title: An atlas of tissue-specific conserved coexpression for functional annotation and disease gene prediction.
abstract: Gene coexpression relationships that are phylogenetically conserved between human and mouse have been shown to provide important clues about gene function that can be efficiently used to identify promising candidate genes for human hereditary disorders. In the past, such approaches have considered mostly generic gene expression profiles that cover multiple tissues and organs. The individual genes of multicellular organisms, however, can participate in different transcriptional programs, operating at scales as different as single-cell types, tissues, organs, body regions or the entire organism. Therefore, systematic analysis of tissue-specific coexpression could be, in principle, a very powerful strategy to dissect those functional relationships among genes that emerge only in particular tissues or organs. In this report, we show that, in fact, conserved coexpression as determined from tissue-specific and condition-specific data sets can predict many functional relationships that are not detected by analyzing heterogeneous microarray data sets. More importantly, we find that, when combined with disease networks, the simultaneous use of both generic (multi-tissue) and tissue-specific conserved coexpression allows a more efficient prediction of human disease genes than the use of generic conserved coexpression alone. Using this strategy, we were able to identify high-probability candidates for 238 orphan disease loci. We provide proof of concept that this combined use of generic and tissue-specific conserved coexpression can be very useful to prioritize the mutational candidates obtained from deep-sequencing projects, even in the case of genetic disorders as heterogeneous as XLMR.
authors.affiliation: Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Rosario Michael
authors.initials: RM
authors.lastname: Piro
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.forename: Ivan
authors.initials: I
authors.lastname: Molineris
authors.forename: Elena
authors.initials: E
authors.lastname: Grassi
authors.forename: Chiara
authors.initials: C
authors.lastname: Bracco
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Perego
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Di Cunto
mesh_terms: D000818:Animals; D041321:Chromosomes, Human, X; D004194:Disease / Q000235:genetics*; D059472:Exome; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype