Introns, exons, and evolution - Human Gene Evolution - page 109

intron of the -actin ( ACTG1 ; 17p11-qter) gene are highly conserved between

human and Xenopus (Erba et al ., 1988). Perhaps the most dramatic example of the
conservation of intronic sequence is that evident in a comparison of 97 kb of the
human and murine T-cell receptor

( TCRA , TCRD ; 14q11.2) gene locus which
exhibits 66% overall sequence homology even though <6% corresponds to exonic
sequence (Koop and Hood, 1994).
There are exceptions to the general rule that intron sequences evolve more
rapidly than exons. For instance, the second exons of the human semenogelin
genes ( SEMG1 , SEMG2 ; 20q12-q13.1) have evolved very rapidly when compared
to their rat homologues, and more so even than the flanking introns (Lundwall
and Lazure, 1995). Similarly, the divergence between the red and green visual pig-
ment ( GCP , RCP ; Xq28) genes in humans, chimpanzees and baboons is lower in
intron 4 than in exons 4 and 5 of these genes (Shyue et al ., 1994; Zhou and Li,
1996). In this case, homogenization of intron 4 sequences is thought to have been
brought about by gene conversion (see Chapter 9, section 9.5) whilst selection has
probably acted so as to confine gene conversion to the intron in order to retain the
distinct functions of exons 4 and 5 between the two genes.
Evolutionary conservation may imply function but we are only just beginning
to elucidate the function of conserved sequences within introns. The introns of
some genes contain the coding sequences of other genes (see Chapter 1, section
1.2.1). Thus, the OMG, EVI2A, EVI2B genes occur within intron 27b of the
human neurofibromatosis type 1 ( NF1 ; 17q11.2) gene and are transcribed in the
opposite direction to the NF1 gene. An orthologue of the EVI2B gene is present
in the corresponding Fugu intron but this intron reveals no trace of the OMG or
EVI2A genes (Kehrer-Sawatzki et al ., 1998). This indicates that the EVI2B gene
must have been inserted into the NF1 gene more than 450 Myrs ago whilst the
OMG gene must have been a more recent acquisition.
Some intronic sequence motifs perform transcriptional regulatory functions.
Positive regulatory (enhancer-like) elements have now been reported from the first
introns of a considerable number of human genes, for example the genes encoding
type X collagen ( COL10A1 ; 6q21-q22.3; Beier et al ., 1997), type I 3

/

-hydroxys-
teroid dehydrogenase ( HSD3B2 ; 1p13.1; Guerin et al ., 1995), tissue inhibitor of
metalloproteinase 1 ( TIMP1 ; Xp11.23-p11.3; Clark et al ., 1997), factor IX ( F9 ;
Xq27; Kurachi et al ., 1995), heat shock protein 90 ( HSPCB ; 6p12; Shen et al .,
1997), Bruton's tyrosine kinase ( BTK ; Xq21.3-q22; Rohrer and Conley 1998),
purine nucleoside phosphorylase ( NP ; 14q13.1; Jonsson et al ., 1992), O6-methyl-
guanine DNA methyltransferase ( MGMT ; 10q26; Harris et al ., 1994), type I colla-
gen ( COL1A1 ; 17q21.3-q22; Hormuzdi et al ., 1998), IgE receptor ( FCER1B ;
11q13; Lacy et al ., 1994), growth hormone ( GH1 ; 17q22-q24; Slater et al ., 1985;
Kolb et al ., 1998), thymidylate synthase ( TYMS ; 18p11.32; Takayanagi et al ., 1992)
and dystrophin ( DMD ; Xp21.2; Klamut et al ., 1996). Although enhancer
sequences are most commonly found within the first intron of genes, such
sequence elements are also occasionally found in other locations, for example the
second intron of the human apolipoprotein B ( APOB ; 2p24) gene (Rosby et al .,
1992), the third intron of the human oxytocin receptor ( OXTR ; 3p26) gene
(Mizumoto et al ., 1997) and intron 8 of the -aminolevulinate synthase 2 ( ALAS2 ;

Xp11.21) gene (Surinya et al ., 1998). Negative regulatory elements (repressors)