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20
| 1 | 2008
Klinisk Biokemi i Norden
(Fortsat fra side 19)
DNA variations
Almost every one of the 100 trillions (10 14) of cells in
the body has its own copy of the genome, so also with
the nucleated white blood cells in circulating blood.
Each cell has two such copies, one maternal and one
paternal, thus having two versions of every gene and
two recipes for the same protein. Even subtle differ-
ences in this recipe may lead to alternative proteins
– generating the variance responsible for making all
human beings biologically unique.
Surprisingly, 99 % of the genome is stipulated to
be identical among different human people, but nev-
ertheless, the presence of only 1 % variance accounts
for the huge phenotypic differences among individu-
als. Variations in DNA have arisen during evolution
as a consequence of mutations. As dividing cells are
produced, each new cell needs to replicate and make
its own copy of the genome, a process that is not error
free. Errors in DNA replication or other damages,
although continually proofread, bring the misincorpo-
rations into existence and a mutation - or a variation
- is born. Novel gene variants may not work as well as
the original version and usually die out within a few
generations. On the contrary, new variants may be
better than or functionally equivalent to the original
version. These good or neutral variants may increase in
frequency in the population due to chance, or because
they confer better odds for survival and successful
reproduction for the ones who have them. DNA vari-
ations may have functional consequences by altering a
protein or its rate of expression or may have no func-
tional consequences at all and constitute merely as a
positional marker in the genome.
DNA variations are often referred to as polymor-
phisms. The term polymorphism is used to indicate
that a particular DNA position has more than one
form (up to three) in the population, although each
individual will only have one or a maximum of two
forms. Classically, a distinction has beenmade between
variations and polymorphisms. A locus is only called
polymorphic if the most common variant occurs in less
than 95 % of the population. Consequently all other
variants will then occur with a total frequency of 5 %
or more (4). It is also common to distinguish between
a polymorphism and a mutation. A mutation refers
to a rare variant that is the primary cause of a clinical
phenotype or a disease, whereas polymorphism is used
to denote a variant that is present in the population
in a relatively high frequency. Polymorphisms are by
themselves more seldom sufficient to cause a disease,
but may contribute to susceptibility to a disease or to
variation in functional properties of a protein.
Single Nucleotide Polymorphisms, termed SNPs,
are the most abundant and the simplest form of DNA
variations in which a single nucleotide is replaced
by another. SNPs are classified into coding and non-
coding polymorphisms according to their position
in or around genes. Coding SNPs are further clas-
sified into synonymous and nonsynonymous varia-
tions. Synonymous codons change into another codon
coding for the same amino acid leading to no change
in the structure of the protein (silent change). Non
synonymous SNPs change the codon to one specifying
for a different amino acid and may therefore change
the protein structure. It has been estimated that the
human genome contains one sequence variant in every
200 to 1000 base pairs and that each gene on average
has 126 SNPs (5).
Other DNA variants include short and long inser-
tions/deletions (“indels”), where as one, a few or many
nucleotides may be added or removed in the genome.
These variants may lead to amino acid addition/
subtraction in the protein or to total disruption of the
protein message depending on the sequence involved.
Incorporation of transposable elements may as well
lead to radical changes at the protein level.
Microsatellite repeats is a more complex type of
DNA variation consisting of short di, tri, tetra or pen-
ta-nucleotides repeated several to hundreds of times
along the DNA. Microsatellite repeats occur in all indi-
viduals, but the length of the repeat and the position of
the sequence in the genome is of vital importance for
the extent of damage.
DNAmethylation status is another well studied gene
regulation mechanism, especially in carcinogensis.
Hypermethylation of CpG-rich islands in the promoter
regions of tumor supressor genes leads to gene silenc-
ing and is one of the most common molecular trans-
formations in a cancer cell. Hypomethylation has also
been recognized as a cause of cancer(6).
In most human cells telomerases shorten during
aging, suggesting that telomere length could be a
biomarker of aging and age-related morbidity (7).
DNA variants as Biomarkers
The introduction of DNA variations in genetic analy-
(Fortsætter side 22)
