Exploiting Single Nucleotide Polymorphisms for Extreme Performance

Advances in DNA sequencing technology have generated a rapid expansion of human genome information and the revelation of extraordinary individual-level genetic variation.  Individual genome sequencing will soon be routine and cost-effective.  To exploit this resource to the benefit of warfighters, we propose an approach for identifying and characterizing genetic variants that compromise metabolic efficiency (and ultimately physical and cognitive performance) yet are amenable to nutritional optimization.  There are 600+ cofactor-dependent enzymes in the human proteome, and preliminary studies provide ample precedence for the remediation of dysfunctional enzyme variants by simple vitamin/mineral supplementation. We describe a technology platform in which all possible enzyme variants are functionally assessed and pre-determined for each enzyme/gene.  These datasets will serve to rapidly identify carriers of variant enzymes who can metabolically benefit from cofactor supplementation.  In Phase I, the key technical aspects of the approach have been validated.  These include:  1) generating comprehensive variant libraries of target genes through a simple, minimal-step process for functional testing, and 2) assessing function of all possible single-nucleotide variants simultaneously by quantitative complementation in a model organism (the yeast, Saccharomyces cerevisiae).  The validation of these processes makes gene atlas generation achievable at a scale large enough to provide meaningful data for genome interpretation.  In a first-use scenario, these studies will facilitate Phase II efforts to query all genes (N = 13) related to clearance of homocysteine, an intermediary metabolite in methionine/one-carbon pathways.  Elevated homocysteine levels can have adverse effects on physical performance and cardio-respiratory fitness, though the metabolic steps surrounding homocysteine are amenable to nutritional “tuning”.  Specifically, we will define the functional impact of all possible single-nucleotide changes within this metabolic cassette to serve as an information resource used to identify at-risk individuals.  These finding will spur a field trial in which individual genotype and metabolite profile are diagnostic for potential performance enhancement, as well as define a first product for subsequent commercialization.  This pioneering work will render genome sequence an asset to improve health, fitness and readiness.