Actionable Variation in Human Genes to Enhance Metabolic Efficiency
Abstract
Advances in DNA sequencing technology have led to a rapid expansion of human genome information and the extent of individual-level genetic variation. While many variants are neutral, many will have a physiological impact. The ability to distinguish among these groups of variants defines the critical challenge in human genetics research for the coming years as the advent of genome sequencing becomes a routine diagnostic tool. We postulate that while some genetic variation is responsible for inherited disease, a larger fraction is responsible for influencing metabolic efficiency and ultimately physical and cognitive performance in all manner of activities. It is this latter set that we are interested in characterizing and, in particular, genetic differences that compromise metabolic steps that are amenable to optimization. To identify and characterize such metabolically remedial variants, we will focus on the effects of polymorphisms in enzymes that require a vitamin or mineral cofactor. There are approximately 600 cofactor-dependent enzymes in the human proteome, many of which play key roles in cellular metabolism. Furthermore, there is precedence for the remediation of mutant enzymes with severe or mild abnormalities by straightforward vitamin/mineral supplementation. Specifically, in the proposed studies, we will concentrate on nutritional optimization of metabolic steps essential for generating cellular energy stores (ATP production and mitochondrial function). Niacin, riboflavin and thiamine are vitamins essential for bioenergetic metabolism as either enzyme cofactors or redox substrates. Thus, we propose to analyze variation in 5 enzymes necessary for the optimal utilization of these nutrients. We will interrogate all known nonsynonymous variation in these genes for effects on enzyme function as well as on metabolic output and mitochondrial function. Importantly, we will also identify which alleles are amenable to vitamin remediation and metabolic tuning. We will use these results, in combination with our previous studies, as a springboard to learn more about the prevalence and characteristics of vitamin-remedial alleles to ultimately enable prediction of such alleles from genome variation data. This pioneering work will close the gap between the description of variation of the human genome and understanding and acting upon that information.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 20, 2019
- Source ID
- W911NF1610022
Entities
People
- Jasper Rine
Organizations
- Army Contracting Command
- United States Army
- University of California, Berkeley