It is well established that changes in genes can alter a protein’s function in the body, potentially causing health problems. Scientists have determined that changes in regions of DNA that do not contain genes (noncoding DNA) can also lead to disease.

Many regions of noncoding DNA play a role in the control of gene activity, meaning they help determine when and where certain genes are turned on or off. Other regions of noncoding DNA are important for protein assembly. By altering one of these regions, a variant (also known as a mutation) in noncoding DNA can turn on a gene and cause a protein to be produced in the wrong place or at the wrong time. Alternatively, a variant can reduce or eliminate the production of an important protein when it is needed. Not all changes in noncoding DNA have an impact on health, but those that alter the pattern of a critical protein can disrupt normal development or cause a health problem.

Variants in noncoding DNA have been linked to several types of cancer and developmental disorders such as isolated Pierre Robin sequence. This condition is caused by changes in regions of noncoding DNA that act as enhancer elements. Enhancers attach proteins that help turn on particular genes. The enhancers altered in isolated Pierre-Robin sequence control the activity of the SOX9 gene. 

In addition to enhancer elements, variants in noncoding DNA can disrupt other regulatory elements. These other elements include promoters, where proteins that turn on genes attach; insulators, where proteins that help shape the activity of genes in different ways attach; and silencers, where proteins that turn off genes attach. 

Some regions of noncoding DNA provide instructions for making certain kinds of RNA molecules that play roles in regulating gene activity or assembling proteins. Variants that interrupt these functional RNA molecules, such as transfer RNAs, microRNAs, or long noncoding RNAs, have also been implicated in disease.

The same types of genetic changes that occur in genes or that alter the structure of chromosomes can affect health and development when they occur in noncoding DNA. These alterations include changes in single DNA building blocks (substitution variants), insertions, deletions, duplications, and translocations. Noncoding DNA variants can be inherited from a parent or acquired during a person’s life.

Much is still unknown about how to identify regions of noncoding DNA that have a function in cells and the roles such regions play. As a result, linking genetic changes in noncoding DNA to their effects on certain genes and to health conditions is difficult. The roles of noncoding DNA and the effects that genetic changes in noncoding DNA have on the body are growing areas of research.

Scientific journal articles for further reading

Scacheri CA, Scacheri PC. Mutations in the noncoding genome. Curr Opin Pediatr. 2015 Dec;27(6):659-64. doi: 10.1097/MOP.0000000000000283. Review. PubMed: 26382709; Free full text from PubMed Central: PMC5084913.

Chatterjee S, Ahituv N. Gene Regulatory Elements, Major Drivers of Human Disease. Annu Rev Genomics Hum Genet. 2017 Aug 31;18:45-63. doi: 10.1146/annurev-genom-091416-035537. Epub 2017 Apr 7. Review. PubMed: 28399667.

Gordon CT, Attanasio C, Bhatia S, Benko S, Ansari M, Tan TY, Munnich A, Pennacchio LA, Abadie V, Temple IK, Goldenberg A, van Heyningen V, Amiel J, FitzPatrick D, Kleinjan DA, Visel A, Lyonnet S. Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence. Hum Mutat. 2014 Aug;35(8):1011-20. doi: 10.1002/humu.22606. PubMed: 24934569; Free full text from PubMed Central: PMC4389788.