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the 54 bp insertion in the promoter of the human liver arginase ( ARG1 ; 6q22.3-
q23.1) gene is absent in the orthologous gene of Macaca fascicularis (Goodman et
al ., 1994). Similarly, a 37 bp insertion has been introduced into the promoter of
the orthologous Duchenne muscular dystrophy ( DMD ; Xp21) gene of the spider
monkey, Ateles geoffroy (Fracasso and Patarnello, 1998); the inserted sequence is
flanked by two TAAA repeats. A 12 bp insertion in the T-cell receptor
-chain
( TCRA ; 14q11.2) gene encodes an Ile-Pro-Ala-Asp tetrapeptide (residues 88-91)
that is specific to the primate lineage (Thiel et al ., 1995). Interestingly, the region
of the T-cell receptor
-chain protein between positions 86 and 91 appears to be a
hotspot for insertional events during evolution: the rabbit and rat genes appear to
have acquired a 3 bp (single amino acid) insertion, whereas the bovine, ovine, and
murine genes manifest a 6 bp (double amino acid) insertion at this position (Thiel
et al ., 1995). Finally, a 24 bp sequence found in the transmembrane domain region
of the human glycophorin E ( GYPE ; 4q28-q31) gene appears to have been
derived from the paralogous glycophorin B ( GYPB ; 4q28-q31) gene during pri-
mate evolution prior to the divergence of the gorilla from the lineage of the other
great apes (Rearden et al ., 1993). It is unclear whether this insertion event was
mediated by homologous unequal recombination or gene conversion.
8.3.2 Microinsertion polymorphisms
Several microinsertion polymorphisms have been reported in human genes.
Thus, a single nucleotide insertion polymorphism has been noted in the promoter
region of the insulin promoter factor 1 ( IPF1 ; 13q12.1; Yamada et al ., 1998) gene.
A single nucleotide insertion polymorphism is also present in the ABO blood
group ( ABO ; 9q34; Olsson and Chester, 1996) gene which serves to inactivate it.
Finally, a 9 bp insertion polymorphism in exon 9 of the cytochrome P450
CYP2D6 (22q13.1) gene occurs in the Japanese population and is associated with
a poor metabolizer phenotype (Yokoi et al ., 1996).
8.3.3 Indels
Clearly, in extant proteins, selection must have ensured the retention of essential
features of tertiary structure. Indeed, insertions or deletions which altered the
reading frame must have been rendered harmless in order for the protein to retain
its biological activity. Thus, the insertion of bases inferred in one member of a
paralogous protein pair often implies a counterbalancing deletion in the immedi-
ate vicinity (or vice versa ) to restore the reading frame. Such 'indels' tend to
involve sequences of between 1 bp and 5 bp in length (Pascarella and Argos, 1992).
They are generally found in turn and coil structures and rarely interrupt
-helices
and strands (Pascarella and Argos, 1992). One example of a simple indel occurring
during evolution is the deletion of an AA doublet and its replacement with a GT
doublet in the 5
9” gene ( Figure 4.26 ).
An example of a more complex indel that has occurred during vertebrate evo-
lution is provided by the human chorionic gonadotropin
flanking region of the human interferon “
-subunit ( CGB ;
19q13.3) gene and is responsible for the introduction of a 24 amino acid C-terminal
extension to the protein product (Talmadge et al ., 1984). The CGB gene emerged
 
 
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