Contractions and expansions in gene size and number - Human Gene Evolution - page 342

Potential acceptor site

Exon 3 Alu Exon 4

OAT gene

C

G
Donor site

OAT mRNA:
splicing introduces
a new Alu exon

Exon 2 Exon 3 Exon 4 Exon 5

STOP

Figure 8.7. Ornithine -aminotransferase deficiency caused by a mutation in a resident

intronic Alu element within the OAT gene. A point mutation within the right subunit of
the inversely oriented intronic Alu repeat activates a donor splice site (from Labuda et al .,
1995).

Splice-mediated insertion of Alu sequences. Alu sequences have also been
found to alter protein coding sequences through the splice-mediated insertion of the
repeat and this probably represents the major mechanism by which Alu sequences
have entered protein coding regions. Figure 8.7 illustrates the principle involved
by reference to the pathological example of ornithine

-aminotransferase defi-
ciency caused by a single base-pair substitution in an intronic Alu element in the
human ornithine -aminotransferase ( OAT ; 10q26) gene; this lesion activates a

cryptic donor splice site which results in the incorporation of the Alu sequence
into the mRNA.
In an evolutionary context, there are several examples of the splice-mediated
insertion of Alu repeats into human gene coding sequences. The splice-mediated
insertion of a 95 bp Alu sequence has been reported in the lecithin: cholesterol
acyltransferase ( LCAT ; 16q22.1) gene (Miller and Zeller, 1997). In humans, the
alternate Alu -containing transcript represents between 5% and 20% of the LCAT
mRNA. It is also present in LCAT mRNA from chimpanzee, gorilla and orang-
utan; in the latter, the Alu -containing mRNA species constitutes 50% of the total
LCAT mRNA pool (Miller and Zeller, 1997). It is not however present in the
LCAT genes of gibbons, or Old World and New World monkeys (Miller and
Zeller, 1997).
In the human biliary glycoprotein ( BGP ; 19q13.2) gene, three mRNA variants
are produced as a result of the alternative splicing of an exon (IIa) with one of two
virtually identical Alu cassettes derived from two intronic repeats ( Figure 8.8 ).
Other such examples are to be found in the human REL (2p12-p13) proto-onco-
gene, and the complement decay-accelerating factor ( DAF ; 1q32) and comple-
ment C5 ( C5 ; 9q33) genes (Makalowski et al ., 1994). Of the 17 Alu sequences
found in mRNA coding regions by Makalowski et al . (1994), seven contained in-
frame Stop codons and three others were predicted to cause frameshifts. Thus it is
perhaps not surprising that in several cases of mRNAs containing Alu sequences,
allelic exclusion is evident and the mRNA containing the Alu sequence is of low
abundance compared to splice variants of the same gene that lack the repeat
(Mighell et al ., 1997). This notwithstanding, it may well be that the splice-