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

Human nutrition and genetic variation
of noncoding human DNA originates from the insertion
of highly mobile and repetitive sequences termed
transposable elements. There are two types of transposable
elements, retrotransposons and DNA transposons
[20–22]. Retrotransposons are classified by size and
include long interspersed nuclear elements (LINEs)
and short interspersed nuclear elements (SINEs).
About 10% of the human genomic sequence consists of
280 base pair Alu SINE elements; there are an estimated
1.4 million in the human genome. Alu elements display
promoter activity, but their transcripts lack an open
reading frame and therefore are not translated. Alu
elements are rich in the dinucleotide sequence CpG,
which is also common in promoter regions of mammalian
genes and is recognized by DNA methylases
that convert CpG sequences to me CpG. Methylation of
CpG sequences within Alu elements usually silences
their promoter activity. Transposable elements are
mutagenic; they can integrate within and disrupt a
gene and can also serve as nucleation sites for unequal
intrachromosomal and interchromosomal homologous
recombination events that lead to chromosomal aberrations,
including deletion and translocation events.
New Alu insertions have been associated with 0.1% of
human genetic disorders, including Apert syndrome,
cholinesterase deficiency, and breast cancer. Other
inherited disorders, including type 2 insulin-resistant
diabetes and familial hypercholesterolemia, comprise
part of the 0.3% of human genetic disease that results
from Alu-mediated unequal homologous recombination
events [12, 22]. Such events are rare, because
Alu-mediated unequal homologous recombination
events are usually inhibited by CpG methylation of
the insertion.
Human populations are polymorphic for viral insertions
[12]. More than 1,200 Alu elements integrated
into the human genome following early human migrations;
a new Alu insertion event occurs every 200 births
[22]. Alu element insertions can alter gene function
and stability around their region of integration and are
thought to be catalysts for organismal evolution [22,
23]. Transposition events that occur near or within
a gene can alter its expression or create a new gene.
Alu elements can function as transcriptional silencers
or activators; some Alu elements have retinoic acid
response elements and therefore can confer new types
of transcriptional regulation to genes neighboring
the insertion site. Alu insertions near gene promoters
can also confer transcriptional regulation by DNA
methylation to that locus because they contain CpG
sequences. The degree of transcriptional silencing
is modifiable by diet [24]. For example, embryonic
CpG methylation density can vary proportionately
with folate status at defined loci during development
[25, 26]. Maternal folate and other methyl donor supplementation
alters the methylation status of targeted
alleles in the mouse embryo, and these methylation
S103
patterns and subsequent effects on gene expression are
retained throughout adulthood [24]. This type of epigenetic
phenomenon may provide mechanistic insight
into the many observational studies that associate risks
of adult chronic diseases with maternal nutrition and
embryonic nutrient exposures [27].
Nutrition and the origin of human genetic
variation
Organismal evolution is driven in part by complex and
reciprocal interactions among genomes and environmental
exposures that result in adaptive phenotypes.
Modern human genetic variation is, in part, a product
of such historical interactions and is manifest through
the formation and propagation of primary sequence differences
in DNA. Changes in DNA primary sequence
constitute the molecular basis for human evolution and
for the generation of adaptive genes that alter an organism’s
response to environmental challenges and hence
to its fitness. Genomic polymorphism arises through
the sequential processes of genetic mutation, followed
by expansion of the mutation within a population;
environment influences both of these processes.
Mutation
Mutation is a consequence of the inherent chemical
instability of DNA bases, stochastic error associated
with DNA replication and recombination, and exposure
to chemical radicals generated during oxidative
metabolism as well as by environmental toxins. Therefore,
a significant portion of mutations are not modifiable,
although DNA repair systems detect and correct
most mutation events. Environmental exposures and
cellular oxidative stress can accelerate DNA mutation
rates by inducing DNA modification reactions
and/or accelerating DNA polymerase error rates. For
example, nutrient deficiencies of iron or B vitamins
impair nucleotide biosynthesis and thereby enhance
polymerase error rates. Folate deficiency inhibits
dTMP synthesis, which increases the incorporation of
dUTP into DNA, resulting in increased rates of single
point mutations as well as increased frequency of DNA
strand breaks [28–32]. Mutation rates are also accelerated
by radiation, cellular oxidative stress, and natural
and synthetic genotoxic xenobiotics that are present in
the food supply. Certain aflatoxins, a common class of
natural xenobiotics, increase DNA mutation rates, leading
to the transformation of somatic cells and localized
cancer epidemics [33]. Furthermore, deficiencies of
dietary antioxidants that scavenge chemical radicals,
or excesses of prooxidant nutrients, including iron,
may increase mutation rates [34–36]. However, only
mutations that occur in the germ line contribute to a
species’ heritable genetic variation.