Identifying variants of interest by imputation

1. A genetic information processing system, comprising:

computer memory storing one or more databases comprising densely sequenced genotype data of a plurality of reference individuals and sparsely sequenced genotype data and phenotype data of a plurality of candidate individuals; and

one or more computer processors coupled to the computer memory, the one or more processors being configured to:

(a) receive an input comprising information pertaining to a genetic variant of unknown significance (VUS);

(b) retrieve the densely sequenced genotype data of the plurality of reference individuals from the one or more databases, wherein the densely sequenced genotype data comprises genotype data at a genetic locus corresponding to the VUS; and

(c) perform statistical imputation, Identity by Descent (IBD)-based imputation, or a combination thereof on the sparsely sequenced genotype data of the plurality of candidate individuals using the densely sequenced genotype data of the plurality of reference individuals, thereby obtaining imputed genotype data with reference to the VUS for the plurality of candidate individuals, wherein the genetic locus corresponding to the VUS for the plurality of candidate individuals is not directly assayed by a genotyping chip or a genotyping platform.

2. The system of claim 1 , wherein (c) comprises to perform statistical imputation.

3. The system of claim 1 , wherein to perform statistical imputation comprises 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 a matching individual who has the VUS.

4. The system of claim 1 , wherein (c) comprises to perform Identity by Descent (IBD)-based imputation.

5. The system of claim 4 , wherein to perform IBD-based imputation includes to:

receive additional genotype information of a proband who has the VUS; and

determine whether a candidate individual shares a variant-overlapping IBD region with the proband.

6. The system of claim 5 , 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 VUS and another one of the two adjacent opposite-homozygous calls is to the right of the VUS; and

determine whether the distance meets a threshold.

7. The system of claim 3 , wherein genetic material of the matching individual is further assayed to validate whether the matching individual actually possesses the VUS.

8. A method of processing genetic information, implemented using a computer system comprising one or more computer processors coupled to computer memory storing one or more databases comprising densely sequenced genotype data of a plurality of reference individuals and sparsely sequenced genotype data and phenotype data of a plurality of candidate individuals, the method comprising:

(a) receiving, by the computer system, an input comprising information pertaining to a genetic variant of unknown significance (VUS);

(b) retrieving, by the computer system, the densely sequenced genotype data of the plurality of reference individuals from the one or more databases, wherein the densely sequenced genotype data comprises genotype data at a genetic locus corresponding to the VUS; and

(c) performing, by the one or more computer processors, statistical imputation, Identity by Descent (IBD)-based imputation, or a combination thereof on the sparsely sequenced genotype data of the plurality of candidate individuals using the densely sequenced genotype data of the plurality of reference individuals, thereby obtaining imputed genotype data with reference to the VUS for the plurality of candidate individuals, wherein the genetic locus corresponding to the VUS for the plurality of candidate individuals is not directly assayed by a genotyping chip or a genotyping platform.

9. The method of claim 8 , wherein (c) comprises performing statistical imputation.

10. The method of claim 8 , wherein performing statistical imputation comprises:

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 a matching individual who has the VUS.

11. The method of claim 8 , wherein (c) comprises performing IBD-based imputation.

12. The method of claim 11 , wherein performing IBD-based imputation comprises:

receiving additional genotype information of a proband who has the VUS; and

determining whether a candidate individual shares a variant-overlapping IBD region with the proband.

13. The method of claim 12 , wherein determining whether the candidate individual shares a variant-overlapping IBD region with the proband comprises:

determining 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 VUS and another one of the two adjacent opposite-homozygous calls is to the right of the VUS; and

determining whether the distance meets a threshold.

14. The method of claim 10 , wherein genetic material of the matching individual is further assayed to validate whether the matching individual actually possesses the VUS.

15. A computer program product for processing genetic information using a computer system comprising one or more computer processors coupled to computer memory storing one or more databases comprising densely sequenced genotype data of a plurality of reference individuals and sparsely sequenced genotype data and phenotype data of a plurality of candidate individuals, the computer program product being embodied in a tangible computer readable storage medium and comprising computer instructions for:

(a) receiving an input comprising information pertaining to a genetic variant of unknown significance (VUS);

(b) retrieving the densely sequenced genotype data of the plurality of reference individuals from the one or more databases, wherein the densely sequenced genotype data comprises genotype data at a genetic locus corresponding to the VUS; and

(c) performing statistical imputation, Identity by Descent (IBD)-based imputation, or a combination thereof on the sparsely sequenced genotype data of the plurality of candidate individuals using the densely sequenced genotype data of the plurality of reference individuals, thereby obtaining imputed genotype data with reference to the VUS for the plurality of candidate individuals, wherein the genetic locus corresponding to the VUS for the plurality of candidate individuals is not directly assayed by a genotyping chip or a genotyping platform.

16. A genetic information processing system, comprising:

computer memory storing one or more databases comprising reference genotype data of a plurality of reference individuals and sparsely sequenced genotype data and phenotype data of a plurality of candidate individuals; and

one or more computer processors coupled to the computer memory, the one or more processors being configured to:

(a) receive an input comprising information pertaining to a genetic variant of unknown significance (VUS);

(b) retrieve the reference genotype data of the plurality of reference individuals from the one or more databases,

wherein

the reference genotype data comprises a haplotype graph having a computer data structure of a Directed Acyclic Graph (DAG),

the DAG comprises nodes and directed edges each connecting an initial node and a terminating node, each node representing a genotype of a genetic marker, each directed edge indicating a probability of observing the terminating node given the initial node, the nodes and directed edges of the DAG being obtained from densely sequenced reference data of the plurality of reference individuals, and

the densely sequenced reference data of the plurality of reference individuals comprise genotype data at a genetic locus corresponding to the VUS; and

(c) perform statistical imputation on the sparsely sequenced genotype data of the plurality of candidate individuals, thereby obtaining imputed genotype data with reference to the VUS for the plurality of candidate individuals,

wherein

performing statistical imputation comprises applying the sparsely sequenced genotype data of the plurality of candidate individuals to the haplotype graph to obtain the imputed genotype data with reference to the VUS for the plurality of candidate individuals, and

the genetic locus corresponding to the VUS for the plurality of candidate individuals is not directly assayed by a genotyping chip or a genotyping platform.

17. The system of claim 16 , wherein the plurality of reference individuals comprises 1,000 or more individuals.

18. A genetic information processing system, comprising:

computer memory storing one or more databases comprising reference genotype data of a plurality of reference individuals and sparsely sequenced genotype data and phenotype data of a plurality of candidate individuals; and

one or more computer processors coupled to the computer memory, the one or more processors being configured to:

(a) receive an input comprising information pertaining to a genetic variant of unknown significance (VUS);

(b) retrieve the reference genotype data of the plurality of reference individuals from the one or more databases,

wherein

the reference genotype data comprises one or more hash tables,

each hash table is a computer data structure that maps words to values,

each of the words comprises one or more genetic markers,

each hash table is obtained using densely sequenced reference data of the plurality of reference individuals,

the densely sequenced reference data of the plurality of reference individuals comprise genotype data at a genetic locus corresponding to the VUS; and

(c) perform Identity by Descent (IBD)-based imputation on the sparsely sequenced genotype data of the plurality of candidate individuals, thereby obtaining imputed genotype data with reference to the VUS for the plurality of candidate individuals,

wherein

performing IBD-based imputation comprises looking up words obtained from the sparsely sequenced genotype data of the plurality of candidate individuals in the one or more hash tables to obtain the imputed genotype data with reference to the VUS for the plurality of candidate individuals, and

the genetic locus corresponding to the VUS for the plurality of candidate individuals is not directly assayed by a genotyping chip or a genotyping platform.

19. The system of claim 18 , wherein the plurality of reference individuals comprises 1,000 or more individuals.

20. The system of claim 1 , wherein the reference genotype data comprise a haplotype graph having a computer data structure of a DAG, genotype data stored in one or more hash tables, opposite homozygous data, or any combinations thereof.