Jumat, 08 Juli 2016

Health Implication of Individual Genomic Variability

source: www.seven-health.com/

The human genome is a complicated blueprint of information. While all
DNA has four relatively simple bases (adenine, guanine, cytosine, and thymidine),
their sequence can have a pronounced effect on what ultimately evolves.
The nearly 3 billion base pairs (3.2 Gb) in the human genome constitute what is
sometimes affectionately called the ‘genome encyclopedia’. If a gene is analogous
to a word, then a chromosome must be a chapter and the genome the whole
book. Similar to a word, a gene may have a single or multiple meanings, and can
be influenced by the context in which it is expressed. Like a chapter, a chromosome
is a large collection of genes organized into a linear string of information.
The complete set of chapters is necessary to form the ‘book’ of information that
comprises the genetic blueprint of each and every organism.
The size of this blueprint is illustrated by assuming each DNA basis creates
a series of words each of which contain 5 characters. Thus, about 600 million
words could be generated from the human genome. If these words were
compiled to an average of 12 words per line then an equivalent of about 50,000
text lines would be generated. Since an average page only has about 70 lines,
this would mean the human genome would contribute about 700,000 pages. If
these pages were assembled into an encyclopedia with 1,000 pages in each volume,
there would be about 700 volumes for late-night reading and enjoyment!
Even this analogy is overly simplistic, since it does not take into consideration
genetics, epigenetics, proteomics and metabolomics variations that occur
within and among individuals. Human genetic predictions are exceedingly
complicated by the presence of comparatively long and variable intron sequences
[13]. These intron sequences (noncoding DNA regions) interrupt the sequences
containing instructions for making a protein (exons). The panoramic views of
the human genome have already begun to reveal a wealth of information and
some early surprises. While much remains to be deciphered in this vast information
source, several fundamental principles have emerged. It is safe to conclude that the more we learn about the human genome, the more there will be to learn.
Interestingly, the coding region of a gene (exons) which is the portion of DNA
that is transcribed into mRNA and translated into proteins only constitutes
about 1.5% of the human genome [14]. Furthermore, transcription units, consisting
of exons, introns, and the regulatory region, constitute about 20% of the
entire human genome. One must wonder if the remainder is simply a filler or
has a yet to be defined role. Evidence already exists that multiple gene messages
can be derived from a single stretch of DNA based on alternative uses of
promoters, exons, and termination sites. Adding to these overlapping transcription
units, somatic recombination events and the existence of highly similar
gene families and pseudogenes make it difficult to identify and categorize
genes. Regardless, the fundamental premise of genomics is that DNA reading
results in the formation of messenger RNA which then codes from proteins
which ultimately bring about changes in small-molecular-weight compounds
and in cellular processes (fig. 2).

It is already known that human genome variability can arise for several
reasons including single nucleotide changes (polymorphisms), deletions, insertions,
and translocations. Translocations and gross deletions are important
causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly
distributed in the human genome as a consequence of selection for
growth advantage and/or the inherent potential of some DNA sequences to be
frequently involved in breakage and recombination. Alu insertional elements,
the most abundant class of short interspersed nucleotide elements in humans,
are dimeric sequences approximately 300 bp in length derived from the 7SL
RNA gene. About 500,000 to 1 106 Alu units are dispersed throughout the human haploid genome primarily in AT-rich neighborhoods located within
larger GC dense chromosomal regions. These sequences contain a bipartite
RNA polymerase III promoter, a central poly-A tract, a 3 poly-A tail, numerous
CpG islands and are bracketed by short direct repeats. Such insertions are
associated with a number of disease states [15].
Restriction fragment length polymorphisms, short tandem repeats, and
variable-number tandem repeats are also present in the genome. Intraspecies
variation in the length of DNA fragments generated by the action of restriction
enzymes or caused by mutations that alter the sites at which these enzymes act
can change the length, number, or production of fragments. Restriction fragment
length polymorphism is a term used in two related contexts: as a characteristic
of DNA molecules (arising from their differing nucleotide sequences)
by which they may be distinguished, and as the laboratory technique which uses
this characteristic to compare DNA molecules. The short tandem repeats are
tandemly repeated DNA sequences of a pattern of length from 2 to 10 bp [for
example (CA)n(TG)n in a genomics region] and the total size is lower than
100 bp. Repeated sequences represent a large part of eukaryotic genomes.
Single nucleotide polymorphisms (SNPs) are the most common DNA
sequence variation. They occur when a single nucleotide in the genome is
altered. A variation in the incidence must occur in at least 1% of the population
to be considered an SNP. Huntington’s disease, cystic fibrosis, and muscular
dystrophy are examples of diseases which are linked to a single gene polymorphism
[16]. While we have known about the genetics of these diseases for a
number of years, reliable and effective therapies have remained largely elusive.
Cancer and possibly several other chronic diseases are likely a result of multiple
genetic shifts and thus present an even more daunting task for understanding
the disease but are important for developing strategies for prevention and/or

Figure : Relationship between dietary components and genomic regulation.

Fortunately, the majority of SNPs do not appear to cause disease; however,
they may assist in determining the likelihood that a particular abnormality may
occur [17]. Nevertheless, some SNPs have been linked to an increased disease
risk. For example, a gene associated with Alzheimer’s disease is apolipoprotein
E. This gene can contain two SNPs which may result in three possible alleles:
E2, E3, and E4. Each allele differs by one DNA base, and the protein product of
each gene differs by one amino acid. Typically an individual inherits one maternal
and one paternal copy of a gene. Research has shown that an individual who
inherits at least one E4 allele has a greater risk of developing Alzheimer’s disease,
presumably as a result of the one amino acid substation in the E4 protein
which influences its structure and function. Inheriting the E2 allele, on the other
hand, appears to protect against Alzheimer’s disease. Of course, SNPs are not
absolute since those inheriting two E4 alleles do not always develop Alzheimer’s disease [18].

Thus, other factors or events, including the environment (diet),
may affect the disease risk. It is certainly possible that either internal or external
stressors set the stage for when bioactive food components are most effective.
Thus, expanded knowledge about genetic and environmental interactions is
fundamental to unraveling global variation in the incidence and/or severity of
several disease states. Evidence is already surfacing that genetic variation can
influence the propensity for the initiating event, the progression to a clinical
disease state, and the trajectory of several diseases. For example, the interleukin
1 family of cytokines has a critical role in mediating inflammation, which is
considered a factor in many chronic diseases, including coronary artery disease,
rheumatoid arthritis and cancer. Recent research has identified several
sequence variations in the regulatory DNA of the genes coding for important
members of the interleukin 1 family, and these variations are associated with
differential effects on the inflammatory response [17]. While inconclusive, evidence
is beginning to surface that the physiological relevance of such genetic
variation can be modified by the foods that are consumed.

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