The Mount Sinai Resilience Project, a genomics research effort for protective alleles, and the Ion Proton System

There is a growing interest in the healthy genetics of aging. Earlier this year, a collaboration between Life Technologies Corporation and several research groups resulted in the publication of a paper in Genome Research analyzing the genome of a super-centenarian, an individual whose blood samples at 80 years and 115 years of age were analyzed for cumulative mutations over time, as well as making a whole-genome dataset available for further research.

With an ‘n=1’ dataset however, many more samples from super-centenarians would need to be collected, sequenced and analyzed, and there are several efforts underway, both private (such as Calico and the Human Longevity Institute) and public (such as the New England Centenarian Study at Boston University and the Longevity Genes project at Albert Einstein University.

Recently, Stephen Friend of Sage BioNetworks and Eric Schadt of Mt. Sinai School of Medicine wrote a Perspective in the May 26 issue of Science entitled “Clues from the Resiliant”. In it they lay out an approach that finds healthy individuals that have clear disease-causing mutations that are somehow ‘buffered’ by protective alleles. This effort, called the Resilience Project, aims to recruit healthy volunteers for targeted sequencing of their genomes to look for highly penetrant, disease-causing mutations, and they know that it will take a large volunteer effort to do so.

The potentially disease-causing mutations found in research are highly penetrant, and catastrophic in nature. To-date, there are 127 catastrophic Mendelian disorders with specific genes responsible^*. These diseases manifest themselves before the age of 18, and so what the Resilience Project aims to identify is a small minority of ‘hero’ genomes where the individual harbors a clearly deleterious mutation but is healthy at the age of 40 or older.

Their Science Journal perspective gives in-depth background of the scientific underpinning for their approach, and this theory of genetic buffering that dates back to 2001. As a proof-of-concept, Dr. Friend and Dr. Schadt collected healthy volunteers whose whole-genome sequence, whole-exome sequence, or whole-genome genotyping datasets were available, more than 500,000 in total. Of these 500,000, they were able to determine 10 individuals who fit the ‘genetic hero’ profile: they had mutations in their genome that should have given them serious disease in childhood, but lead healthy, ordinary lives.

Their goal is to sequence 50,000 volunteers the first year, with an over goal of 1 million within three years. They are actively seeking volunteers for the Resilience Project through their website, and have made a TED video available to learn more about this project and the hunt for genetic heroes.

One challenge is doing the sequencing of all Mendelian disorder genes, and to this end the Mount Sinai School of Medicine designed a 26,000-amplicon Ion AmpliSeq™ Custom Research Panel and after sequencing on the Ion Proton™ System chose Ion Torrent for their new sequencing facility under construction in Connecticut. They have cited the low-cost, fast turnaround time and accuracy of the Ion AmpliSeq^TM Custom Panels as the reasons for their choice.

After identifying the few-dozen samples from the million-sample effort, much will undoubtedly be learned about the mechanism of buffering against the harmful effects of the known mutated causative gene, and could represent major progress in understanding the biology of health and disease in the future.