ALLELIC DETERMINATION

• US 20100256917A1
• Filed: 06/13/2008
• Published: 10/07/2010
• Est. Priority Date: 06/15/2007
• Status: Abandoned Application

• Current Assignee: Gilean Mcvean, Peter James Donnelly, Stephen James Leslie
• Original Assignee: Gilean Mcvean, Peter James Donnelly, Stephen James Leslie
• Inventors: Leslie, Stephen James, Donnelly, Peter James, McVean, Gilean
• Application Number:
  US12/664,276
• Publication Number:
  US 20100256917A1
• Time in Patent Office: Days
• US Class Current: 702/19
• 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 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/30 Unsupervised data analysis
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16B 5/20 Probabilistic models
• CPC Class Codes: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/10 Ontologies; Annotations

Abstract

A method of determining an allelic type of a specific individual, comprising: accessing a database of genetic information on a plurality of individuals, the genetic information comprising: the allelic type of each individual; and the type of each of a plurality of genetic markers for each individual; categorizing the data in the database into a plurality of groups of individuals, such that all individuals having the same allelic type are in the same group, and each group represents a different allelic type; inputting data comprising the type of each of a plurality of genetic markers of the specific individual having an unknown allelic type; specifying a set of genetic markers for which type information is known both for the individuals in the database and for the specific individual; applying a population genetic model to calculate the likelihood of sampling, from some or all of the groups in turn, the input type data of the specified set of genetic markers for the specific individual; and determining the allelic type of the specific individual based on the calculated likelihoods.

Claims

1. A method of determining an allelic type of a specific individual, comprising:

accessing a database of genetic information on a plurality of individuals, the genetic information comprising;

the allelic type of each individual; and

the type of each of a plurality of genetic markers for each individual;

categorizing the data in the database into a plurality of groups of individuals, such that all individuals having the same allelic type are in the same group, and each group represents a different allelic type;

inputting data comprising the type of each of a plurality of genetic markers of the specific individual having an unknown allelic type;

specifying a set of genetic markers for which type information is known both for the individuals in the database and for the specific individual;

applying a population genetic model to calculate the likelihood of sampling, from some or all of the groups in turn, the input type data of the specified set of genetic markers for the specific individual; and

determining the allelic type of the specific individual based on the calculated likelihoods.

2. A method according to claim 1, comprising using the likelihood to calculate the probability that the specific individual has each of the different allelic types.

3. A method according to claim 2, comprising incorporating prior knowledge of the probability in the calculation of the probability that the specific individual has each of the different allelic types.

4. A method according to claim 2, comprising determining that the allelic type of the specific individual is the same as the allelic type of the individuals in the group for which the calculated probability of sampling the input type data is highest.

5. A method according to claim 4, wherein the allelic type is only determined if said probability exceeds a predetermined threshold.

6. A method according to claim 1, wherein the population genetic model includes at least one of the following parameters:

recombination rate, mutation rate, gene conversion, admixture, migration, selection and marker positions.

11. A method of determining an allelic type of a specific individual according to claim 1, further comprising determining the type of each of the genetic markers of the specified set of genetic markers of a DNA sample of the specific individual as the data for inputting in the inputting step.

12. A method according to claim 1, wherein the step of specifying a set of genetic markers comprises

accessing a database of genetic information on a plurality of individuals, the genetic information comprising:

the allelic type of each individual; and

the type of each of a plurality of genetic markers for each individual;

initialising to define a current set of genetic markers;

determining the allelic type of each individual in the database using the current set of genetic markers;

measuring the performance of the current set of markers by calculating a predetermined performance measure on the basis of the allelic types found in the determining step and the actual allelic types known from the database;

keeping as the current set of markers the set that gives the best measured performance seen so far for a set of a given size;

modifying the current set of markers;

repeating the determining, measuring, keeping and modifying steps;

terminating when a predetermined condition is met; and

outputting the set of markers that gives the best measured performance seen as the selected set of genetic markers for use in determining an allelic type of an individual.

14. A method according to claim 1, wherein said genetic markers comprise one or more of:

SNPs, insertions, deletions, deletion-insertion polymorphisms (DIPs), microsatellites, and short tandem repeats.

15. A method according claim 14, wherein the markers are known at the resolution of genotype or haplotype.

16. A method according to claim 1, wherein said genetic markers comprise haplotype information, where the haplotype phase is determined before applying the method or is imputed in the course of applying the method.

17. A method according to claim 1, wherein instead of determining allelic type, a function or manifestation of allelic type is determined.

18. A method according to claim 17, wherein said function or manifestation of allelic type comprises at least one of serotype, blood group, susceptibility to a disease, resistance to a disease, presence or absence of a gene or allele with known consequence.

19. A method according to claim 1, wherein the allelic type to be determined is part of the Major Histocompatability Complex.

20. A method according to claim 1, comprising determining the Human Leukocyte Antigen allelic type of the specific individual.

21. A method of determining an allelic type of a specific individual according to claim 1, further comprising determining the type of a set of genetic markers of a DNA sample of the specific individual as the data for inputting in the inputting step, wherein the set of genetic markers comprises at least one, or at least 10, or at least 20, or at least 50, or at least 80, or all SNP positions specified in Table 3.

23. A computer program comprising computer-executable code that when executed on a computer system causes the computer system to perform a method according to claim 1.

7. A method of selecting a set of genetic markers for use in determining an allelic type of a specific individual, the method comprising:

accessing a database of genetic information on a plurality of individuals, the genetic information comprising;

the allelic type of each individual; and

the type of each of a plurality of genetic markers for each individual;

initialising to define a current set of genetic markers;

determining the allelic type of each individual in the database using the current set of genetic markers;

measuring the performance of the current set of markers by calculating a predetermined performance measure on the basis of the allelic types found in the determining step and the actual allelic types known from the database;

keeping as the current set of markers the set that gives the best measured performance seen so far for a set of a given size;

modifying the current set of markers;

repeating the determining, measuring, keeping and modifying steps;

terminating when a predetermined condition is met; and

outputting the set of markers that gives the best measured performance seen as the selected set of genetic markers for use in determining an allelic type of an individual.

10. A method according to claim 7, wherein each individual in the database is in turn treated as the specific individual of unknown allelic type, and the allelic type is determined on the basis of the data on the remaining individuals in the database, and wherein the current set of genetic markers is used as the specified set of genetic markers.

13. A method of determining an allelic type of a specific individual, comprising:

determining the type of each of the genetic markers of the specified set of genetic markers of a DNA sample of the specific individual, wherein the set of genetic markers are selected according to the method of claim 7.

8. (canceled)

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26. (canceled)