Non-coding genomic variants shown to cause disease

12 November 2013

Novel disease-causing mutations have been identified in a non-coding region of the genome.
An international collaboration using the most advanced forms of genome sequencing technology found that the rare but severe condition pancreatic agenesis, which causes babies to be born without a pancreas, was caused by mutations in the PTF1A regulatory region of the genome. Several mutations in the same region, which is involved in control of PTF1A gene expression, were identified in eleven individuals with the disease.
Writing in Nature Genetics, the researchers say their finding is important for improving understanding of this condition, of the normal development and function of the pancreas and of how pancreatic dysfunction operates in diabetes.
Lead researcher Dr Mike Weedon also commented: “This breakthrough delves into the ‘dark matter’ of the genome, which, until recently, was very difficult to systematically study. Now, advances in DNA sequencing technology mean we have the tools to explore these non-protein coding regions far more thoroughly, and we are finding it has a significant impact on development and disease”.
Whilst the non-coding regions that comprise roughly 99% of the entire human genome sequence and were once thought to be non-functional or ‘junk’ DNA are now known to play an important role on the control of gene expression, the contribution of mutations within regulatory regions to human diseases remain poorly understood. In this study the researchers first used genome sequencing of patients to identify a region on chromosome 10 including the PTF1A gene as the likely source of the disease, but found no mutations in the coding regions of PTF1A or other nearby genes.
They therefore searched for non-coding mutations, reasoning that these would disrupt a ‘noncoding genomic element that is active in cells that are relevant to this disease’. Examination of the epigenome (patterns of non-sequence DNA modifications) of human embryonic pancreatic progenitor cells identified thousands of active gene regulatory regions (enhancers). Genetic variants observed in different patients were mapped to a single region, which the researchers were able to show acts as an enhancer of PTF1A gene expression during normal development, and that this function is disrupted by mutations.
Comment: Combining genome sequencing with what the researchers term ‘epigenomic annotation’ (attaching biological information to epigenomic elements in a similar manner to genome sequence annotation) is shown to have the potential to identify those relevant to human disease and development. Deciphering the human genome sequence was once thought to hold the key to understanding human health and disease, but almost as soon as this challenge had been met, it became increasingly evident that there was much more information still to be grappled with in the form of the epigenome. Along with other recent reports, this paper demonstrates an important first step towards addressing this enormous complexity of information.

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