Single-letter genetic variations within parts of the genome once dismissed as “junk DNA” can increase cancer risk through remote effects on far-off genes, new research by scientists at The Institute of Cancer Research, London shows.

The researchers found that DNA sequences within “gene deserts” — so called because they are completely devoid of genes — can regulate gene activity elsewhere by forming DNA loops across relatively large distances.

The study helps solve a mystery about how genetic variations in parts of the genome that don’t appear to be doing very much can increase cancer risk.

Their study, published in Nature Communications, also has implications for the study of other complex genetic diseases.

The researchers developed a technique called Capture Hi-C to investigate long-range physical interactions between stretches of DNA – allowing them to look at how specific areas of chromosomes interact physically in more detail.

The researchers assessed 14 regions of DNA that contain single-letter variations previously linked to bowel cancer risk. They detected significant long-range interactions for all 14 regions, confirming their role in gene regulation.

“Our new technique shows that genetic variations are able to increase cancer risk through long-range looping interactions with cancer-causing genes elsewhere in the genome,” study leader Professor Richard Houlston, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London said.

“It is sometimes described as analogous to a wormhole, where distortions in space and time could in theory bring together distant parts of the universe.”

The research was funded by the EU, Cancer Research UK, Leukaemia & Lymphoma Research, and The Institute of Cancer Research (ICR).

Abstract for Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer–promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci.