A new study finds individuals who appear healthy despite having mutations associated with severe childhood diseases, a finding that could help uncover factors that protect against these diseases. “Finding those individuals is the starting point for searching for the other changes, for example in the genome, that might give us clues to develop therapies,” says study senior author Stephen Friend, a cancer biologist at non-profit research organization Sage Bionetworks in Seattle, WA.
Friend started the large-scale Resilience Project in 2014 along with co-author Eric Schadt at the Icahn School of Medicine at Mount Sinai. The goal of the project is to identify “resilient” individuals who carry genes for severe childhood diseases without falling sick. (See also The Genetic Mutations You Want) The new study, published online on April 11, 2016 in Nature Biotechnology, is a proof-of-concept that the technology exists to find such individuals, Friend says. “We now have tools that allow us to search for people who should have gotten sick among normal individuals.”
Scientists have known for decades that some individuals carry genes for severe diseases without being affected by them. “But such individuals are rare,” notes Michael Bamshad, a geneticist at the University of Washington who was not involved in the study. “So the human genetics community has been eagerly awaiting the release of big data sets that could be mined to identify persons predicted to have a severe condition but who don’t.
The new study searched genomic and genotypic data generated by several organizations, including The Cancer Genome Atlas, the 1000 Genomes Projects, and nearly 400,000 samples from genetic testing company 23andMe. The researchers analyzed the genomes of nearly 600,000 individuals to look for more than 800 gene mutations associated with nearly 600 distinct childhood disorders. They focused on Mendelian diseases, those caused by a mutation in a single gene.
The team initially found more than 15,000 candidates with mutations in at least one gene associated with a severe childhood disease. “We thought ‘wow, it’s going to be a lot,’” says Friend. After one round of careful filtering using bioinformatics, which included weeding out individuals whose genetic data wasn’t of sufficient quality, they were left with 303 candidates. Manual reviews and sequencing then verified that the candidates were healthy individuals and truly had mutations that should have caused disease. That left 13 individuals who were “resilient” to one of eight severe childhood diseases, including cystic fibrosis.
But the terms of the informed consent did not allow the researchers to recontact the 13 individuals they identified. The scientists were left with information about specific genotypic markers, not whole genome sequences, and hence could not scour entire genomes to uncover the factors responsible for resilience. “It’s almost as if you got to take the wrapping off the box and you couldn’t open the box up,” says Friend.
Kym Boycott, a clinician scientist at Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, who was not involved in the study, says, “This really is the first group to ever try to do this, so I find that incredibly exciting. It’s brave, it’s innovative, and it’s pointing us in the direction that we need to go.” She hopes such insights will eventually lead to protective therapies not just for childhood disorders, but for adult onset diseases as well.
Boycott says the lack of follow-up was the biggest limitation of the study. “That’s just the nature of where we’re at with respect to data sharing and the datasets we have available,” she says. “With this pilot information in hand, we can then move on to the bigger studies.”
Friend and his collaborators are now gearing up for a larger scale prospective study in which participants will be given consent forms that allow them to be re-contacted. This time, says Friend, they’re hoping to get millions of samples.