Case story: Tissue-specific expression of diseases

Transcription

1 Systems Biology Workshop Case story: Tissue-specific expression of diseases Center for Biological Sequence Analysis

2 Tissue specificity of disease genes and complexes Most disease, including cancers, are tissue specific. We wanted to investigate how such a tissue specificity can arise. To do this we have devloped methods for analyzing and integrating heterogenous data 1. Find the connection between genes and diseases using biomedical databases 2. Determin in which tissue a given geen is expressed and how much 3. Find the correlation between a disease and the tissue in which it is manifested

3 Necessary steps Lage K, Hansen NT, et al., in review

4 Computer-based analysis of medical text Text mining of disease descriptions in OMIM, to deduce disease-causing genes In total description of more than 1000 diseases, including 50 cancers, where analyzed to find disease-causing genes

5 Computer-baserede analyser 1. Lade computeren læse medicinske databaser, såsom OMIM, og finde sammenhænge mellem sygdomme og gener. 2. Microarrays kan måle hvor meget et gen er tilstede. Vi har analyseret data fra 73 raske væv. 3. Lade computeren læse artikler og finde sammenhænge mellem sygdomme og væv. I alt har vi computer-genereret 1,524 proteinkomplekser med mere end 5000 proteins, som er involveret i 1000 sygdomme og 50 cancere på tværs af 73 væv. Systems Biology Workshop, May 14th-15th, 2009

6 Finding protein complexes Lage et al. Nat. Biotech 2007 Systems Biology Workshop, May 14th-15th, 2009

7 Lage K, Hansen NT, et al., PNAS

8 Validation of protein complexes Lage K, Hansen NT, et al., PNAS

9 Validation of protein complexes Lage K, Hansen NT, et al., PNAS

10 Tissue-specific expression Gene expression data for 73 healthy tissues Lage K, Hansen NT, et al., PNAS

11 Mapping diseases to tissues Text mining of articles to find correlations between tissues and diseases

12 Mapping diseases to tissues - details Lage K, Hansen NT, et al., PNAS

13 Mapping diseases to tissues - details Lage K, Hansen NT, et al., PNAS

14 Mapping diseases to tissues - results

15 Large scale integration We generated a set of 1,524 raw complexes, comprising 45,662 interactions between 5,202 proteins with tissue and phenotype resolution. Complexes are mapped to more than 1000 diseases, 50 cancers, and 73 tissues

16 Expression in diseased tissues Legend Genes Complexes Non-cancer disease Cancer gain of function e.g. oncogenes like the BCR-ABL kinase Cancer loss of function e.g. check point and DNA repair proteins 13/05/2009 PhD Lecture 16

17 Expression in diseased tissues Across all diseases complexes are overexpressed in tissues where they are involved in pathology. Genes Complexes Cancer genes and complexes show converse trends, that are not as robust when different normalization algorithms are used on the expression data. 13/05/2009 PhD Lecture 17

18 Lage K, Hansen NT, et al., in review

19 Possible mechanism Disease gene are expressed in selected tissues only They can cause diseases in these tissues Cancer genes are ubiquitously expressed They cause cancer when activity falls below critical threshold