Shortcut Map Could Simplify The Hunt For Disease-Causing Genes
March 19, 2013

Shortcut Map Could Simplify The Hunt For Disease-Causing Genes

April Flowers for - Your Universe Online

Certain diseases are caused by single gene mutations, and with current techniques for identifying the disease-causing gene producing hundreds of potential gene candidates, it is difficult for scientists to pinpoint the single causative gene. New research led by Rockefeller University scientists has led to the creation of a map of gene "shortcuts" to simplify the hunt for disease-causing genes.

Yuval Itan, a postdoctoral fellow in the St. Giles Laboratory of Human Genetics of Infectious Diseases, spearheaded the investigation that has led to the creation of what he calls the human gene connectome. The connectome is the full set of distances, routes (the genes on the way), and degrees of separation between any two human genes. Itan, a computational biologist, says the program he designed to generate the connectome uses the same principles GPS navigation uses to plan a trip between two locations.

The research team reported their findings in the online early edition of Proceedings of the National Academy of Sciences (PNAS).

"High throughput genome sequencing technologies generate a plethora of data, which can take months to search through," says Itan. "We believe the human gene connectome will provide a shortcut in the search for disease-causing mutations in monogenic diseases."

The team designed applications for use of the human gene connectome, beginning with a gene called TLR3, which is important for resistance to herpes simplex encephalitis — a life threatening infection from the herpes virus that can cause significant brain damage in genetically susceptible children. Previous research from the St. Giles laboratory, led by Jean-Laurent Casanova, revealed children with HSE have mutations in TLR3 or in genes that are closely functionally related to TLR3. To follow the GPS metaphor, these genes are biologically a short distance from TLR3, leading scientists to believe novel herpes simplex encephalitis-causing genes are also expected to have a short biological distance from TLR3.

The team included researchers from the Necker Hospital for Sick Children, the Pasteur Institute in Paris, and Ben-Gurion University in Israel. They tested the capability of the human gene connectome to predict a disease-causing gene by sequencing exomes, (which are all DNA of the genome that is coding for proteins), of two patients recently shown to carry mutations of a separate gene, TBK1.

"Each patient's exome contained hundreds of genes with potentially morbid mutations," says Itan. "The challenge was to detect the single disease-causing gene."

The researchers sorted the genes by their predicted biological proximity to TLR3, finding TBK1 at the top of the list in both patients. They successfully predicted two other genes, EFGR and SRC, as part of the TLR3 pathway before they were experimentally validated, using the TLR3 connectome. They applied other gene connectomes — the set of all human genes sorted by their distance to a particular gene — to detect Ehlers-Danlos syndrome and sensorineural hearing loss disease causing genes.

"The human gene connectome is, to the best of our knowledge, the only currently available prediction of the specific route and distance between any two human genes of interest, making it ideal to solve the needle in the haystack problem of detecting the single disease causing gene in a large set of potentially fatal genes," says Itan. "This can now be performed by prioritizing any number of genes by their biological distance from genes that are already known to cause the disease.

"Approaches based on the human gene connectome have the potential to significantly increase the discovery of disease-causing genes for diseases that are genetically understood in some patients as well as for those that are not well studied. The human gene connectome should also progress the general field of human genetics by predicting the nature of unknown genetic mechanisms."