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100 Myrs since the divergence of the rodent and human lineages. Another possi-
ble example of a late insertional event is provided by the human forkhead
FKHL13 ( FKHL13 ; 17q22-q25) gene which contains a single intron that has
interrrupted the forkhead DNA-binding domain (Murphy et al ., 1997).
The evolution of the human HLA-DRB6 (6p21.3) gene has been characterized not
only by the deletion of an exon and the original promoter region but also by the de
novo creation of an exon. This is thought to have occurred in association with the
insertion of a retroviral LTR into intron 1 of the gene >23 Myrs ago, prior to the
divergence of Old World monkeys from the human-ape lineage (Mayer et al ., 1993).
Whether the exon/promoter deletion accompanied or followed the LTR insertion is
unclear. Whichever, the gene is still capable of being transcribed. That this is so is
due to the creation of an open reading frame for a new exon by the insertion which
serendipitously encoded a hydrophobic sequence that was able to function as a leader
for the truncated HLA-DRB6 protein. The new exon also provided a functional
donor splice site at its 3
end which potentiated in-register splicing with exon 2 of the
HLA-DRB6 gene. Finally, since the LTR also provided a substitute promoter
region, the downstream HLA-DRB6 gene could be transcribed.
Retrotransposition of an mRNA intermediate is one mechanism that would serve
to erase completely the original exon-intron distribution of a gene. One potential
example of this phenomenon is provided by the 68 kDa neurofilament protein
( NEFL ; 8p21) gene, a member of the intermediate filament multigene family that
diverged over 600 Myrs ago. Other members of this family include desmin ( DES ;
2q35), vimentin ( VIM ; 10p13), glial fibrillary acidic protein ( GFAP ; 17q21), and
the type I and II keratins. Whereas these latter genes possess seven or eight introns,
six of which occur at homologous locations, the NEFL gene possesses only three,
none of which correspond in terms of their location to introns in the other known
intermediate filament genes (Lewis and Cowan 1986). Retrotransposition of a
cDNA intermediate could account for the present day structure of the NEFL gene
but three new introns would still have to have been acquired, presumably by inser-
tion. In other cases of putative intron loss, the retrotransposition of semiprocessed
mRNAs (Chapter 6, section 6.1.3) should also be considered. Such retrotransposed
sequences will, by definition, contain fewer introns than their parent genes but the
retention of some introns will often serve to obscure their origin.
The best characterized example of the insertion of an intron into a gene is from
the sex-determining gene which in humans ( SRY ; Yp11.3) and other placental
mammals is intronless. However, in dasyurid marsupials, an intron was inserted
de novo into the Sry gene about 45 Myrs ago (O'Neill et al ., 1998). The 825 bp
intron lies within the coding sequence 550 bp from the start codon and was
inserted in phase 1 (between the first and second bases of the codon). The intron,
which contains a repetitive sequence element specific to marsupials, is correctly
spliced out of the primary transcript. Since the SRY gene is essential for mam-
malian sex determination, it is very unlikely that intron insertion could have
inactivated the gene even temporarily. We must therefore conclude that the
inserted sequence probably contained functional splice junction motifs that
ensured its accurate removal from the marsupial Sry transcript.
Some gene families have evolved by multiple rounds of gene duplication accom-
panied by the gain or loss of both introns and exons, for example the human
 
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