Biology Reference
In-Depth Information
absence of each restriction site. RFLPs are not rare, being distributed throughout
the genome at a frequency of between 1/200 and 1/1000 bp (Collins
et al
., 1997;
Cooper
et al
., 1985; Li and Sadler, 1991; Wang
et al
., 1998). Some 25% of single
nucleotide polymorphisms (SNPs) in higher primates occur in CpG dinucleotides
(Savatier
et al.
, 1985; Yang
et al.
, 1996), consistent with a model of methylation-
mediated deamination.
Not unexpectedly, the vast majority of polymorphisms occur in introns or inter-
genic regions rather than within coding sequences and may thus be expected to be
neutral with respect to fitness (Bowcock
et al
., 1991). Those polymorphisms that
occur either within coding regions (see Chapter 2, section 2.3.7) or in the promoter
region (see Chapter 5, section 5.1.9) may however affect either the structure or func-
tion of the gene product or the expression of the gene and may therefore have the
potential to be of phenotypic or even pathological significance (Cooper and
Krawczak, 1993). Those coding sequence polymorphisms that alter the amino acid
sequence of the encoded protein are found at a lower rate and with lower allele fre-
quencies than silent substitutions (Cargill
et al.
, 1999). This probably reflects the
action of negative selection on deleterious alleles during human evolution.
Some polymorphisms may be missense mutations, for example those underlying
the Lewis
Le
alleles in the
FUT3
gene (19p13.3; Nishihara
et al
., 1994) or the
Arg/Gln 353 polymorphism in the factor VII (
F7
; 13q34) gene (see Chapter 2, sec-
tion 2.3.7). Others are nonsense mutations that serve to inactivate the gene in ques-
tion, for example the secretor
se
allele in the
FUT2
gene (19cen-qter) present in 20%
of the population (Kelly
et al
., 1995). Further types of gene-associated polymor-
phism in the human genome include triplet repeat copy number (see Chapter 8, sec-
tion 8.9), gene deletions (see Chapter 8, section 8.1), gene duplications (see Chapter
8, section 8.5), intragenic duplications (see Chapter 8, section 8.6), micro-insertions
(see Chapter 8, section 8.3), inversions (see Chapter 9, section 9.1), gene fusion (see
Chapter 9, section 9.3), and gene copy number (see Chapter 8, sections 8.1 and 8.5).
Various databases of human DNA polymorphisms are available for online consulta-
tion: The Genome Database (
http://gdbwww.gdb.org/
), the Database of Single
Nucleotide Polymorphisms (
http://www.ncbi.nlm.nih.gov/SNP/
), and the database
of Human Genic Bi-Allelic Sequences (
http://hgbase.interactiva.de/intro.html
).
The mechanisms by which polymorphisms are maintained in human popula-
tions are likely to be varied. The neutralist theory assumes no selection on the
alleles of a polymorphic locus and the frequency of an allele may therefore
increase simply by
genetic drift
(the change of allele frequency due to random
sampling). Such 'transient polymorphisms' often remain at a low frequency in
the population before being lost or may instead increase in frequency under the
influence of either genetic drift or positive selection until one allele reaches fix-
ation. Most known polymorphisms are probably of this type. However, if the
alternative alleles are not neutral with respect to fitness (see Chapter 2, section
2.3.7), the DNA polymorphisms may be maintained by selection pressure, possi-
bly overdominant selection ('balanced polymorphisms'). Finally, a 'hitchhiker
effect' may operate if the polymorphisms are closely linked to a locus which is
itself under strong selection. In some special cases, such as polymorphisms
within CpG dinucleotides, recurrent mutation may serve to maintain the allele
frequency in the population.
