Granted Patent B2

US 8,805,620 · App. 12/908,636 · Granted Aug 12, 2014

Abstract

Claims (74)

1. A method of selecting a donor or reproductive partner for a potential parent from a pool of sperm donors, or from a pool of oocyte donors or from a pool of potential reproductive partners, the method implemented by a computer processor executing program instructions, the method comprising the steps of:

(a) using the processor, generating a recipient haplopath H i recipient ={h 1 , h 2 , . . . , h N } including a single allele h x ∈(1,2) of a genotype at each of a plurality of loci (1, . . . , N) from a recipient genome profile of a potential parent;

(b) using the processor, generating a donor haplopath H i donor ={h 1 , h 2 , . . . , h N } including a single allele h x ∈(1,2) of a genotype at each of the plurality of loci x=1, . . . , N from a donor genome profile of a member of a pool of sperm donors, oocyte donors or potential reproductive partners;

(c) using the processor, combining said recipient haplopath H i recipient with said donor haplopath H i donor to generate a virtual progeny genome sampling

G

i

VP

=

{

[

h

x

recipient

h

x

donor

]

}

including two alleles h x recipient and h x donor of a genotype at each of the plurality of loci x=1, . . . , N for a potential progeny;

(d) using the processor, comparing genotypes of said virtual progeny genome sampling to one or more databases of genotype-phenotype associations to determine a likelihood of expression of one or more phenotypes for the potential progeny having said virtual progeny genome sampling; and

(e) repeating steps (a)-(d) for a plurality of recipient and donor haplopaths from, respectively, the recipient and donor potential parents i=1, . . . ,p to generate a virtual progeny genome G VP including a plurality of the virtual progeny genome samplings G VP =G 1 VP , G 2 VP , . . . , G p VP );

(f) generating probabilities or probability distributions for said potential progeny expressing said one or more phenotypes based on the likelihoods determined for the plurality of virtual progeny genome samplings in the virtual progeny genome G VP ; and

(g) repeating steps (a)-(f) for each member of said pool of sperm donors, oocyte donors or potential reproductive partners.

2. The method of claim 1 , wherein:

i. said recipient genome profile includes phased DNA sequences and each of said donor genome profiles includes phased DNA sequences;

ii. generating said recipient haplopath H i recipient includes simulating recombination between the phased DNA sequences from said recipient genome profile; and

iii. generating said donor haplopath H i donor includes simulating recombination between the phased DNA sequences from said donor genome profile.

3. The method of claim 1 , wherein, prior to step (a):

variants are identified comprising single base substitutions, insertion/deletions, copy number polymorphisms and combinations thereof at defined genetic loci in genomic DNA samples obtained from said potential parent and from each member of said pool of sperm donors, oocyte donors or potential partners.

4. The method of claim 3 , further comprising the steps of:

i. using the processor, for each potential parent, comparing the identified variants for the genomic DNA sample to a plurality of predetermined genomic sequences of haplotypes to identify haplotypes present in the genomic DNA of said potential parent; and

ii. using the processor, constructing each genome profile, wherein each genome profile comprises the identified haplotypes present and association frequencies of consecutive haplotypes, respectively.

5. The method of claim 1 wherein said pool of sperm donors, oocyte donors or potential partners is a pool of sperm donors from a sperm bank.

6. The method of claim 1 , wherein said haplopaths H i recipient and H i donor are constructed using Monte Carlo simulations and linkage disequilibrium association probabilities of haplotypes in the respective genome profiles.

7. The method of claim 1 , wherein a selected member of said pool is excluded for consideration as a potential donor or reproductive partner if the potential progeny is determined to have an increased risk of disease relative to another member of said pool or to a pre-determined standard.

8. The method of claim 1 , wherein a selected member of said pool is included for consideration as a potential donor or reproductive partner if the potential progeny is determined to have an increased likelihood of expression of a trait relative to another member of said pool or to a pre-determined standard.

9. A system for selecting a donor or reproductive partner for a potential parent from a pool of sperm donors, or from a pool of oocyte donors or from a pool of potential reproductive partners, the system comprising:

a memory; and

a computer processor to:

(a) generate a recipient haplopath H i recipient ={h 1 , h 2 , . . . , h N } including a single allele h x ∈(1,2) of a genotype at each of a plurality of loci (1, . . . , N) from a recipient genome profile of a potential parent;

(b) generate a donor haplopath H i donor ={h 1 , h 2 , . . . , h N } including a single allele h x ∈(1,2) of a genotype at each of the plurality of loci x=1, . . . , N from a donor genome profile of a member of a pool of sperm donors, oocyte donors or potential reproductive partners;

(c) combine said recipient haplopath H i recipient with said donor haplopath H i donor to generate a virtual progeny genome sampling

G

i

VP

=

{

[

h

x

recipient

h

x

donor

]

}

including two alleles h x recipient and h x donor of a genotype at each of the plurality of loci x=1, . . . , N for a potential progeny;

(d) compare genotypes of said virtual progeny genome sampling to one or more databases of genotype-phenotype associations to determine a likelihood of expression of one or more phenotypes for the potential progeny having said virtual progeny genome sampling; and

(e) repeat steps (a)-(d) for a plurality of recipient and donor haplopaths from, respectively, the recipient and donor potential parents i=1, . . . , p to generate a virtual progeny genome G VP including a plurality of the virtual progeny genome samplings G VP ={G 1 VP , G 2 VP , . . . , G p VP };

(f) generate probabilities or probability distributions for said potential progeny expressing said one or more phenotypes based on the likelihoods determined for the plurality of virtual progeny genome samplings in the virtual progeny genome G VP ; and

(g) repeat steps (a)-(f) for each member of said pool of sperm donors, oocyte donors or potential reproductive partners.

10. The system of claim 9 , wherein:

i. said recipient genome profile includes phased DNA sequences and each of said donor genome profiles includes phased DNA sequences;

ii. generating said recipient haplopath H i recipient includes simulating recombination between the phased DNA sequences from said recipient genome profile; and

iii. generating said donor haplopath H i donor includes simulating recombination between the phased DNA sequences from said donor genome profile.

11. The system of claim 9 , wherein, prior to step (a):

variants are identified comprising single base substitutions, insertion/deletions, copy number polymorphisms and combinations thereof at defined genetic loci in genomic DNA samples obtained from said potential parent and from each member of said pool of sperm donors, oocyte donors or potential partners.

12. The system of claim 11 , wherein the processor is to:

i. for each potential parent, compare the identified variants for the genomic DNA sample to a plurality of predetermined genomic sequences of haplotypes to identify haplotypes present in the genomic DNA of said potential parent; and

ii. construct each genome profile, wherein each genome profile comprises the identified haplotypes present and association frequencies of consecutive haplotypes, respectively.

13. The system of claim 9 wherein said pool of sperm donors, oocyte donors or potential partners is a pool of sperm donors from a sperm bank.

14. The system of claim 9 , wherein said haplopaths H i recipient and H i donor are constructed using Monte Carlo simulations and linkage disequilibrium association probabilities of haplotypes in the respective genome profiles.

15. The system of claim 9 , wherein a selected member of said pool is excluded for consideration as a potential donor or reproductive partner if the potential progeny is determined to have an increased risk of disease relative to another member of said pool or to a pre-determined standard.

16. The system of claim 9 , wherein a selected member of said pool is included for consideration as a potential donor or reproductive partner if the potential progeny is determined to have an increased likelihood of expression of a trait relative to another member of said pool or to a pre-determined standard.

Assignments (9)