Methods for obtaining and using haplotype data

• US 7,058,517 B1
• Filed: 06/26/2000
• Issued: 06/06/2006
• Est. Priority Date: 06/25/1999
• Status: Expired due to Fees

• Current Assignee: Genaissance Pharmaceuticals Incorporated (Abbvie Incorporated)
• Original Assignee: Genaissance Pharmaceuticals Incorporated (Abbvie Incorporated)
• Inventors: Ruaño, Gualberto, Denton, R. Rex, Judson, Richard S., Stephens, J. Claiborne, Windemuth, Andreas K., Xu, Chuanbo
• Primary Examiner(s): Allen, Marianne P.
• Application Number:
  US10/019,415
• Time in Patent Office: 2,171 Days
• Field of Search: 702/19, 702/20, 435/6, 703/2
• US Class Current: 702/20
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 20/40 Population genetics; Linkage disequilibrium
• CPC Class Codes: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/30 Data warehousing; Computing architectures
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods, computer program(s) and database(s) to analyze and make use of gene haplotype information. These include methods, program, and database to find and measure the frequency of haplotypes in the general population; methods, program, and database to find correlation'"'"'s between an individual'"'"'s haplotypes or genotypes and a clinical outcome; methods, program, and database to predict an individual'"'"'s haplotypes from the individual'"'"'s genotype for a gene; and methods, program, and database to predict an individual'"'"'s clinical response to a treatment based on the individual'"'"'s genotype or haplotype.

Claims

1. A method of inferring a pair of haplotypes present in an individual for a locus having at least m polymorphic sites, comprising

(a) providing a database comprising (i) haplotypes of the locus for a set of m polymorphic sites present in a reference population and (ii) a frequency of occurrence in the reference population of each haplotype;

(b) constructing a list of all genotypes that could result from all possible pairs of the haplotypes in the database for the reference population;

(c) calculating a frequency for each genotype on the list, wherein the frequency of a given genotype is a function of a frequency for a pair of haplotypes from which the given genotype results, calculated assuming Hardy-Weinberg equilibrium;

(d) generating a set of all possible masks for the m polymorphic sites, wherein each mask blocks the identity of the nucleotides present at m-n of the polymorphic sites and admits the identity of nucleotides present at the other n polymorphic sites;

(e) for each mask, calculating the ambiguity resulting from genotyping only the n polymorphic sites at which nucleotide identity is admitted by the mask;

(f) from among those masks having zero ambiguity, selecting a mask which has the lowest value of n;

(g) determining the genotype of the individual at the n polymorphic sites at which nucleotide identity is admitted by the selected mask; and

(h) assigning to the individual a pair of m polymorphic site haplotypes in the database for the reference population by matching the individual'"'"'s determined genotype to a genotype on the list of genotypes, at the n polymorphic sites at which nucleotide identity is admitted by the selected mask.

2. A computer-usable medium having computer-readable program code stored thereon, for causing a computer to infer a pair of haplotypes present in an individual for a locus having at least m polymorphic sites, the computer-readable program code comprising:

(a) computer-readable program code for causing a computer to access a database comprising (i) haplotypes of the locus for a set of m polymorphic sites present in a reference population and (ii) a frequency of occurrence in the reference population of each haplotype;

(b) computer-readable program code for causing a computer to construct a list of all genotypes that could result from all possible pairs of the haplotypes in the database for the reference population;

(c) computer-readable program code for causing a computer to calculate a frequency for each genotype on the list, wherein the frequency of a given genotype is a function of a frequency for a pair of haplotypes from which the given genotype results, calculated assuming Hardy-Weinberg equilibrium;

(d) computer-readable program code for causing a computer to generate a set of all possible masks for the m polymorphic sites, wherein each mask blocks the identity of the nucleotides present at m-n of the polymorphic sites and admits the identity of nucleotides present at the other n polymorphic sites;

(e) computer-readable program code for causing a computer to calculate, for each mask, the ambiguity resulting from genotyping with only the n polymorphic sites at which nucleotide identity is admitted by the mask;

(f) computer-readable program code for causing a computer to output or display on a display device the calculated ambiguity for one or more masks and permitting the operator to select a mask;

(g) computer-readable program code for causing a computer to accept as input an individual'"'"'s genotype data at the n polymorphic sites of the selected mask; and

(h) computer-readable program code for causing a computer to assign to the individual a pair of m polymorphic site haplotypes in the database for the reference population by matching the individual'"'"'s determined genotype to a genotype on the list of genotypes at the n polymorphic sites at which nucleotide identity is admitted by the selected mask.

3. The computer-usable medium of claim 2, wherein the computer-readable program code of part (e) comprises:

(a) computer-readable program code for causing a computer to identify all pairs of genotypes on the list that are rendered identical by application of the mask;

(b) computer-readable program code for causing a computer to calculate the geometric mean of the calculated frequencies of each pair of genotypes rendered identical by application of the mask; and

(c) computer-readable program code for causing a computer to sum the geometric mean of all pairs of genotypes rendered identical by application of the mask to obtain an ambiguity score for the mask.

4. The computer-usable medium of claim 2, wherein the computer-readable program code of part (h) comprises additional computer-readable code for causing a computer to assign the individual two haplotype pairs, A and B, that could explain the individual'"'"'s determined genotype at the n polymorphic sites of the selected mask, where p_A is the calculated frequency of haplotype pair A and p_B is the calculated frequency of haplotype pair B and p_A+p_B=1, wherein the additional computer-readable program code comprises:

(a) computer-readable program code for causing a computer to select a random number between 0 and 1;

(b) computer-readable program code for causing a computer to assign the individual haplotype pair A if the random number is less than or equal to p_A; and

(c) computer-readable program code for causing a computer to assign the individual haplotype pair B if the number is greater than p_A.