Biology Reference
In-Depth Information
(Hanscombe
et al
., 1991). Another example of this phenomenon is provided by the
HOX
genes which are organized chromosomally according to their order of
expression (van der Hoeven
et al
., 1996). Intriguingly, the encoded Hox proteins
vary in their affinity for their target DNA sequences and these affinities also cor-
relate with the linear order of the genes (Pellerin
et al
., 1994). By contrast, the
order of the human
ADH
genes on chromosome 4q21, 5
-
ADH3
-
ADH2
-
ADH1
-
3
, is opposite to their order of transcriptional activation in hepatic development
(Yasunami
et al
., 1990) although the significance of this observation, if any, is
unknown. The reflection of temporal order of expression in the physical order on
the chromosome is not however a universal phenomenon as is evidenced by the
human and murine myosin heavy chain (
MYH
) gene clusters on chromosomes 17
and 11, respectively (Weiss
et al
., 1999). Finally, it may be significant that the
order of four human mucin genes (
MUC2
,
MUC5AC
,
MUC5B
,
MUC6
) on chro-
mosome 11p15 corresponds to their order in terms of the anterior-posterior axis
of the epithelial areas where they are preferentially expressed (Pigny
et al
., 1996).
Pseudogenes.
Pseudogenes are DNA sequences which are closely related to func-
tional genes but which are incapable of encoding a protein product on account of
the presence of deletions, insertions and nonsense mutations which abolish the
reading frame or otherwise prevent gene expression (reviewed by Wilde, 1985; see
Chapter 6 for an in-depth treatment). Some human pseudogenes are transcribed
(e.g. Bristow
et al
., 1993; Nguyen
et al
., 1991; Takahashi
et al
., 1992) but these tran-
scripts are not translated. There are two major types of pseudogene: the first arises
through the duplication and subsequent inactivation of a gene (see Chapter 6, sec-
tion 6.1.1). This type of pseudogene retains the exon/intron organization of the
parental gene and are often closely linked to the parental gene. Examples include
the pseudogenes in the
-globin clusters (e.g. Cheng
et al
., 1988). The sec-
ond type of pseudogene contains only the exons of the parental gene, usually pos-
sess a poly(A) tail at the 3
- and
end and are dispersed randomly in the genome (see
Chapter 6, section 6.1.2). These
processed
genes are thought to have originated as
mRNAs which have then become integrated into the genome by
retrotransposition
(i.e. the reverse transcription of the mRNA and the integration of the resulting
cDNA).
Pseudogenes are relatively common in the human genome (McAlpine
et al
.,
1993; many hundreds are known) and may be especially prevalent in multigene
families (e.g.
-globin, actin, HLA, interferons, snRNAs, keratins, T-cell recep-
tors, immunoglobulin gene clusters; see Chapter 6). However, single copy genes
may also have multiple pseudogenes (e.g. prohibitin,
PHB
, four pseudogenes;
argininosuccinate synthetase,
ASS
, 14 pseudogenes).
Promoter elements.
The archetypal gene contains promoter elements upstream
(5
) of the transcriptional initiation site (i.e. the beginning of the mRNA) which
serve to specify the temporal and spatial pattern of expression of the downstream
gene and define its potential for induction by external stimuli (
Figure 1.3
). Some
genes contain multiple alternative promoters which are utilized in a tissue-specific
fashion (e.g.
DMD
; Nishio
et al
., 1994;
Figure 1.4
; reviewed by Ayoubi and van de
Ven, 1996). Some promoters may be located within an intron (e.g. within the first
