"polymorphism" - Color Atlas of Genetics, - Eberhard Passarge

Genetic polymorphism is the existence of variants
with respect to a gene locus (alleles), a
chromosome structure (e.g., size of centromeric
heterochromatin), a gene product (variants in
enzymatic activity or binding affinity), or a
phenotype. The term DNA polymorphism refers
to a wide range of variations in nucleotide base
composition, length of nucleotide repeats, or
single nucleotide variants. DNA polymorphisms
are important as genetic markers to identify
and distinguish alleles at a gene locus and to determine
their parental origin.


A. Single nucleotide polymorphism (SNP)

These allelic variants differ in a single nucleotide
at a specific position. At least one in a
thousand DNA bases differs among individuals
(1). The detection of SNPs does not require gel
electrophoresis. This facilitates large-scale detection.
A SNP can be visualized in a Southern
blot as a restriction fragment length polymorphism
(RFLP) if the difference in the two alleles
corresponds to a difference in the recognition
site of a restriction enzyme.
B. Simple sequence length polymorphism (SSLP)

These allelic variants differ in the number of
tandemly repeated short nucleotide sequences
in noncoding DNA. Short tandem repeats (STRs)
consist of units of 1, 2, 3, or 4 base pairs repeated
from 3 to about 10 times. Typical short tandem
repeats are CA repeats in the 5! to 3! strand, i.e.,
alternating CG and AT base pairs in the double
strand. Each allele is defined by the number of
CA repeats, e.g., 3 and 5, as shown (1). These are
also called microsatellites. The size differences
due to the number of repeats are determined by
PCR. Variable number of tandem repeats
(VNTR), also called minisatellites, consist of repeat
units of 20–200 base pairs (2).

C. Detection of SNP by oligonucleotide

hybridization analysis
Oligonucleotides, short stretches of about 20
nucleotides with a complementary sequence to
the single-stranded DNA to be examined, will
hybridize completely only if perfectly matched.
If there is a difference of even one base, such as
due to an SNP, the resulting mismatch can be
detected because the DNA hybrid is unstable
and gives no signal.

D. Detection of STRs by PCR

Short tandem repeats (STRs) can be detected by
the polymerase chain reaction (PCR). The allelic
regions of a stretch ofDNA are amplified; the resulting
DNA fragments of different sizes are
subjected to electrophoresis; and their sizes are
determined.

E. CEPH families

An important step in gene identification is the
analysis of large families by linkage analysis of
polymorphic marker loci on a specific chromosomal
region near a locus of interest. Large
families are of particular value. DNA from such
families has been collected by the Centre pour
l’Étude du Polymorphisme Humain (CEPH) in
Paris, now called the Centre Jean Dausset, after
the founder. Immortalized cell lines are stored
from each family. A CEPH family consists of four
grandparents, the two parents, and eight
children. If four alleles are present at a given
locus they are designated A, B, C, and D. Starting
with the grandparents, the inheritance of each
allele through the parents to the grandchildren
can be traced (shown here as a schematic pattern
in a Southern blot). Of the four grandparents
shown, three are heterozygous (AB, CD,
BC) and one is homozygous (CC). Since the
parents are heterozygous for different alleles
(AD the father and BC the mother), all eight
children are heterozygous (BD, AB, AC, or CD).

References

Brown, T.A.: Genomes. Bios Scientific Publ., Oxford,
1999.
Collins, F.S. , Guyer, M.S. , Chakravarti, A.: Variations
on a theme: cataloguing human DNA
sequence variation. Science 282:682–689,
1998.
Deloukas, P., Schuler, G., Gyapay, G., et al.: A
physical map of 30,000 human genes.
Science 282:744–746, 1998.
Lewin, B.: Genes VII. Oxford Univ. Press, Oxford,
2000.
Strachan, T., Read, A.P.: Human Molecular
Genetics. 2nd ed. Bios Scientific Publishers,
Oxford, 1999.