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It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.
Micronutrients are involved in specific biochemical pathways and have dedicated functions in the body, but they are also interconnected in complex metabolic networks, such as oxidative-reductive and inflammatory pathways and hormonal regulation, in which the overarching function is to optimise health. Post-genomic technologies, in particular metabolomics and proteomics, both of which are appropriate for plasma samples, provide a new opportunity to study the metabolic effects of micronutrients in relation to optimal health. The study of micronutrient-related health status requires a combination of data on markers of dietary exposure, markers of target function and biological response, health status metabolites, and disease parameters. When these nutrient-centred and physiology/health-centred parameters are combined and studied using a systems biology approach with bioinformatics and multivariate statistical tools, it should be possible to generate a micronutrient phenotype database. From this we can explore external factors that define the phenotype, such as lifestage and lifestyle, and the impact of genotype, and the results can also be used to define micronutrient requirements and provide dietary advice. New mechanistic insights have already been developed using biological network models, for example genes and protein-protein interactions in the aetiology of type 2 diabetes mellitus. It is hoped that the challenge of applying this approach to micronutrients will, in time, result in a change from micronutrient oriented to a health oriented views and provide a more holistic understanding of the role played by multiple micronutrients in the maintenance of homeostasis and prevention of chronic disease, for example through their involvement in oxidation and inflammation.
Personalised, genotype-based nutrition is a concept that links genotyping with specific nutritional advice in order to improve the prevention of nutrition-associated, chronic diseases. This review describes the current scientific basis of the concept and discusses its problems. There is convincing evidence that variant genes may indeed determine the biological response to nutrients. The effects of single-gene variants on risk or risk factor levels of a complex disease are, however, usually small and sometimes inconsistent. Thus, information on the effects of combinations of relevant gene variants appears to be required in order to improve the predictive precision of the genetic information. Furthermore, very few associations between genotype and response have been tested for causality in human intervention studies, and little is known about potential adverse effects of a genotype-derived intervention. These issues need to be addressed before genotyping can become an acceptable method to guide nutritional recommendations.
Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene–nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient–genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries.
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