A molecular mechanism explains why individuals carrying identical gene mutations for a disease end up with different severity or symptoms of the condition. Photo by gopixa/Shutterstock
Aug. 20 (UPI) -- A molecular mechanism has been found that explains why individuals carrying identical gene mutations for a disease end up having different severity or symptoms of the condition.
Researchers at the New York Genome Center and Columbia University studied this phenomenon, called variable penetrance, in which the severity of the effect of disease-causing variants differs among individuals who carry them. Their findings were published Monday in the journal Nature Genetics.
"Our findings suggest that a person's disease risk is potentially determined by a combination of their regulatory and coding variants, and not just one or the other," Dr. Tuuli Lappalainen, an assistant professor at Columbia University's Department of Systems Biology, said in a press release. "Most previous studies have focused on either looking for coding variants or regulatory variants that affect disease in these individuals or potentially looking at common variants that could affect disease. We have merged these two fields into one clear hypothesis that uses data from both of them, which was fairly unheard of before."
The researchers developed their hypothesis based on variants that regulate genes could also play a role in modifying coding differences for the same gene.
The researchers analyzed data from the Genotype-Tissue Expression project, which is a large catalog of genetic variants that affect gene expression in humans.
They found enriched regulatory and coding variants, called haplotypes, that are protective against disease by decreasing the penetrance of coding variants associated with disease development. They expected this situation in people without disease.
Then, they analyzed data from the National Institutes of Health's The Cancer Genome Atlas and the Simons Simplex Collection, a permanent repository of genetic samples from 2,600 families. One of their children was affected with an autism spectrum disorder as well as unaffected parents and siblings.
In the cancer patients and individuals with autism, there was enrichment of haplotypes predicted to increase the number of coding variants associated with cancer and autism spectrum disorder.
Finally, they used CRISPR/Cas9 genome editing technology to test the modified penetrance hypothesis with a coding variant known to be associated with a disease -- a coding variant associated with Birt-Hogg-Dube Syndrome, a rare hereditary disease that increases the risk of certain types of tumors.
By editing syndrome into a cell line on different haplotypes with a regulatory variant, they found it indeed modified the effect of the coding disease-causing variant.
"In future, studies of the genetic causes of severe diseases should take into account this idea that regulatory variants need to be considered alongside coding variants," Dr. Stephane Castel, a post-doctoral research fellow, said. "This should eventually lead to a more fine-grained understanding of the risk of coding variants associated with disease."