Biology Reference
In-Depth Information
in vivo
(Pollak
et al
., 1996; Humphries
et al
., 1996). The occurrence of two func-
tionally significant polymorphisms in the same gene is consistent with the idea
of a selective advantage accruing to individuals with reduced factor VII activity.
A similar hemostatic system polymorphism is factor V Leiden. This variant,
which underlies the phenomenon of activated protein C resistance, results from
the substitution of Arg506 by Gln in coagulation factor V (
F5
; 1q23). Factor Va
serves as a cofactor in the activation of prothrombin by factor Xa and the factor V
Leiden variant is relatively resistant to activated protein C-mediated inactivation.
Between 1% and 7% of the Caucasian population possess the factor V Leiden
mutation (Cooper and Krawczak, 1997) which may therefore be regarded as a
fairly frequent polymorphism with phenotypic effect. Since the factor V Leiden
mutation is also associated with a relative risk of ~6.0 for venous thrombosis, this
is also a polymorphism with clinical effect. Why is this factor V variant so com-
mon? Its high frequency in the general population suggests that it confers, or has
conferred, some selective advantage on its bearers. Dahlbäck (1994) speculated
that a slight hypercoagulable state associated with possession of the factor V
Leiden variant might have been advantageous in certain situations such as trau-
matic injury and childbirth. Consistent with this postulate, Lindqvist
et al
. (1998)
have shown that carriers of the factor V Leiden variant have a significantly
reduced risk of bleeding during childbirth. It may be that other common poly-
morphic variants in hemostatic factor genes e.g. the G20210A transition in the 3
untranslated region of the prothrombin (
F2
; 11p11-q12; Zivelin
et al
., 1998) gene,
are explicable by similar models.
Other examples of polymorphic variants which may have conferred a selective
advantage on carriers are the 'insertion' (I) allele of the angiotensin-converting
enzyme (
DCP1
; 17q23) gene which appears to be associated with improved
human endurance (Montgomery
et al
., 1998) and the Glu487/Lys polymorphism
in the aldehyde dehydrogenase 2 (
ALDH2
; 12q24) gene which is associated with
alcohol sensitivity and alcohol avoidance (Goedde
et al
., 1992). Selection is likely
to have also operated on a variety of other human characteristics including cogni-
tive ability (McClearn
et al
., 1997), body form, skin pigmentation (Smith, 1993)
and pharmacogenetic variation (Kalow, 1997).
2.4 Sequencing the genomes of model organisms and
humans
The characterization of the genomes of a number of different and disparate
species should aid significantly our understanding of the human genome, its
structure, function and evolution. Such species ('model organisms') include a bac-
terium (
Escherichia coli
), a yeast (
Saccharomyces cerevisiae
), a nematode
(
Caenorhabditis elegans
), the fruitfly (
Drosophila melanogaster
), the pufferfish (
Fugu
rubripes
), the mouse, and the rat. Sequencing of the genomes of these model organ-
isms is essential for the discovery, description and characterization of all genes
within those genomes and the proteins that these genes encode. It will provide
information not only on the chromosomal organization of genes and gene families
but also on the elements that control their expression.
