Promoters and transcription factors - Human Gene Evolution - page 248

Chapter 4.2.1, Homeobox genes ). The molecular basis of such a role has long been a
puzzle but new studies are now providing a glimpse of how subtle genetic changes
can have fairly dramatic effects on morphology. One of the best characterized
examples is provided by a promoter mutation which appears to have morpholog-
ical consequences for the evolution of the mammalian body plan: a 4 bp deletion
in element C of the early enhancer region of the Hoxc8 gene of baleen whales
(Shashikant et al ., 1998). This lesion (TTAATTG TT-G) is specific to baleen

whales (five species tested) and is not found in the highly conserved Hoxc8 gene
promoters of humans ( HOXC8 ; 12q12-q13), rodents, artiodactyls or the toothed
whales including sperm whales (Shashikant et al ., 1998). In mice, the early
enhancer region of the Hoxc8 gene promoter is required to initiate expression of
the gene in the posterior region of the day 8.5 mouse embryo and to establish spa-
tial domains of expression in the neural tube and mesoderm. After day 9.0, the
late enhancer maintains anterior Hoxc8 gene expression and down-regulates pos-
terior expression. The baleen whale Hoxc8 early enhancer region containing the 4
bp deletion has been assayed in transgenic mouse embryos where it was found to
direct the expression of the reporter gene to more posterior regions (4-5 somite
levels posterior as compared with human or murine Hoxc8 enhancers) of the
neural tube but failed to direct expression to the posterior mesoderm (Shashikant
et al ., 1998). Similar results were obtained when site-directed mutagenesis was
used to introduce the same lesion into the murine Hoxc8 early enhancer region.
Thus the 4 bp deletion in the Hoxc8 gene promoter of baleen whales may have
played a role in modifying the developmental program of these cetaceans. One
wider implication of this work is that there may be additional mutations yet to
discover in the cis -acting regulatory sequences of other Hox genes and these
lesions could have contributed to the evolution of body plan diversity during
mammalian evolution.
It is anticipated that mutational changes in a number of other genes encoding
transcription factors that play a role in embryonic development will be character-
ized in the coming years thereby shedding new light on the molecular basis of
morphogenesis. Possible candidate genes would include the Pax gene family
(Chapter 4.1.6; Balczarek et al ., 1997; Noll 1993), the Sox gene family (Wegner,
1999), the engrailed ( EN1 , 2q13-q21; EN2 , 7q36) and Wingless ( WNT1 ; 12q12-
q13) genes (Joyner 1996), the brachyury ( T ; 6q27) gene (Yasuo and Satoh, 1998)
and the snail family of transcription factors (Sefton et al ., 1998) as well as the heat
shock protein 90 (HSP90) family of signal transduction chaperonins (Rutherford
and Lindquist, 1998). Sequence differences between orthologous developmental
regulatory genes should provide insights into the process of molecular evolution
underlying morphological change (Budd, 1999; Eizinger et al. , 1999).

5.2 Transcription factors

You geneticists may know something about the hereditary mechanisms that
distinguish a red-eyed from a white-eyed fruit fly but you haven't the slightest
inkling about the hereditary mechanism that distinguishes fruit flies from ele-
phants.
W.J. Osterhout (1925)