Identifying variants of interest by imputation

Abstract

Processing genetic information comprises: receiving an input that includes information pertaining to a specific genetic variant; and identifying, in a database comprising genotype information of a plurality of candidate individuals, a matching individual imputed to have the specific genetic variant. The genotype information of the matching individual corresponding to the specific genetic variant is not directly assayed.

What is claimed is: 
     
         1 . A genetic information processing system, comprising:
 one or more computer processors configured to:
 receive an input that includes information pertaining to a specific genetic variant; and 
 identify, in a database comprising genotype information of a plurality of candidate individuals, a matching individual imputed to have the specific genetic variant; and 
   one or more memories coupled to the one or more computer processors and configured to provide the one or more computer processors with instructions; wherein   genotype information of the matching individual corresponding to the specific genetic variant is not directly assayed.   
     
     
         2 . The system of  claim 1 , wherein the specific genetic variant is a variant of unknown significance. 
     
     
         3 . The system of  claim 1 , wherein the one or more computer processors are further configured to:
 identify additional matching individuals imputed to have the specific genetic variant; and   process phenotype information of the matching individuals to determine an association of the specific genetic variant and a phenotype.   
     
     
         4 . The system of  claim 1 , wherein the specific genetic variant is known to be associated with a phenotype, and the one or more computer processors are further configured to notify the matching individual of the association. 
     
     
         5 . The system of  claim 1 , wherein to identify the matching individual includes to perform statistical imputation. 
     
     
         6 . The system of  claim 1 , wherein to identify the matching individual includes to perform statistical imputation, including to:
 establish a statistical model based on genotype information of a set of reference individuals; and   apply a candidate individual's genotype information to the statistical model to determine whether the candidate individual is the matching individual who has the specific genetic variant.   
     
     
         6 . The system of  claim 6 , wherein:
 the statistical model includes a haplotype graph; and   to apply the candidate individual's genotype information to the statistical model includes to:
 identify a likely genotype sequence based on the candidate individual's genotype and the haplotype graph; and 
 determine, according to the likely genotype sequence, whether the candidate individual has the specific genetic variant. 
   
     
     
         8 . The system of  claim 6 , wherein:
 the genotype information of the set of reference individuals is more densely assayed than genotype information of the plurality of candidate individuals.   
     
     
         9 . The system of  claim 1 , wherein to identify the matching individual includes to perform Identity by Descent (IBD)-based imputation. 
     
     
         10 . The system of  claim 9 , wherein to perform IBD-based imputation includes to:
 receive additional genotype information of a proband who has the specific genetic variant; and   determine whether a candidate individual shares a variant-overlapping IBD region with the proband.   
     
     
         11 . The system of  claim 10 , wherein to determine whether the candidate individual shares a variant-overlapping IBD region with the proband includes to:
 determine a distance between two adjacent opposite-homozygous calls in the proband's genotype sequence and the candidate individual's genotype sequence, one of the two adjacent opposite-homozygous calls is to the left of the specific genetic variant and another one of the two adjacent opposite-homozygous calls is to the right of the specific genetic variant; and   determine whether the distance meets a threshold.   
     
     
         12 . The system of  claim 1 , wherein genetic material of the matching individual is further assayed to validate whether the matching individual actually possesses the specific genetic variant. 
     
     
         13 . A method of processing genetic information, comprising:
 receiving an input that includes information pertaining to a specific genetic variant; and   identifying, using one or more computer processors and in a database comprising genotype information of a plurality of candidate individuals, a matching individual imputed to have the specific genetic variant; wherein   genotype information of the matching individual corresponding to the specific genetic variant is not directly assayed.   
     
     
         14 . The method of  claim 13 , wherein the specific genetic variant is a variant of unknown significance. 
     
     
         15 . The method of  claim 13 , further comprising:
 identifying additional matching individuals imputed to have the specific genetic variant; and   processing phenotype information of the matching individuals to determine an association of the specific genetic variant and a phenotype.   
     
     
         16 . The method of  claim 13 , wherein the specific genetic variant is known to be associated with a phenotype, and the method further comprises notifying the matching individual of the association. 
     
     
         17 . The method of  claim 13 , wherein identifying the matching individual includes performing statistical imputation. 
     
     
         18 . The method of  claim 13 , wherein identifying the matching individual includes performing statistical imputation, including:
 establishing a statistical model based on genotype information of a set of reference individuals; and   applying a candidate individual's genotype information to the statistical model to determine whether the candidate individual is the matching individual who has the specific genetic variant.   
     
     
         19 . The method of  claim 18 , wherein:
 the statistical model includes a haplotype graph; and   applying the candidate individual's genotype information to the statistical model includes:
 identifying a likely genotype sequence based on the candidate individual's genotype and the haplotype graph; and 
 determining, according to the likely genotype sequence, whether the candidate individual has the specific genetic variant. 
   
     
     
         20 . The method of  claim 18 , wherein:
 the genotype information of the set of reference individuals is more densely assayed than genotype information of the plurality of candidate individuals.