Scientists at the University of California have created the most complete atlas of chromosome regions that are potentially associated with the inheritance of complex human traits or the development of diseases. These hotspots amplify the activity of genes underlying disorders such as diabetes, Alzheimer's disease or autoimmune disorders. The results of the study are published in the journal Cell.
In the human body, there are many different types of cells (nerve, muscle, fat, etc.) that share the same set of DNA. The type of cell depends on which genes are active and which are suppressed. It is known that this is controlled by special regulators, for example, promoters and enhancers. They are regions of DNA that are on the same chromosome as the gene they regulate (hence they are called cis-regulatory elements or cCRE). Current catalogs of human regulatory sequences are still incomplete, although scientists speculate that many of these elements may be associated with disease.
Scientists analyzed 615,998 cell nuclei from 30 types of human tissue obtained from several adult donors to compile a profile of open chromatin – regions of chromosomes that are involved in interactions with other biological molecules, for example, with transcription factors, which, in turn, affect gene activity. Experts found 890 130 regions of open chromatin corresponding to cCRE.
The researchers combined the obtained data with the results of a previous study, which identified areas of open chromatin for cells of 15 tissue types of human embryos. This made it possible to trace how chromatin profiles change over the course of a person's life. In all, the scientists identified 1.3 million cell profiles and mapped 1.15 million cis-regulatory sequences covering 14.8 percent of the genome in 222 cell types.
The team then used their cCRE atlas in order to associate certain genetic variants with complex human traits or diseases. For example, researchers have identified a variant of the rs16940186 gene that is most likely associated with ulcerative colitis. This variant enhances the expression of the IRF8 molecule in epithelial cells of the gastrointestinal tract through the creation of open chromatin in the place where the enhancer that binds to transcription factors is located. This confirms that the atlas is useful in identifying the molecular mechanisms of various genetic disorders.