Scientists create map of gene 'shortcuts'

Scientists have generated the full set of distances, routes and degrees of separation between any two human genes, creating a map of gene 'shortcuts' to simplify the hunt for disease-causing genes.
Some diseases are caused by single gene mutations. Current techniques for identifying the disease-causing gene in a patient produce hundreds of potential gene candidates, making it difficult for scientists to pinpoint the single causative gene.
Yuval Itan, lead researcher from Rockefeller University said the computer programme he developed to generate the connectome uses the same principles that GPS navigation devices use to plan a trip between two locations.
"High throughput genome sequencing technologies generate a plethora of data, which can take months to search through," said Itan.

"We believe the human gene connectome will provide a shortcut in the search for disease-causing mutations in monogenic diseases," Itan said in a statement.
Researchers began 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.

Researchers in the St Giles lab, headed by Jean-Laurent Casanova, previously showed that children with HSE have mutations in TLR3 or in genes that are closely functionally related to TLR3.
In other words, these genes are located at a short biological distance from TLR3. As a result, novel herpes simplex encephalitis-causing genes are also expected to have a short biological distance from TLR3.

To test how well the human gene connectome could predict a disease-causing gene, the researchers sequenced exomes - 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. The challenge was to detect the single disease-causing gene," said Itan.
After sorting the genes by their predicted biological proximity to TLR3, Itan and his colleagues found TBK1 at the top of the list of genes in both patients.
The researchers also used the TLR3 connectome - the set of all human genes sorted by their predicted distance from TLR3 - to successfully predict two other genes, EFGR and SRC, as part of the TLR3 pathway before they were experimentally validated, and applied other gene connectomes to detect Ehlers-Danlos syndrome and sensorineural hearing loss disease causing genes.

The study was published in the journal Proceedings of the National Academy of Sciences.