NEW YORK (GenomeWeb News) – Computer modeling of tissue-specific differences in gene expression and pathology can reveal new clues for understanding and treating a range human diseases ranging from heart disease and cancer to Parkinson disease and autism, according to new research.
An international team of researchers used computational approaches to map molecular interactions and networks in human tissues by pinpointing tissues affected by more than a thousand diseases and incorporating expression data on more than 2,000 genes and 1,500 protein complexes related to disease.
The work, scheduled to appear in an upcoming issue of the Proceedings of the National Academy of Sciences, suggests specific disease genes and complexes tend to be more highly expressed in tissues affected by that disease.
“We let supercomputers model biological processes in tissues across the human organism, based on the knowledge from millions of already published articles,” co-lead author Niclas Tue Hansen, a graduate researcher at the Technical University of Denmark, said in a statement. “In this way, we were able to create an extensive map of the interactions of molecules in many diseases — a sort of molecular manual — without carrying out experiments in patients.”
Although inherited genetic diseases are caused by mutations carried in all tissues, the effects are usually observed in just a few. This tissue-specific pathology suggests that disease genes and complexes have spatially and temporally defined effects. But although research suggests many single disease genes are expressed in just a few tissues, the larger picture of how tissue-specific gene expression influences disease pathology in tissues remains unclear.
“Disease processes in humans are far from being exhaustively understood and characterized, in part because they are the result of complex interactions between many molecules that may take place only in specific tissues or organs,” co-lead author Kasper Lage, a researcher affiliated with the Technical University of Denmark, Massachusetts General Hospital, and Harvard Medical School, said in a statement.
“Experiments to directly study these interactions in human patients would not be possible, which limits our understanding of how diseases arise and which molecules and genes are involved,” Lage added.
To overcome such limitations, the researchers used the GeneCards database to come up with a list of 2,227 disease-related proteins, using information from an inferred protein-protein interaction network to identify 1,524 protein complexes.
They then mapped these complexes to tissues based on gene expression data on 73 healthy tissues found in the Novartis Research Foundation Gene Expression Database and incorporated information from the Online Mendelian Inheritance in Man, or OMIM, database. The 1,524 protein complexes they assessed corresponded to 1,054 diseases in OMIM.
In general, the researchers found that disease genes are tissue-specific and tend to be more highly expressed in tissues showing disease pathology.
By combining pathology and tissue-specific expression data, the researchers were able to uncover additional patterns relevant to human diseases. For instance, they found that a protein complex influencing a condition called XY sex reversal is over-expressed in the testis and is down regulated in ovarian tissue. The team also saw tissue-specific expression of protein complexes implicated in diseases such as Parkinson disease, cardiomyopathy, and muscular dystrophy.
“Across all examples the tissue-specific expression patterns correlate with the pathological changes observed when one or several members of the complex are defective,” the authors wrote.
They saw slightly different patterns when comparing the tissue-specific pathology and expression patterns of cancer-initiating genes and protein complexes with non-cancer related genes and proteins. In particular, cancer-related genes and proteins were less likely to be over-expressed in affected tissues.
Although they noted that more research is needed to determine whether gene expression data accurately predicts protein complexes present in various tissues, the researchers are optimistic that their technique holds promise for shedding light on many human diseases.
“Our findings have the potential to advance the knowledge of pathways, genes, and proteins involved in hundreds of human disorders and perhaps contribute to better treatment strategies for some of these serious diseases,” co-author Patricia Donahoe, a Harvard Medical School surgery researcher and director of Massachusetts General Hospital’s Pediatric Surgery Research, said in a statement.
In the future, the authors predicted, information provided by functional genomics research and sequencing will be further augmented by systems biology research that builds on approaches such as theirs and ties together entire systems.
“[O]ur dataset and the scaffold of the analysis presented could be useful in disease systems biology of humans, and provides draft mechanistic pathways that can serve as potential molecular drug targets,” they concluded.
An atlas containing the tissue-specific complexes uncovered in the study will reportedly be made available online through the Technical University of Denmark’s Center for Biological Sequence Analysis web page.