Promoters and transcription factors - Human Gene Evolution - page 252

the glucocorticoid receptor group appears to have evolved from a progenitor
resembling the present-day estrogen receptor (Amero et al ., 1992; Laudet et al .,
1992; Martinez et al ., 1991; see Figure 5.9 ). Thus, mutations in the P-box have
altered the DNA-binding specificity of a receptor with high affinity for TGACCT
sites and low affinity for TGTTCT sequences, to proteins with the opposite speci-
ficity. Residues Glu439 and Ser440 are critical for conferring binding specificity on
the receptor (Zilliacus et al ., 1994).
Another example of a functional change in the DNA-binding domain within a
family of paralogous transcription factors is provided by Pax6 ( PAX6 ; 11p13)
which possesses an Asn at amino acid residue 47 in the third

-helix of the paired
domain (Balczarek et al ., 1997); this amino acid recognizes the nucleotide T. All
other known Pax genes encode proteins with a His at this position; this amino
acid shows higher affinity toward the nucleotide G.

5.2.5 Orthologous transcription factors

Orthologous transcription factors have also diverged over evolutionary time.
Divergence has occurred by, for example, incorporation of novel motifs or the
amplification of existing motifs. Thus, the human transcription factor MOK2
( MOK2 ; 19q13.2-q13.3) contains 10 zinc-finger motifs in comparison to seven in
its murine homologue (Ernoult-Lange et al ., 1995). Similarly, the human ery-
throid-specific transcription factor Eryth 1 contains different numbers of repeat
motifs as compared with its chicken counterpart (Trainor et al ., 1990). Finally, gene
sequences encoding TBP, the general transcription factor, exhibit a considerable
degree of sequence simplicity as a direct result of simple repeat amplification, per-
haps by replication slippage (Hancock, 1993). The incorporation of new repeats
and the consequent enlargement of TBP may have permitted novel interactions
with domains of other proteins leading to the acquisition of new functions.

5.2.6 Alternative splicing of transcription factor genes

Alternative splicing provides the means to generate transcription factor diversity
in the absence of gene duplication. Thus, alternative splicing of the PAX8 (2q12-
q14) gene results in the alternative presence or absence of a single Ser residue in
the recognition helix of the paired domain which is critical for DNA binding
(Kozmik et al ., 1997). The two forms of Pax8 differ in their binding specificity.

5.2.7 Promoter shuffling in transcription factor genes

Promoter modularity arising from the shuffling of component motifs (Section
5.1) often occurs in the promoters of paralogous transcription factor genes. This
provides the means for changes in the expression of single genes to lead to
changes in the expression of many downstream target genes, a process which has
contributed significantly to the evolution of complex gene expression networks.

5.2.8 Transcription factor-binding site interactions

DNA sequence elements that play a role in gene regulation have evolved so as to
provide appropriate binding sites for their cognate transcription factors. In many