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causing human genetic disease (Krawczak et al ., 1992). Mutations appear to occur
disproportionately at the most evolutionarily conserved positions within the
splice site (Krawczak et al ., 1992). This is due to a detection bias resulting from
the relative phenotypic severity of these lesions. Phenotypic consequences of
splice site mutations include exon skipping and cryptic splice site utilization.
Single base-pair substitutions within promoter regions. A wide variety of
mutations are now known which occur within gene promoter regions (Cooper and
Krawczak, 1993). These lesions disrupt the normal processes of gene activation and
transcriptional initiation and serve to decrease (or rather less often, increase) the
level of mRNA/protein product synthesized. What these lesions have in common is
their ability to alter or abolish the binding capacity of cis -acting DNA sequence
motifs for the trans -acting protein factors that normally interact with them.
Gross gene deletions. Gross gene deletions may arise through a number of dif-
ferent recombinational mechanisms including homologous unequal recombina-
tion (occurring either between related gene sequences or repetitive elements). Alu
sequences have been noted to flank deletion breakpoints in a considerable num-
ber of human genetic conditions and may represent hotspots for gene deletions
(Cooper and Krawczak, 1993).
Microdeletions. Deletion breakpoint junctions flanking short (<20 bp) human
gene deletions are non-random both at the nucleotide and dinucleotide levels, an
observation consistent with a sequence-directed mechanism of mutagenesis
(Cooper and Krawczak, 1993). Direct repeats flanking the deleted sequence are a
common finding, consistent with a model of slipped mispairing at the replication
fork. Two specific types of sequence have been found at high frequency in the vicin-
ity of short gene deletions: polypyrimidine runs of at least 5 bp (YYYYY) and a
'deletion hotspot consensus sequence' (TGRRKM) (Cooper and Krawczak, 1993).
Insertions. That insertional mutagenesis might be as intrinsically non-random as
point mutations and gene deletions was strongly suggested by the findings of
Fearon et al . (1990), who reported 10 independent examples of DNA insertion
within the same 170 bp intronic region of the DCC (18q21) gene (a locus which
has been proposed to play an important role in human colorectal neoplasia).
Insertional mutations involving the introduction of <10 bp DNA sequence into a
gene coding region are (i) nonrandom and appear to be highly dependent upon
the local DNA sequence context and (ii) may be explained by those mechanisms
held to be responsible for gene deletions (Cooper and Krawczak, 1993).
Inversions. Inversions are a highly unusual mutational mechanism causing
human genetic disease. The best known example is that found recently in the fac-
tor VIII ( F8C ) gene causing hemophilia A: this rearrangement occurs in about
40% of severely affected patients and recurs at high frequency (Lakich et al ., 1993;
Naylor et al ., 1993). The mechanism responsible is thought to be homologous
intrachromosomal recombination between a gene ( F8A ) located in intron 22 of
the F8C gene and two additional homologues of the F8A gene situated 500 kb
upstream of the F8C gene.
 
 
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