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European Patent Office Principal Directorate Tools/Documentation Trilateral Technical conference Washington May 17-20, 2004 Subject: Study on Single Nucleotide Polymorphism (SNP) / Haplotype Databases and Search Tools for Examiners (Status Report) Project: DR2 Author: EPO EPO Responsible: Gérard Giroud Prepared by: Ana Richart de la Torre & Stéphane Nauche 1 1. Introduction 2. Patent applications disclosing SNPs/ Haplotypes 2.1 Filing figures 2.2 Concealed workload 2.3 Origin of Patent applications 2.4 Source of claimed SNPs 3. Provision of SNP information in Patent Applications: Representation of SNPs in Sequence Listings 4. Representation of SNPs and Haplotypes in General Sequence Databases 4.1 Example of variation release 4.2 Example of haplotype release 5. Specific Databases Conclusion 2 1. Introduction During the last few years the development of pharmacogenetics, based on how variation in human genes leads to variation in our response to drugs, has gained a great importance. This, together with the development of the "Human genome project", focused on determining the sequences of the chemical base pairs that make up human DNA, has lead to the discovery of multiple variations of genomic DNA, such as single nucleotide polymorphisms (SNPs) (1) and haplotypes (2), a combination of those. Therefore it has sparked a great interest in patent protection resulting in an increase in the number of patent applications claiming SNPs and haplotypes as disease markers, as well as corresponding methods of use (figure 1). Furthermore, patent applications disclosing SNPs and haplotypes claim hundreds or thousands of related nucleic acid molecules. Claims to SNPs and haplotypes do present special search and examination challenges. Currently examiners, do not have optimized tools to perform exhaustive searches, therefore the analysis of claimed SNPs or haplotypes comprises multiple searches where a plurality of sequences and keywords needs to be entered for a search to be complete. The search for prior art relating to the specific use of SNPs or haplotypes should be done using automated tools, whereby a limited number of sequences and keywords suffice for the whole search (Trilateral Project DR2). The EPO presented a report on SNPs/Haplotypes databases during the last trilateral working group. The Trilateral Offices agreed to further study Single Nucleotide Polymorphism (SNP)/Haplotype Databases and Search Tools for Examiners. The EPO provided a questionnaire to its partners to identify most relevant SNP/Haplotype Databases. This document provides a further status report (1) SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist in normal individuals in some population(s), wherein the least frequent allele has an abundance of 1% or greater. "SNPs what they are & what might they tell us", Anthony Brookes Research Group, available at http://www.cgr.ki.se/cgb/groups/brookes/snps.htm. (2) The term 'haplotype' refers to a combination of SNPs on a chromosome, usually within the context of a particular gene. "Haplotype identification" at http://www.variagenics.com/articles/haplotypeid.html. 3 2. Patent applications disclosing SNPs/Haplotypes 2.1 Filing figures As a consequence of the great development of research in this field, an increase in the number of patent applications has also taken place during the last few years. It is reflected by the analysis of published and incoming applications disclosing SNPs and haplotypes, recorded at WPI, EPODOC, and DOSYS databases, as shown in figure 1. Filing SNPs at trilateral Offices 1400 Relative growth 1200 1000 800 600 400 200 0 250 journals. Contains also links to unpublished mutation data available in online public locus-specific mutation databases. LINKS (Xref) The records are cross-referenced to different LSDBs. Other useful links to core databases home pages are provided. SRS-EMBL (Availability) NO QUERY SEQUENCES NO SNPdb CONTENTS NCBI's SNPs database, reporting data from several species. . URL http://www.ncbi.nih.gov/SNP/ SPECIES COVERAGE It covers amongst many other species, human, rodents, pig, cattle sps, and plant species. ENTRIES 11,805,698 RefSNPs REDUNDANCY no answer UPDATES every 4-8 weeks SOURCES SNPs derived from ~300 sources. The major contributors to the database are laboratories associated with the National Human Genome Research Institute (NHGRI) grants program. LINKS (Xref) GenBank eventually SRS-EMBL (Availability) NO QUERY SEQUENCES NO 11 Human Genome Variation Database (HGVbase) CONTENTS Summarizes all known variations in the human genome, facilitating genotype-phenotype association analyses that explore how SNPs and other sequence variations may influence phenotypes. . URL http://hgvbase.cgb.ki.se/ SPECIES COVERAGE Human ENTRIES 2,859,130 records (99% reporting SNPs) REDUNDANCY non redundant UPDATES Last update on 23-July-2003. This activity has ceased for the moment due to limitations of funding. HGVbase is presently more focused into a phenotype-genotype project. SOURCES SNPs derived from nearly 800 sources. HGVbase data is harvested (with permission) or submitted from all major public genome databases and extracted from published literature. Individual or bulk submissions from research groups are also received. LINKS (Xref) EMBL, Ensembl, GenBank, dbSNP, OMIM, PubMed, PolyPhen. YES SRS-EMBL (Availability) QUERY SEQUENCES Direct DNA sequence searches use the BLAST program. It is possible to enter a query sequence up to 25,000 bases in raw format as well as DNA sequences of the allelic variations plus their flanking domains. ALFRED CONTENTS Focused on allele frequencies, comprising DNA polymorphisms and other sequence variations, sufficiently defined and studied in at least 6 human populations. . URL http://alfred.med.yale.edu/alfred/index.asp SPECIES COVERAGE Human ENTRIES 932 polymorphisms, including SNPs, STRPs, VNTRs, INDELs, and Haplotypes. It's estimated that at least half of them are SNPs. REDUNDANCY Some redundancy UPDATES Daily SOURCES Data from the published literature, and directly submitted from researchers. LINKS (Xref) PubMed, Gene Bank, dbSNP, OMIM, GDB, CHLC, CEPH, and LSDBs. SRS-EMBL (Availability) NO QUERY SEQUENCES NO 12 The SNP Consortium ltd CONTENTS Database reporting more than 1,8 million of single nucleotide polymorphisms. URL http://snp.cshl.org/ SPECIES COVERAGE Human ENTRIES ~1.8 million SNPs. REDUNDANCY no answer UPDATES Last update on October 24 , 2002: final ~400,000 previously unreleased TSC SNPs made available via website. These SNPs have also been submitted to dbSNP. SOURCES TSC allele frequency/genotype project member laboratories (Celera, Motorola, Sanger, WICGR) LINKS (Xref) no answer th SRS-EMBL (Availability) NO QUERY SEQUENCES NO JSNP database CONTENTS A database of common gene variations in the Japanese population. URL http://snp.ims.u-tokyo.ac.jp/ SPECIES COVERAGE Human ENTRIES 195,059 SNPs; 84,566 SNPs with allele frequency REDUNDANCY non- redundant UPDATES bimonthly SOURCES NCBI, Laboratory for Genotyping, the SNP Research Center, the Institute of Physical and Chemical Research (RIKEN), JBIC, dbSNP, UniSTS, UniGene, Model mRNA, RefSeq. LINKS (Xref) Search through HOWDY (human organized whole genome database) linked to GenBank, OMIM, dbSNP, GDB. Search by Blast SNP, linked to dbSNP, GenBank, and HGVbase. NO SRS-EMBL (Availability) QUERY SEQUENCES YES, they use BLAT (BLAST-Like Alignment Tool) search against NCBI build 34 of the human genome. 13 TM HAP database CONTENTS Database reporting both SNPs and gene-based haplotypes, discovered in pharmaceutically relevant genes. Includes information for ~9,000 genes reporting frequency values in each population group. It's a subscription-based database. URL http://www.dna.com/products_services/hapdatabase.html SPECIES COVERAGE Human ENTRIES Aprox. 180,000 unique SNPs. Aprox. 180,000 unique haplotypes. REDUNDANCY non-redundant UPDATES It varies depending on internal research programs necessities. SOURCES Data generated by re-sequencing of 93 individuals from various ethnic backgrounds. (Geinanssance Pharmaceuticals research groups) Data from the two major public databases: dbSNP and HGVbase. LINKS (Xref) Public databases for comparison purposes. NO SRS-EMBL (Availability) QUERY SEQUENCES Could be possible, they use BLAST algorithm. OMIM CONTENTS OMIM, Online Mendelian Inheritance in Man. This database is a catalog of human genes and genetic disorders The database contains textual information and references. It also contains links to MEDLINE an other databases. URL http://www3.ncbi.nlm.nih.gov/omim/ SPECIES COVERAGE Human ENTRIES 15 325 REDUNDANCY No UPDATES once per month SOURCES NCBI LINKS (Xref) LSDBs, MEDLINE, Entrez, related resources at NCBI. SRS-EMBL (Availability) Yes QUERY SEQUENCES NO 14 Celera Human SNP reference database CONTENTS It reports mapped genetic variations to help further the understanding of genetic basis of disease. Thus, the polymorphisms present at Celera database are correlated with genes, gene structure, conserved and regulatory regions, protein changes and disease. It's a subscription-based database. URL http://www.celeradiscoverysystem.com/index.cfm SPECIES COVERAGE Human ENTRIES 3.5 million mapped genetic variations REDUNDANCY non-redundant UPDATES 4 times a year. SOURCES Celera discovery system, OMIM, TSC, dbSNP, HGVbase, HGMDB LINKS (Xref) OMIM, TSC, dbSNP, HGVbase, HGMDB NO SRS-EMBL (Availability) QUERY SEQUENCES YES, NCBI BLAST version 2,2,5, Celera Mouse SNP reference database CONTENTS It reports over 3 million non-redundantly mapped variations distributed throughout the mouse genome. These variations are correlated with gene structure and protein changes to aid in the identification or validation of potential disease genes. It's a subscription-based database. URL http://www.celeradiscoverysystem.com/index.cfm SPECIES COVERAGE Mouse strains (129x1/SvJ, DAB/2J, A/J, C57BL/6J, 129s1/SvlmJ). Human-mouse synthetic gene regions? ENTRIES Over 3,1 million mouse SNPs REDUNDANCY non-redundant UPDATES every 4 months, corrections in annotations, but new SNPs are registered every 1-2 years SOURCES Celera discovery system for the following four strains of mouse: 129s1/svimj, 129x1/svj, a/j and dba/2j. C57bl/6j data, imported from the publicly available sequence. LINKS (Xref) They do not cross-reference to other sources. NO SRS-EMBL (Availability) QUERY SEQUENCES It's possible to BLAST a query sequence and retrieve the corresponding SNP IDs. 15 Integrated Information Databases TM HOWDY DATABASE GeneCards URL http://bioinfo.weizmann.ac.il/cards/ CONTENTS GeneCards is a database of human genes, their products and their involvement in diseases. HOWDY is a database system to retrieve human genome information of most of the important public data sources in the world. SPECIES COVERAGE Human Human SOURCES (SNPs information) SNPdb SNPdb, JSNP LINKS (SNPs repositories) SNPdb SNPdb, JSNP http://gdb.jst.go.jp/HOWDY/ TM Minor SNP repositories DATABASE URL CONTENTS COVERAGE GenesSNP http://www.genome.utah.edu/genesn ps/ Integrates gene, sequence and polymorphism data into individually annotated gene models. The human genes included are related to DNA repair and cell cycle pathways; these genes are though to play a role in susceptibility to environmental exposure. Human Leelab SNP database http://www.bioinformatics.ucla.edu/s np/ Leelab has developed some programs such as, PHRAP, BRO and POA, to identify in coding regions (cSNPs) from publicly available expressed sequence tag (EST) databases. All data has been deposited in dbSNP. human EST data rSNP guide http://util.bionet.nsc.ru/databases/rsn p.html SNPs in regulatory gene regions onto their interaction with nuclear proteins. Human topoSNP http://gila.bioengr.uic.edu/snp/toposn p/ Visualization of non-synonymous SNPs. Online resource for analyzing nsSNPs that can be mapped onto known 3D structures of proteins. Human 16