title: Differential network analysis reveals genetic effects on catalepsy modules.
abstract: We performed short-term bi-directional selective breeding for haloperidol-induced catalepsy, starting from three mouse populations of increasingly complex genetic structure: an F2 intercross, a heterogeneous stock (HS) formed by crossing four inbred strains (HS4) and a heterogeneous stock (HS-CC) formed from the inbred strain founders of the Collaborative Cross (CC). All three selections were successful, with large differences in haloperidol response emerging within three generations. Using a custom differential network analysis procedure, we found that gene coexpression patterns changed significantly; importantly, a number of these changes were concordant across genetic backgrounds. In contrast, absolute gene-expression changes were modest and not concordant across genetic backgrounds, in spite of the large and similar phenotypic differences. By inferring strain contributions from the parental lines, we are able to identify significant differences in allelic content between the selected lines concurrent with large changes in transcript connectivity. Importantly, this observation implies that genetic polymorphisms can affect transcript and module connectivity without large changes in absolute expression levels. We conclude that, in this case, selective breeding acts at the subnetwork level, with the same modules but not the same transcripts affected across the three selections.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA. iancuo@ohsu.edu
authors.forename: Ovidiu D
authors.initials: OD
authors.lastname: Iancu
authors.forename: Denesa
authors.initials: D
authors.lastname: Oberbeck
authors.forename: Priscila
authors.initials: P
authors.lastname: Darakjian
authors.forename: Sunita
authors.initials: S
authors.lastname: Kawane
authors.forename: Jason
authors.initials: J
authors.lastname: Erk
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.forename: Robert
authors.initials: R
authors.lastname: Hitzemann
mesh_terms: D000483:Alleles; D000818:Animals; D001947:Breeding; D002375:Catalepsy / Q000139:chemically induced / Q000235:genetics*; D016000:Cluster Analysis; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D005838:Genotype; D051379:Mice; D058977:Molecular Sequence Annotation; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics; D015203:Reproducibility of Results; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C511143:Bcl11b protein, mouse; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins
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