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fusion and recombination. Family members have sometimes been inactivated or
lost so that in some cases, the immediate ancestors of extant genes may now no
longer exist (molecular 'missing links'). In others, promoter changes have led to
the emergence of differences in gene expression either in terms of tissue specificity
or level of expression or in responsiveness to inductive stimuli whether of envi-
ronmental (e.g. temperature), systemic (e.g. hormonal) or intra-cellular origin (e.g.
transcription factors). Some multigene family members have evolved more quickly
than others whether as a result of selection pressure or the stochastic processes of
neutralist evolution. What is common to all the gene families cited above is the
principle that gene duplication has created redundancy which has then allowed
evolutionary experimentation through diversification, ultimately leading to the
recruitment of a new generation of genes encoding proteins with novel properties.
4.2.2 Highly repetitive multigene families
Histone genes.
Histones are basic nuclear proteins which make up the nucleo-
some within the chromatin fibre. Pairs of H2A, H2B, H3, and H4 form the
octamer with H1 being responsible for linking the nucleosomes and potentiating
the formation of higher order chromosome structure. In mammals, the histones
may be sub-divided into three types: (i) main-type replication-dependent his-
tones, (ii) replication-independent 'replacement' histones, and (iii) tissue-specific
histones. The genes encoding the replication-dependent and tissue-specific his-
tones lack introns, give rise to non-polyadenylated mRNAs, contain 3
elements
with dyadic symmetry essential for mRNA processing, and are chromosomally
clustered. By contrast, the genes encoding the replacement histones can contain
introns, give rise to polyadenylated mRNAs and are solitary rather than clustered
(Brush
et al
., 1985; Doenecke
et al
., 1994).
Three main clusters of histone genes are apparent in the human genome and
contain between them about 60 genes. Two clusters, located at 6p21.3, are sepa-
rated by ~2 Mb and contain all replication-dependent H1 histone (
H1F1
,
H1F2
,
H1F3
,
H1F4
,
H1F5
;
Figure 4.24
) genes and surrounding core histone (
H2A
,
H2B
,
H3
,
H4
) genes (Albig
et al
., 1993; Albig and Doenecke, 1997; Albig
et al
.,
1997a, 1997b). The other cluster at 1q21 is smaller consisting of at least four core
histone genes. Various solitary replacement histone genes have been located on
different chromosomes, for example H1° (
H1F0
; 22q13; Albig
et al
., 1993),
H2A.X (
H2AX
; 11q23; Ivanova
et al
., 1994), H2A.Z (
H2AZ
; 4q24; Popescu
et al
.,
1994) and H3.3B (
H3F3B
; 17q25; Albig
et al
., 1995). Finally, testis-specific his-
tone genes
H3F3A
(Albig
et al
., 1996) and
H1FT
(Albig
et al
., 1997) have been
localized to chromosomes 1q42 and 6p21, respectively.
Histones are very ancient proteins as evidenced by homologies between
prokaryotic and eukaryotic histones H2A/B, H3, and H4 (Slesarev
et al
., 1998;
Ouzounis and Kyrpides, 1996). Interestingly, homology also exists between the
core histones and the CCAAT-binding factor (Ouzounis and Kyrpides, 1996) sug-
gesting that transcriptional regulation and nucleosomal packing may have been
intimately related for a very considerable period of evolutionary time.
In lower eukaryotes, histone genes usually occur in long tandemly repetitive
arrays but in mammals, although the genes are clustered, they are less ordered and
