Implementing food-based dietary guidelines for - United Nations ...

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S104 DNA mutation rates and polymorphism frequencies vary throughout the human genome. These differences have been attributed to the region-specific differences in DNA recombination rates (sites of more frequent recombination may exhibit elevated mutation rates), the mutagenic potential of specific nucleotide sequences, and local chromatin structure [12, 37]. For example, the sequence CpG is underrepresented in the human genome and its frequency has decayed throughout evolution because of its inherent instability [38]. Methylation of CpG sequences increases mutation rates, because methylcytosine ( me C) deaminates spontaneously to thymidine (T), whereas cytosine (C) deaminates to uracil (U), which is recognized as foreign to DNA and excised by the DNA repair enzymes [16]. Selection Mutation of the germ line is necessary but not sufficient for the creation of genetic variation. Germ line mutation that does not affect or confer function is assumed to be both phenotypically silent and selectively neutral, and therefore its frequency is exclusively a function of the DNA mutation rate (estimated to be 2.5 × 10 –8 on average for autosomes in regions of the genome presumed to be nonfunctional, including intronic and intergenic regions) [12, 16]. Only mutations that expand and become fixed within a population contribute to human genetic variation. Mutations that become fixed within a population contribute to genetic variation as polymorphisms, and this expansion is the basis for the molecular evolution of genomes. Fixation is a function of effective population size, population demographic history, and the effect of the mutation on an organism’s fitness [12]. Polymorphisms expand within a population through the processes of genetic drift and natural selection. Drift is a stochastic process that results from random assortment of chromosomes at meiosis, because only a fraction of all possible zygotes are generated or survive to reproduce [12]. Therefore, mutations can expand from one generation to the next through the random sampling of gametes in the absence of selection. Drift generally has a greater impact on allele frequencies in small populations that are expanding rapidly. Drift in static large populations is not usually as significant because of the greater dilutional effect of such populations. Genetic drift can have a greater than expected impact in large populations when they undergo bottlenecks (massive reductions in population) or founding events that have occurred during human migrations, e.g., in population groups that include the Old Order Amish, Hutterite, and Ashkenazi Jewish [12]. In these populations, rare disease alleles can expand rapidly and increase the incidence of disease, including breast cancer, Tay- Sachs, Gaucher, Niemann-Pick, and familial hyper- P. J. Stover cholesterolemia [12]. It is assumed that the majority of human genetic variation arose as a result of the neutral processes of mutation and genetic drift and rarely has physiological consequences. The neutral theory of evolution does not account for the proportion of amino acid substitutions observed in mammalian genomes [6, 37, 39, 40]. Although proteincoding sequences are conserved among mammals in general, rates of amino acid substitution vary markedly among proteins compared with rates of synonymous substitution among genes (changes in the coding region of genes that do not affect protein sequence) [37]. Whereas patterns of genetic variation across the entire human genome are affected by the demographic histories of populations, variation at particular genetic loci is influenced by the effects of natural selection, mutation, and recombination [12]. Mutations that alter amino acid sequence may influence protein structure and function, and the resulting physiological consequences may be beneficial, deleterious, or neutral and thereby may influence an organism’s fitness in specific environmental contexts. Likewise, mutations that affect protein expression level can alter metabolism and other physiological processes and therefore are also under constraint and subject to positive, balancing, or negative selection. Natural selection, which is the differential contribution of genetic variants to future generations, is the only evolutionary force that has adaptive consequences [41]. Darwinian selection favors the maintenance and expansion of favorable mutations (by positive or balancing selection) and the elimination of mutations that are deleterious (referred to as negative or purifying selection). Positive selection increases the rates of fixation at defined loci within the genome, indicating that not all genes are expected to evolve at the same rate. Adaptive mutations expand within populations at accelerated rates relative to neutral mutations and replace a population’s preexisting variation. The proportion of amino acid substitutions that result from positive selection is estimated to be 35% to 45% [37]. Comparison of genomic sequence divergence among mammalian species (to identify ancient selection) and comparison of the diversity of genomic sequences among human populations (to identify more recent selection following human migrations out of Africa) are complementary approaches that have permitted the identification of genes that have undergone accelerated or adaptive evolution (table 1) [6, 42]. Rapidly evolving genes are inferred to have enabled adaptation and thus became fixed in populations by positive or balancing selection. Genes that have been subject to positive selection exhibit specific genomic signatures, which include an excess of rare variants within a population (which can be indicative of a selective sweep), large allele frequency differences among populations, and
Human nutrition and genetic variation TABLE 1. Diet-related genes and pathways that display genomic signatures of adaptive evolution Gene Species/function Reference Lysozyme Langur monkey 37, 117, 118 Ribonuclease Langur monkey 37, 118 Cox4 Primates 119 LCT Human lactose metabolism 52 ADH1B Human ethanol metabolism 59 ALDH2 Human ethanol metabolism 61 HFE Human iron homeostasis 55 PPARg Human nuclear receptor 41 PTC Human bitter-taste receptor 72 KEL Human protein metabolism 42 TRPV5 Human calcium transport 42 TRPV6 Human calcium transport 42 ABO Human protein metabolism 42 ACE2 Human protein metabolism 42 CYP1A2 Human arylamine metabolism 120 G6PD Human NADP metabolism 65 Pathway Amino acid metabolism Amino acid transport Purine metabolism Human, chimpanzee 6 Chimpanzee 6 Chimpanzee 6 a common haplotype that remains intact over long distances [23, 41–43]. These genomic signatures are expected to arise from region-specific selective factors and therefore concentrate in specific geographic regions where the selection occurred [12]. Signatures of positive selection can be used to predict the geographic origins of an individual to the degree that different selective pressures are operative across populations, but they do not always correspond to specific ethnic or racial groups because races are not homogeneous [15, 44]. Understanding the historical selection of gene variants enables the identification of human disease alleles that arose from nutritional challenges, including single-gene as well as low-penetrant complex disease alleles [12, 42]. The common disease-common variant hypothesis predicts that disease-susceptibility alleles will exist at high frequency across all human populations and therefore arose prior to human migrations out of Africa [45, 46]. However, both single-gene disorders, including cystic fibrosis and hemochromatosis, and complex diseases are also associated with less common and geographically restricted alleles that arose after migrations out of Africa [15, 23, 42, 47–49]. Therefore, although 85% to 90% of all human genetic variation is found within populations, some of the 10% to 15% of variation among populations arose S105 from recent selective pressures that contribute to both simple and complex disease [50, 51]. In fact, many of the human alleles known to affect metabolism, food tolerance, or optimal nutrient intake display signatures of positive selection (table 1); some examples are described below. Lactose and calcium metabolism The metabolism of lactose requires expression of the enzyme lactase-phlorizin hydrolase encoded by the LCT gene. LCT expression declines after weaning in most mammals, including most humans, resulting in primary lactose intolerance. The expression of LCT persists into adulthood for some human populations, including humans of northwest European descent and nomads of the Afro-Arabian desert region. An SNP was identified 14 kilobases upstream of the LCT transcriptional initiation site in a cis-acting transcriptional element that is enriched in individuals of northern European descent and displays genomic signatures of positive selection [11, 52, 53]. Its prevalence correlates with, but does not account fully for, the persistence of LCT expression and resistance to primary lactose intolerance throughout adulthood [53]. The benefits of milk consumption in cattle-herding populations, both as a source of liquid in arid regions and for prevention of rickets and osteomalacia in regions of low solar irradiation, may have driven the fixation of this polymorphism [43, 52, 54]. The need for efficient calcium absorption may also have driven alleles for TRPV5 and TRPV6 to fixation in the same populations (table 1) [42]. Iron metabolism Hereditary hemochromatosis is a recessive iron-storage disease prevalent in populations of European descent with an incidence of 1 in 300 persons. A common polymorphism in the HFE gene (C282Y), which encodes a protein that regulates iron homeostasis, is associated with the disease phenotype in 60% to 100% of Europeans and arose approximately 138 generations ago [23, 55, 56]. The HFE C282Y allele is not present in Asian and African populations where iron-storage diseases exist; mutations in other genes are also associated with the phenotype. The penetrance of the C282Y HFE allele for the iron overload phenotype varies widely among homozygotes, with some individuals being asymptomatic, indicating the presence of modifying alleles. The recent expansion of this polymorphism may have conferred selective advantages in iron-poor environments [55, 56] or resistance to microbial infection [57]. Alcohol metabolism The efficiency of ethanol metabolism varies widely among human ethnic populations [58]. ADH encodes the enzyme alcohol dehydrogenase, which oxidizes
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Contents International harmonizatio
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Executive summary Harmonization of
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Executive summary [11]. These are l
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Executive summary and converted to
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Executive summary very rapidly and
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Executive summary References Concep
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Introduction Janet C. King and Cutb
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Introduction References 1. King JC,
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Terminology and framework for nutri
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Nutrient risk assessment: Setting u
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Setting upper levels for nutrient r
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Establishing nutrient intake values
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Methods for using nutrient intake v
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