genotypes using the genome browser After a researcher has browsed a region graphically and has centered his view on a candidate gene and the region surrounding it he may want to generate a space delimited text dump of the genotyping results across this region dump in the region This data can then be imported into an Excel spreadsheet or other data analysis tools 1 Starting at step 6 from recipe 1 navigate to the region of interest 2 Locate the Reports and Analysis menu above the Detail panel and select the menu item Dump SNP genotype data Next click the Configure button This will open a configuration page that allows you to select the desired HapMap population and whether to
22. ny other genomic features particularly those relating to evolutionary conservation Over a somewhat longer term we will provide tools that will allow researchers to upload genetic association data in a secure and anonymous manner and view association data on top of the LD map genes and other genomic features This feature will be integrated with databases provided information on biological pathways protein protein interactions and known disease genes allowing researchers to correlate their association data with what is known about the biological processes involving the genes in the region We will add to the tag SNP picker a suite of tools to help researchers create SNP sets tuned for genome wide association studies for association studies directed at a particular region or regions and for different types of study design We also hope to provide increasingly sophisticated visualization services that assist in interpreting the results of association studies and comparing the results of one association study to another Finally because the BioMart system allows queries to span multiple databases we will make it possible to perform simultaneous queries across HapMart and the EnsMart genome annotation database at Ensembl This will allow researchers to make queries that combine both Ensembl information e g find all genes that contain a zinc finger domain and a strong homologue in mouse with HapMap 10 Thorisson et al
23. o sending it to your browser and may reduce the time it takes to download the report 6 To retrieve the results select the Export button The reports generated by HapMart are in a tab delimited text format suitable for importation into Excel or for loading into a relational database The engine underlying HapMart is a generic data mining The HapMart report generator allows you to filter the HapMap data set by genomic region or framework named BioMart Gilbert various characteristics of the SNPs and derived genotypes After adjusting the filters you will be etal 2003 asked to select which fields to include in a tab delimited report Thorisson et al Recipe 11 Retrieve data via bulk download Finally users can obtain the entire unfiltered HapMap data set by batch download This recipe describes what downloads are available l To access bulk data browse to the download page http www hapmap org downloads Links and descriptions can be found for each category of available data 2 To download genotypes click the Genotypes link to go to the genotypes download directory The latest subdirectory always points to the current data freeze 3 The download repository can also be accessed via anonymous FTP at ftp www hapmap org The two main categories of data are on one hand the full whole chromosome dumps found in the full subdirectory and on the other hand specialized data dumps such as that fo
24. s that work well with a particular genotyping system for example those that have been included on a particular SNP chip and may be willing to accept different tradeoffs between the cost of genotyping a study population and the strength of the association they can detect For this reason the HapMap web site does not offer a static set of preselected tag SNPs but instead offers researchers a tool for interactively selecting tag SNPs based on user provided criteria There is no single set of tag SNPs that will satisfy the diverse requirements of every association study design Instead of offering a static set of tag SNPs the HapMap web site offers a tool for To find tag SNPs in a region first browse to the region see Recipe 1 l Starting at step 6 from recipe 1 navigate to the region of interest 2 Select the Annotate tag SNP Picker option under the Reports and Analysis menu 3 Press Configure to select the desired options for tag SNP selection see figure 5 Options include selecting a population and an algorithm uploading a list of SNP IDs to be included in the set of tag SNPs uploading a list of SNP IDs to be excluded from the set of tag SNPs uploading a list of design scores priorities for each SNP and selecting cutoffs for minimum acceptable LD value and allele frequency for SNPs to be included in the set 4 After setting the desired options click the Configure button to run the analysis and return
25. ser is that it displays simultaneous high and low power views of regions of LD and gives immediate feedback during scrolling and zooming operations Its current disadvantage is that it does not display gene structures or other genomic features although this feature is planned as a future enhancement loj xj Key 3 Download the Haploview program appropriate for your operating system For Windows computers download the windows installer file Double clicking the installer file will create a Haploview folder on the Start 1s10966239 157860471 Menu For MacOS X and Unix download the HaploView jar file 4 Download genotypes from a region of interest using recipe 82298619 jG 4 1 ss 82298621 1810966245 i 4 rs 751445 157869530 31412981 154007536 31819498 1510124183 1512342873 13944855 15944854 157850234 taza errr ee 2 EG Rs 5 To start Haploview open the z Haploview jar file On Windows computers open Figure 7 Haploview LD triangle plot Haploview jar Paar ihe This image shows a high resolution LD triangle plot of two regions with high levels of linkage Haploview folder on the Start see Figures 3 and 4 disequilibrium The color scheme is similar to that used in the LD viewer in the genome browser Thorisson et al Recipe 10 Retrieve HapMap data using HapMart Because of performance considerations interactive access to HapMap dat
26. the next button to go to the output Grew ENE Cie biosssmart selection page This page allows you to select the fields you wish to be dback next gt F count DATASET 1 7 output in the report There are Summary P FILTERS eq many output options organized as in gt si a series of tabs along the top of the M POPULATION BASED FILTERS EE EEr PIE B e Dataset All 5443600 Entries Total gt filter Not yet initialised ALLELE FREQUENCY FILTER gt Coo E O SNP FILTERS Monomorphic SNPs Ony le CoE Monomorphic SNPS E gt Excluded Not yet initialised SNPs found in Only 3 utr Regions B O Excluded Limit SNPs with these IDs H Choose File no file selected O REGION Chromosome Chri By Position From f To J GENE FILTERS Gene IDs known gene i List of Genes J ENCODE REGION ENm010 7 26699793 27199792 dback next gt Figure 8 Filter selection page for the HapMart report generator population defaultSchema_HapMap screen To retrieve genotypes for example select the Genotypes tab at the top of the page Then select the genotypes checkbox Other output options include SNP chromosome position alleles genotype frequencies and allele frequencies 5 optional If the number of SNPs to be retrieved is large you may wish to select gzip file compression This will compress the report prior t
27. the extent of linkage disequilibrium in a region using the genome browser When a researcher designs a study to detect the association between a common allelic variation of a gene and a disease of interest knowledge of the extent of linkage disequilibrium LD in the region is essential for reducing the number of SNPs that need to be genotyped across the region If there is high linkage disequilibrium in the region then only a few SNPs need to be genotyped because their linkage to other SNPs in the region will serve as proxies for the genotypes of non characterized SNPs In contrast a region of low linkage disequilibrium will need to be sampled more Configure LD Plot Segment Size so 7 Genotype SNPs Box Size 200 Proportionate LD Properties Color Pairwise ee Color data not a plot oe available EAT Populations CEU coff on JPT Soff oon YRI off oon normal Invert CHB off on normal invert Orientation Cancel Configure Home About the Project Data Publications Conference Please send questions and comments on website to help hapmap org Note This page uses cookies to save and restore preference information No information is shared Generic genome browser version 1 63 Figure 3 The configuration screen for the LD Plot viewer Use the LD Plot viewer configuration screen to select the size of the region to display LD values over how many genotyped SNPs to display what measure of
28. ting upward or downward color scheme and whether the box size in the plot should be proportional to genomic distance between markers or of uniform size see Figure 3 Thorisson et al 3 After configuring the parameters as desired click on the Configure button to return to the main display The display will now show one triangle plot for each population selected see Figure 4 The triangle plot is constructed by connecting every pair of SNPs along lines at 45 degrees to the horizontal track line The color of the diamond at the position that two SNPs intersect indicates the amount of LD more intense colors indicate higher LD A grey diamond indicates that data is missing Figure 4 shows a typical region of LD which demonstrates patches of high LD separated by relatively well defined boundaries of low LD 4 In regions with many genotyped SNPs the LD plugin adds significantly to the time it takes for the web page to load You may turn off the LD display at any time to deselecting the appropriate checkbox in the Tracks section of the browser The LD plugin settings are stored in a browser cookie so there is no need to visit the configuration page each time the plugin is turned on The traditional D and r metrics reflect the degree of pairwise LD between two SNPs but differ in their sensitivity Showing 200 kbp from chr5 positions 88 070 197 to 88 270 196 E Instructions magnification and position
29. to the main display Results are shown on a new feature track see Figure 6 under the track labeled tSNPs_Tagger_CEU As with the LD display above settings are stored in a browser ceu 3 Population Pairwise Methods Tagger Pairwise RSquare cut off 0 8 MAF cut off 0 2 F Include SNPs Exclude SNPs Design scores Output format Choose File no file selected Choose File no file selected Choose File no file selected text Save to Disk Cancel Configure Go Figure 5 Options screen for the tag SNP Picker The tag SNP Picker configuration page allows you to select which population to pick SNPs on what algorithm to use for the selection and which SNPs to include or exclude from the resulting tag SNP set Additional options allow you to fine tune the tag selection algorithms The fine tuning options that are displayed change according to the algorithm selected cookie and the plugin track can be turned off when it is not needed The tag SNP lists are generated from algorithms in the Tagger program de Bakker 2005 In the near future we will enhance the tag picking service in the future by adding additional tag SNP selection algorithms and we welcome inquiries from the authors of such algorithm Recipe 7 Generate a text listing of tag SNPs using the genome browser Using the interactive tag SNP selection track described in the previous recipe the researcher can adjust selection criterion until
30. tt et al 2005 This program works well in combination with the HapMap genome browser To install Haploview go to http www broad mit edu mpg haploview and follow the download link 2 Haploview requires that the Java Runtime Environment JRE is installed on the local computer If the JRE is not installed the newest version can be found at http www java com amp Haploview 3 2 dumped_region txt e Depay Analysts Help LD Piot Haplotypes Check Markers Tagger Menu On other operating systems double click on the Haploview jar file 6 To load genotypes click on the Load HapMap Data button which appears in the Haploview welcome window Browse to the downloaded file containing genotypes and open the file 7 Once the data is loaded Haploview provides you with options to view a high resolution triangle plot of LD across the region view shared haplotypes and their recombination frequencies and select tag SNP sets by a number of methods You may select among these analyses and visualizations by choosing the appropriately labeled tab along the top of the Haploview window see Figure 7 8 The Display and Analysis menus allows you to change the size and coloring scheme of the LD triangle plot as well as to select among a variety of algorithms for defining haplotype blocks regions of SNPs that are in high mutual LD A big advantage of Haploview over the HapMap web site genome brow
31. und in ENCODE data from the 10 ENCODE regions in which all available SNPs are genotyped Datafiles in both categories are split by chromosome region and population and come in three varieties each within its own subdirectory a non redundant Cleaned These datasets contain only one set of genotypes per SNP population All genotype sets have passed quality control checks and multiple submissions of the same SNP which occur because of QA exercises corrected submissions and planned redundancy in the project have been removed This is the dataset most users will want b redundant filtered All These datasets have passed quality control checks but redundant data has not been removed c redundant unfiltered All This dataset contains all SNPs genotyped by the project irrespective of quality control checks This constutes the raw data for users who want to look at potentially biologically interesting data that are normally filtered out by project quality control checks 3 To download LD values click the LD Data link to go to the LD data download directory The latest directory again points to the most recent datafreeze available LD values are represented as D LOD and r values 4 To download phased genotypes click the Phased Data link This will take you to a directory containing data files representing the output of the PHASE program Discussion A number of public online resources have be
32. ype Display Press Configure to set options for Haplotype display The options give you the ability to select the population for which to display haplotype information After selecting the desired population s click the Configure button to return to the main display A new feature track will appear for each population selected Each track shows the haplotypes for that population using the two color scheme described earlier Figure 6 track haplo_CEU The order of chromosomes is determined by a fast hierarchical clustering methodology which places chromosomes that share similar haplotypes together To retrieve the detailed phased genotypes click on the track of the desired population This will take you to a page that provides the haplotype information in tabular Reports amp Analysis Annotate tag SNP Picker Fs Configure Go Scroll Zoom KZ Show 100 kbp 2 BD OF lip Population descriptors YRI Yoruba in Ibadan Nigeria JPT Japanese in Tokyo Japan CHB Han Chinese in Beijing China CEU CEPH Utah residents with ancestry from northern and western Europe a Overview Overview of chri M 10M 20M 30M dom SOM 60M 70M 80M 90M 100M 110M 120M 130M 140M 150M 160M 170l 180M 190M 200M 210M 220M 230M 240M CE 1E E E a Details 172170k 172180k 172190k 172200k 172210k RefSeq mRNAs NM_O14557 NN_o144 Tir tSNPs_PairviseTagger_CEU g2is7541 cpu Phased Haplot
33. ypes 12 172220k 172 30k 172240k 172260k NM 022190 er rs11590474 rs1034462 g210798330 gotses418 gsi0s12067 rs1048932 N Figure 6 Graphical display of tag SNPs and phased haplotypes The phased haplotype track represents each phased chromosome in the selected population as a one pixel high horizontal line The alleles are represented using a simple two color scheme and the chromosomes are sorted in order to maximize the lengths of shared alleles Thorisson et al form Each row of the table is an individual chromosome and each column is an individual SNP The background of each table entry is set to a color corresponding to what is seen in the graphical track The advantage of this display over the pairwise LD triangle display described earlier is that it is more compact and therefore better suited for the display of large regions This makes it easy to correlate the position of long common haplotypes with SNPs chosen by the tag SNP picker The disadvantage of this display is that it conceals much of the fine structure of LD in the region in particular strong linkage among SNPs that are not adjacent to one another Recipe 9 Manipulate HapMap data using Haploview Advanced users who wish to exercise finer control over the display of regions of high LD or who wish to experiment with new algorithms for tag SNP picking may wish to analyze HapMap data using the Haploview program Barre
Download Pdf Manuals
Related Search