Biology Reference
In-Depth Information
(
Figure 1.2
) with which it interferes. Mutations are firstly divided on the basis of
whether they result in the reduced synthesis of a gene product (A) or the synthe-
sis of a structurally/functionally abnormal gene product (B). Mutations are then
secondarily divided into four categories; promoter function, gene structure, RNA
processing and translation. Some gene lesions may be placed into more than one
category. For example, missense mutations with drastic effects on protein struc-
ture and stability or which serve to activate an exonic cryptic splice site can fall
into both categories. Similarly, a missense mutation close to an intron/exon splice
junction could affect mRNA splicing efficiency as well as protein structure. The
effects of specific amino acid substitutions on protein structure are the subject of
several reviews (Pakula and Sauer, 1989; Alber, 1989; Wacey
et al
., 1994).
In the context of human pathology, by far the most frequent genetic lesions in
the genome are point mutations and deletions. The remainder comprise a mixed
assortment of insertions, duplications, inversions, sequence amplifications and
complex rearrangements. A brief review of the different types of known patholog-
ical lesion will be given.
Single base-pair substitutions within the coding region.
Some 23% of point
mutations are CG
CA transitions, representing a five-fold higher
frequency for this dinucleotide than that predicted from random expectation
(Krawczak
et al
., 1998). This is thought to be due to the hypermutability of the
methylated dinucleotide CpG; spontaneous deamination of 5-methylcytosine
(5mC) to thymidine in this doublet gives rise to C
TG or CG
A transitions
depending upon the strand in which the 5mC is mutated. CpG hypermutability in
inherited disease implies that the CpG sites in question are methylated in the
germline and thereby rendered prone to 5mC deamination.
The spectrum of point mutations occurring outwith CpG dinucleotides is also
nonrandom (Cooper and Krawczak, 1993; Krawczak
et al
., 1998). In principle, the
nonrandomness of the initial mutation event, the nonrandomness of the DNA
sequences under study, differences in the relative efficiency with which certain
mutations are repaired, differences in phenotypic effect (and hence selection), or
a bias in the clinical detection of such variants, may all play a role in determining
the observed mutational spectrum.
The majority of single base-pair substitutions causing human genetic disease
alter the amino acid encoded (missense mutations) but a sizeable proportion
result in the introduction of a termination codon (nonsense mutations). The like-
lihood of clinical detection is estimated to be about three times as high for non-
sense mutations as for missense mutations (Krawczak
et al
., 1998). Using a
multidomain molecular model of the human factor IX protein, Wacey
et al
. (1994)
have shown that the likelihood that a factor IX gene (
F9
; Xq28) mutation (caus-
ing hemophilia B) will come to clinical attention is a complex function of the
sequence characteristics of the
F9
gene, the nature of the amino acid substitution,
its precise location and immediate environment within the protein molecule, and
its resulting effects on the structure and function of the protein.
T or G
Single base-pair substitutions within splice sites.
Splicing defects have been
estimated to make up between 8% and 15% of all single base-pair substitutions
