Biology Reference
In-Depth Information
reflect either a common evolutionary origin or alternatively convergent evolu-
tion, is as yet unclear.
Recombination may have been involved in at least some instances of 'exon
shuffling', the process of intron-mediated recombination by which functional
domains encoded by one or more exons are dispersed to a variety of different
proteins (reviewed in more detail in Chapter 3, section 3.6). For example, a com-
bination of X-ray crystallographic data and studies of exon organization have led
to the conclusion that the two exons encoding the nucleotide-binding domain
have been independently transferred to the human phosphoglycerate kinase
(
PGK1
; Xq13.3) gene as well as to the maize alcohol dehydrogenase and chicken
glyceraldehyde-3-phosphate dehydrogenase genes (Michelson
et al
., 1985). Whilst
the almost ubiquitous presence of introns may permit exon shuffling by intron-
mediated recombination (see Chapter 3, section 3.6), it has been suggested
(Matsuo
et al
., 1994) that the presence of short unconserved introns with different
types of splice junction may serve to prevent recombination between exon clus-
ters encoding highly conserved functional domains without inhibiting the poten-
tial for domain (multiexon) shuffling.
9.4.2 V(D)J recombination
It is natural selection that gives direction to changes, orients chance, and
slowly, progressively produces more complex structures, new organs, and new
species. Novelties come from previously unseen association of old material. To
create is to recombine.
F. Jacob (1977)
In the lymphocyte, functional immunoglobulin and T-cell receptor genes are
assembled from their constituent gene coding segments by V(D)J recombination
(Gellert, 1997; see Chapter 4, section 4.2.4,
Immunoglobulin genes
and
T-cell receptor
genes
). Recombination is directed by recombination signal sequences (RSS) adja-
cent to each coding sequence. The RSS comprises conserved heptamer and non-
amer motifs separated by a non-conserved spacer region of either 12 bp or 23 bp
(termed 12 signals and 23 signals); recombination only occurs between a 12 signal
and a 23 signal. V(D)J recombination is initiated by the products of two lym-
phoid-specific intronless recombination-activating genes,
RAG1
and
RAG2
,
closely linked to each other on human chromosome 11p13. The RAG1 and RAG2
proteins bind the two recombination signals, bringing them into close juxtaposi-
tion and cleaving the DNA molecule thereby separating the recombination sig-
nals from the flanking coding segments. The
RAG1
and
RAG2
genes are present
in all vertebrates but have not been reported either in jawless vertebrates or inver-
tebrates.
Together RAG1 and RAG2 constitute a transposase that is capable of excising a
DNA segment containing recombination signals from a donor site and inserting
it into a target DNA molecule (Agrawal
et al
., 1998; Hiom
et al
., 1998). The prod-
uct of transposition contains a short target site duplication immediately flanking
the transposed fragment that is reminiscent both of retroviral integration and the
insertional mechanisms employed by other transposases. It is therefore reason-
able to speculate that the
RAG1
and
RAG2
genes may once have been contained
