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is the (TCAT) n repeat element in the first intron of the human tyrosine hydroxy-
lase ( TH ; 11p15.5) gene (Meloni et al ., 1998). This repeat is similar to the consen-
sus thyroid response element (TRE) present in the human and rat TH genes and
gel shift assays have provided evidence for the formation of specific complexes
between the tetranucleotide repeat and proteins found in HeLa cell extracts. A
(CCTTT) n pentanucleotide repeat polymorphism (51-72 copies) found within the
promoter region of the human inducible nitric oxide synthase 2A ( NOS2A ;
17q11-q12) gene is also polymorphic in chimpanzees and gorillas but is
monomorphic in orangutans and macaques (Xu et al ., 1997); its influence, if any,
on promoter function is not known.
5.1.13 mRNA editing
The existence of mRNA editing represents something of an evolutionary puzzle
since its selective advantage is not immediately obvious (Covello and Gray, 1993).
The best understood example in humans is that involving the apolipoprotein B
mRNA. ApoB-100, produced in the liver, is essential for the production of very
low density lipoprotein whereas ApoB-48 is required for fat absorption in the
small intestine. Both proteins are encoded by the same ( APOB ; 2p23-p24) gene.
ApoB-48 mRNA is generated as a result of the introduction of an in-frame trans-
lational termination codon at the mRNA level by the deamination of cytosine to
uracil (C6666T) in the first base of the CAA codon encoding Gln2153. A con-
served 29 nucleotide element flanking the edited base (6662-6690) is found in
mammals; this includes a regulator region, a spacer and a mooring sequence
which is required for the mRNA editing process. By contrast to the situation
found in mammals, chicken Apob mRNA is not edited although the various tis-
sue-specific factors that serve to mediate the modification in mammals are pre-
sent (Teng and Davidson, 1992). The absence of mRNA editing in chicken is
thought to be due to the presence of several single base-pair substitutions in the
mooring region of the chicken Apob mRNA since the experimental introduction
of A6671T, G6674T and C6680T substitutions into the chicken gene served to
confer mRNA editing ability upon chicken cells (Nakamuta et al ., 1999).
The editing of the APOB mRNA is performed by a multi-protein complex
('editosome') whose catalytic component has been termed apobec-1. The
APOBEC1 gene, localized to chromosome 12p13.1 in human, is not highly con-
served when compared with its homologues in other mammals, consistent with its
recent rapid evolution (Chan et al ., 1997; Fujino et al ., 1998). Apobec-1 shows sub-
stantial sequence homology to cytidine/cytidylate deaminases (Chan et al ., 1997)
and it would thus appear that a protein with a nucleoside as substrate has evolved
from a protein with a nucleotide as a substrate. It is unlikely, however, that
apobec-1 evolved simply by gene duplication and divergence since mRNA editing
requires multiple factors which would have had to have coevolved in order to
function as a cohesive complex. Even although the separation of apobec-1 and the
cytidine/cytidylate deaminases is ancient (Chan et al ., 1997), apobec-1 is only
found in mammals suggesting that the ancestral apobec-1 protein might have had
a function other than mRNA editing.
 
 
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