Systems and methods for reconstructing gene networks in segregating populations
View Patent ↗The reconstruction of genetic networks in mammalian systems is one of the primary goals in biological research, especially as such reconstructions relate to elucidating not only common, polygenic human disease, but living systems more generally. The present invention provides novel gene network reconstruction algorithms that utilize naturally occurring genetic variations as a source of perturbations to elucidate the networks. The algorithms incorporate relative transcript abundance and genotypic data from segregating populations by employing a generalized scoring function of maximum likelihood commonly used in Bayesian network reconstruction problems. The utility of these novel algorithms can be demonstrated via application to gene expression data from a segregating mouse population. The network derived from such data using the novel network reconstruction algorithm is able to capture causal associations between genes that result in increased predictive power, compared to more classically reconstructed networks derived from the same data.
1. A method for constructing a model of a biological pathway comprising a plurality of genes, the method comprising:
(A) obtaining an eQTL vector for a gene X in said plurality of genes;
(B) obtaining an eQTL vector for a gene Y in said plurality of genes;
(C) constructing a prior p(X→Y) that represents a probability that said gene X is upstream of said gene Y in said biological pathway, wherein
p
(
X
->
Y
)
=
r
(
X
,
Y
)
N
(
Y
)
N
(
X
)
+
N
(
Y
)
,
wherein
N(Y) is a number of eQTL in the eQTL vector for said gene Y;
N(X) is a number of eQTL in the eQTL vector for said gene X; and
r(X,Y) is a weight that represents a correlation between the eQTL vector for said gene X and the eQTL vector for said gene Y; and
(D) computing said model of said biological pathway using Bayesian analysis that incorporates the prior p(X→Y) constructed in step (C), wherein said computing step is carried out on a suitably programmed computer.
2. The method of claim 1 , wherein said plurality of genes is between 100 and 1000 genes.
3. The method of claim 1 , wherein said plurality of genes is between 500 and 10,000 genes.
4. The method of claim 1 , wherein said plurality of genes is between 1000 and 5,000 genes.
5. The method of claim 1 , wherein each eQTL in the eQTL vector for said gene Y has a LOD score of 3.0 or more.
6. The method of claim 1 , wherein each eQTL in the eQTL vector for said gene Y has a LOD score of 4.0 or more.
7. The method of claim 1 , wherein each eQTL in the eQTL vector for said gene Y has a LOD score of 5.0 or more.
8. A computer program product for use in conjunction with a computer system, wherein the computer program product comprises a tangible, non-transitory computer readable storage medium on which computer-executable instructions are stored for implementing a method comprising:
(A) obtaining an eQTL vector for a gene X in a plurality of genes;
(B) obtaining an eQTL vector for a gene Y in said plurality of genes;
(C) constructing a prior p(X→Y) that represents a probability that said gene X is upstream of said gene Y in said biological pathway, wherein
p
(
X
->
Y
)
=
r
(
X
,
Y
)
N
(
Y
)
N
(
X
)
+
N
(
Y
)
,
wherein
N(Y) is a number of eQTL in the eQTL vector for said gene Y;
N(X) is a number of eQTL in the eQTL vector for said gene X; and
r(X,Y) is a weight that represents a correlation between the eQTL vector for said gene X and the eQTL vector for said gene Y; and
(D) computing a model of a biological pathway using Bayesian analysis that incorporates the prior p(X→Y) constructed by said instructions for constructing (C).
9. A computer comprising:
a central processing unit;
a memory coupled to the central processing unit, the memory storing computer-executable instructions for implementing a method comprising:
(A) obtaining an eQTL vector for a gene X in a plurality of genes;
(B) obtaining an eQTL vector for a gene Y in said plurality of genes;
(C) constructing a prior p(X→Y) that represents a probability that said gene X is upstream of said gene Y in said biological pathway, wherein
p
(
X
->
Y
)
=
r
(
X
,
Y
)
N
(
Y
)
N
(
X
)
+
N
(
Y
)
,
wherein
N(Y) is a number of eQTL in the eQTL vector for said gene Y;
N(X) is a number of eQTL in the eQTL vector for said gene X; and
r(X,Y) is a weight that represents a correlation between the eQTL vector for said gene X and the eQTL vector for said gene Y; and
(D) computing a model of a biological pathway using Bayesian analysis that incorporates the prior p(X→Y) constructed by said instructions for constructing (C).