Methods for genomic analysis

Abstract

The present invention relates to methods for identifying variations that occur in the human genome and relating these variations to the genetic basis of disease and drug response. In particular, the present invention relates to identifying individual SNPs, determining SNP haplotype blocks and patterns, and, further, using the SNP haplotype blocks and patterns to dissect the genetic bases of disease and drug response. The methods of the present invention are useful in whole genome analysis.

1 . A method for identifying pharmacogenomic-related genetic loci, comprising: 
 a) determining SNP haplotype patterns comprising a set of SNP alleles from a plurality of individuals in a first population, wherein said individuals in said first population react in a particular manner to administration of a substance;    b) determining SNP haplotype patterns comprising a set of SNP alleles from a plurality of individuals in a second population, wherein said individuals in said second population do not react in said particular manner to administration of said substance; and    c) comparing frequencies of said SNP haplotype patterns from said individuals in said first population with frequencies from said SNP haplotype patterns of said individuals in said second population, wherein genomic locations of SNP haplotype patterns that exhibit a difference in said frequencies are pharmacogenomic-related genetic loci.    
     
     
         2 . The method of  claim 1 , wherein said identifying is performed without a priori knowledge of a sequence or location of said pharmacogenomic-related genetic loci.  
     
     
         3 . The method of  claim 1 , wherein said SNP haplotype patterns are determined in at least 10 individuals in at least one of said first population or said second population.  
     
     
         4 . The method of  claim 1 , wherein said SNP haplotype patterns recited in steps a) and b) are determined using informative SNPs.  
     
     
         5 . The method of  claim 1 , wherein in step a) and step b) said determining of SNP haplotype patterns is performed using pooled genomic DNA samples from individuals of said first population and said second population, respectively.  
     
     
         6 . The method of  claim 1 , further comprising using said pharmacogenomic-related genetic loci as diagnostic markers for a given condition or phenotypic trait.  
     
     
         7 . The method of  claim 6 , wherein said diagnostic markers are included in a kit for diagnosis of a disease, disease susceptibility, or treatment response.  
     
     
         8 . The method of  claim 7 , wherein said kit further comprises means for detecting a presence or absence of said pharmacogenomic-related genetic loci in a sample of genomic DNA from a patient.  
     
     
         9 . The method of  claim 1  further comprising building a baseline of SNP haplotype patterns, wherein said building a baseline of SNP haplotype patterns comprises: 
 identifying genetic variations in a plurality of individuals;    identifying at least some of said genetic variations in individuals that occur with at least some other of said genetic variations;    grouping said some of said variations in individuals that occur with said some other of said genetic variations into SNP haplotype blocks;    identifying SNP haplotype patterns in said SNP haplotype blocks; and    adding said SNP haplotype patterns in said SNP haplotype blocks to said baseline of SNP haplotype patterns, thereby building said baseline of SNP haplotype patterns, wherein said baseline of SNP haplotype patterns comprises said SNP haplotype patterns from said individuals in said second population, and wherein said baseline of SNP haplotype patterns further comprises said SNP haplotype patterns from said individuals in said first population.    
     
     
         10 . The method of  claim 1  further comprising building a baseline of SNP haplotype patterns, wherein said building a baseline of SNP haplotype patterns comprises: 
 determining a sequence of an organism;    scanning additional individuals of said organism for variants from said sequence;    identifying some of said variants that occur with others of said variants in a first SNP haplotype block;    identifying some of said variants that occur with others of said variants in a second SNP haplotype block;    identifying SNP haplotype patterns in said first SNP haplotype block and said second SNP haplotype block; and    adding said SNP haplotype patterns in said first SNP haplotype block and said second SNP haplotype block to said baseline of SNP haplotype patterns, thereby building said baseline of SNP haplotype patterns, wherein said baseline of SNP haplotype patterns comprises said SNP haplotype patterns from said individuals in said second population, and wherein said baseline of SNP haplotype patterns further comprises said SNP haplotype patterns from said individuals in said first population.    
     
     
         11 . A method for identifying pharmacogenomic-related loci without a priori knowledge of a sequence or location of said pharmacogenomic-related loci, comprising: 
 identifying genetic variations in a plurality of individuals;    identifying at least some of said genetic variations that occur with at least some others of said genetic variations;    genotyping a subset of said at least some of said genetic variations that occur with at least some others of said genetic variations in both a case population and a control population to generate a data set of genotypes, wherein said case population consists of individuals who exhibit a particular response to a treatment and said control population consists of individuals who do not exhibit said particular response;    based on said data set of genotypes, computing a genotype frequency in said case population and a genotype frequency in said control population for each of said subset; and    identifying as pharmacogenomic-related loci a set of genetic variants for which said genotype frequency in said case population is different than said genotype frequency in said control population.    
     
     
         12 . The method of  claim 11 , wherein said genetic variants are SNPs.  
     
     
         13 . The method of  claim 11 , wherein one or more of said pharmacogenomic related loci occur within one or more coding regions of a genome.  
     
     
         14 . The method of  claim 11 , wherein one or more of said pharmacogenomic related loci occur within one or more noncoding regions of a genome.  
     
     
         15 . The method of  claim 11 , wherein said individuals are mammals.  
     
     
         16 . The method of  claim 11 , wherein said genotyping is performed using probes bound to a solid surface.  
     
     
         17 . The method of  claim 11 , further comprising using said pharmacogenomic-related loci for a purpose selected from the group consisting of: 
 testing of a candidate agent;    stratification of a population for clinical studies;    development of a gene therapy; and    use as a drug discovery target.    
     
     
         18 . A method for identifying pharmacogenomic-related loci without a priori knowledge of a sequence or location of said pharmacogenomic-related loci, comprising: 
 determining a sequence of an organism;    scanning additional individuals of said organism for genetic variants from said sequence;    identifying a first subset of said genetic variants that occur with others of said genetic variants in a first group;    identifying a second subset of said genetic variants that occur with others of said genetic variants in a second group; and    using some, but not all, of said genetic variants in said first and second groups in an association study to identify which of said genetic variants is correlated with a phenotypic state, wherein said phenotypic state is a response to a pharmaceutical treatment, and further wherein genetic variants that are correlated with said phenotypic state are pharmacogenomic-related loci.    
     
     
         19 . The method of  claim 18 , wherein said genetic variants are SNPs.  
     
     
         20 . The method of  claim 18 , wherein one or more of said pharmacogenomic related loci occur within one or more coding regions of a genome.  
     
     
         21 . The method of  claim 18 , wherein one or more of said pharmacogenomic related loci occur within one or more noncoding regions of a genome.  
     
     
         22 . The method of  claim 18 , wherein said sequence of an organism comprises at least 10,000 bases of genomic DNA of said organism.  
     
     
         23 . The method of  claim 18 , wherein said organism is a mammal.  
     
     
         24 . The method of  claim 18 , further comprising using said pharmacogenomic-related loci for a purpose selected from the group consisting of: 
 testing of a candidate agent;    stratification of a population for clinical studies;    development of a gene therapy; and    use as a drug discovery target.    
     
     
         25 . A method for determining pharmacogenomic-related genetic loci without a priori knowledge of a sequence or location of said pharmacogenomic-related genetic loci, comprising: 
 a) determining control genotypes, wherein said control genotypes are genotypes from at least 16 individuals in a control population for a set of genomic loci;    b) determining case genotypes, wherein said case genotypes are genotypes from individuals that react in an altered manner to administration of a substance for said set of genomic loci; and    c) comparing frequencies of said control genotypes with frequencies of said case genotypes, wherein members of said set of genomic loci that exhibit differences in said frequencies indicate locations of pharmacogenomic-related genetic loci.    
     
     
         24 . The method of  claim 25 , further comprising using said pharmacogenomic-related genetic loci for a purpose selected from the group consisting of: 
 testing of a candidate agent;    stratification of a population for clinical studies;    development of a gene therapy; and    use as a drug discovery target.