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

S102
outcomes for assessing nutrient adequacy and risk for
disease prevention.
Human genetic variation
The primary sequence of the human genome was determined
from 5 to 10 individuals of diverse ancestry and
geographic history. The human genome is composed of
approximately 3.1 billion nucleotide base pairs that are
organized into 24 nuclear chromosomes [12]. There are
an estimated 30,000 genes within the human genome
that encode information required for the synthesis of
all cellular proteins and functional RNA molecules,
although less than half of human genes have been
assigned known or putative functions. Only about 2%
of the total human DNA primary sequence encodes
genes. Most nuclear DNA is termed noncoding and has
structural or regulatory roles or no known roles. The
biological complexity of the mammalian cell is not limited
by the number of genes encoded by its genome. A
single gene can encode more than one RNA or protein
product through posttranscriptional and posttranslational
processing reactions, including RNA editing,
alternative splicing, and other modifications including
differential phosphorylation or methylation. Therefore,
human cells contain more than 100,000 proteins with
distinct primary sequences as a result of these processing
and modification reactions [13].
The primary nucleotide sequence of the human
genome varies by approximately 0.2% to 0.4% among
humans [14, 15]. Sequence variations are referred to
as polymorphism and constitute a primary molecular
basis for human phenotypic variation. There are
several distinct classes of polymorphism, including
single nucleotide polymorphisms (SNPs), micro- and
macrosatellite repeat sequences, and viral insertions.
SNPs are defined as common nucleotide base pair differences
in the primary sequence of DNA and are the
most common variation in human DNA.
SNPs and haplotypes
There are estimated to be more than 10 million SNPs
in the human genome; over 4.5 million SNPs were
validated as of 2004 [15]. SNPs can be single base pair
insertions, deletions, or substitutions of one base pair
for another. Nucleotide substitutions are the most
common polymorphisms, whereas insertion/deletion
mutations occur at 1/10 the frequency [16]. SNPs differ
from DNA mutations in two regards: they are present
in the germ line and therefore are heritable, and they
must have a prevalence of at least 1% in humans. The
generation of high-density SNP maps of the human
genome facilitates the identification of human disease
alleles, including low-penetrant alleles that may make
relatively small contributions to the initiation and/or
progression of complex disease [12].
DNA sequence is inherited in “blocks” that average
25,000 base pairs during meiotic recombination [13].
Therefore, SNPs that are physically close with respect
to DNA primary sequence segregate rarely and are
inherited together [13, 17]. SNPs captured within these
blocks are said to be in linkage disequilibrium, which
is defined as the nonrandom association of alleles
at a nearby locus. Linkage disequilibrium is usually
correlated with physical distance between loci but is
also influenced by distance from the centromere and
recombination frequency, which can vary throughout
the genome. Inherited blocks of genetic variation are
referred to as haplotypes, and the size of the haplotype
blocks decays as the number of meiotic recombination
events increases within a population. Ancestral
populations that maintain a high effective population
size for long periods are expected to have smaller haplotype
sizes and therefore decreased linkage disequilibrium
because of the increased number of historical
recombination and mutation events, both of which
cause linkage disequilibrium decay [12]. As predicted
from evolutionary theory, African populations display
higher levels of genetic diversity than all other human
populations whose founder groups probably exhibited
less genetic variation than the population from which
they emerged and had less time to respond to their
new environments. African linkage disequilibrium patterns
exhibit a greater number of haplotypes and more
divergent patterns of linkage disequilibrium than non-
African populations [12]. Linkage disequilibrium in the
Nigerian population extends an average distance of 5
kilobases, whereas European linkage disequilibrium
can extend nearly 60 kilobases, a finding consistent
with the increased number of recombination events
that have occurred in ancestral populations [12]. Haplotype
maps of human genetic variation offer advantages
for disease associational studies because of their
reduced complexity compared with SNP maps [18], but
their utility may be limited because of the variability
in haplotype diversity across candidate genes [19].
Furthermore, haplotype associations do not identify
disease-causing mutations due to genetic hitchhiking
[12] (polymorphisms that are in linkage disequilibrium
with a mutation that is under selection will change in
frequency along with the site undergoing selection).
Because otherwise rare disease alleles can be enriched
in geographically or culturally isolated populations,
full characterization of SNP diversity and haplotype
structure from ethnically diverse populations is critical
for the identification of risk alleles that may be specific
to small but identifiable subpopulations.
Transposable elements
P. J. Stover
Genetic variation can also result from the integration
and/or transposition of viral DNA. Approximately half