Comments on conservation of regulatory elements

Arthur V. Chadwick (chadwicka@swac.edu)
Tue, 14 Nov 1995 16:01:34 -0800

>Date: Tue, 14 Nov 1995 13:40:29 -0800
>From: pnelson2@ix.netcom.com (Paul A. Nelson )
>Subject: Comments on conservation of regulatory elements
>To: chadwicka@swac.edu
>
>Art:
>
>In glancing at the reflector web site, I noticed your comments on Terry
>Gray's lecture to his students, in particular, about his argument that
>because of the conservation of structural proteins between organisms
>like chimps and humans, significant evolutionary change must occur at
>regulatory loci (which by implication are not conserved).
>
>In response, you pointed out that the key regulators appear to be
>conserved as well, even between organisms as different as Drosophila and
>humans. This "paradox of conservation" has been commented on recently
>by several investigators. Actually, with regard to the homeodomain
>itself (the 61 amino acid helix-turn-helix domain), I think the puzzle
>was first noticed by Miklos and John ("From genotype to phenotype," in
>_Rates of Evolution_ eds. K. Campbell and M. Day [London: Allen & Unwin,
>1987], p. 273):
>
> Since the homeo-box domain has been so well conserved
> between organisms such as yeast (which is not segmented) and
> man, and indeed has good homology to DNA binding proteins in
> prokaryotes, its evolutionary significance in morphogenetic
> terms is difficult to evaluate. Since these organisms
> differ considerably in phenotype, there must be modes of
> escaping from this strict conservatism, if indeed it is the
> homeo-box domain which is so important.
>
>Several years later, surveying a much greater range of examples, Scott
>raises the same puzzle, albeit now referring to the conservation of the
>Hox gene clusters:
>
> Animal architecture is guided by many conserved regulators,
> among them homeobox genes that have related functions in
> mammals, insects, and worms. The surprising conservation of
> the regulators stands in stark contrast to the diversity of
> animal form....However, if Hox genes are conserved, what is
> not conserved? What makes animals different, the regulation
> of Hox genes or their effects on the genes they control?
>
>(Matthew P. Scott, "Intimations of a Creature," _Cell_ 79 [1994]: 1121-
>1124.) Or, as he puts it in another article,
>
> The Hox clusters remain the most remarkable example of
> conservation of regulatory genes involved in
> development....The major problem we face is in trying to
> understand what it means for a gene to define a certain
> region of the body. What is in common between the thorax of
> a fly and a human?
>
>(J. Robert Manak and M.P. Scott, "A class act: conservation of
>homeodomain protein functions," in _The Evolution of Developmental
>Mechanisms_, eds. M. Akam, P. Holland, P. Ingham, and G. Wray,
>_Development 1994 Supplement_, pp. 61-71.)
>
>Eric Davidson puts his finger precisely on the problem:
>
> An extreme interpretation is that the common recurrence in
> diverse animals of particular elements of developmental
> circuitry signify that these are actually the only really
> important aspects of development, just because they *are* so
> general. Thus the basic nature of all forms of development
> is the same; know one, know them all; the rest is just
> details. Developmental biologists of the future might well
> invert this argument, however. Obviously animals do develop
> differently. They utilize differently assembled
> morphogenetic programs, and particular downstream batteries
> of structural genes, defined by natural selection. Sooner
> or later we need to understand the genetic mechanisms that
> program the development of phylogenetically distinct kinds
> of animals, and of their specific morphological structures.
>
>(E. Davidson, "Molecular biology of embryonic development: how far have
>we come in the past ten years?" _BioEssays_ 16 [1994]: 603-615.)
>
>"Obviously animals do develop differently," says Davidson. What's
>puzzling is how those differences arise. Terry Gray suggests changes in
>regulatory elements, yet it's hard to find good experimental examples
>for that. In model systems like Drosophila, for instance, the organism
>doesn't tolerate mutations to Hox genes (lethality is the usual result).
>"An adaptive model," Ruddle et al. observe, "supposes that a sequence
>may be crucial for executing a vital function, and thus will be severely
>constrained with respect to change." As Ruddle et al. continue:
>
> We submit that genes involved in developmental processes may
> fall largely into the latter [adaptively constrained]
> category, since developmental mechanisms are highly
> interdependent, and thus variation is likely to be
> destructive. This view gives rise to an enigma: If
> developmental genes are constrained to change, how does
> evolution progress?
>
>(Frank H. Ruddle et al., "Evolution of Hox genes," _Ann. Rev. Ecol.
>Syst. 28 [1994]: 423-42.) Ruddle suggests gene duplication -- "the
>original genetic material is largely maintained and duplicated elements
>may undergo unconstrained change until they too become integrated into
>the developmental fabric" (p. 426).
>
>Once a duplicated sequence is freed from selective maintenance, however,
>it should accumulate mutations (hits) along its length randomly. How
>that process will lead to an new integrated function, rather than to
>genetic rubbish, is unclear.
>
>Puzzles abound. I really must stop glancing at the web site, because it
>tempts me to post commentary like this when I really should be doing
>other things!
>
>Paul Nelson
>
Art
http://chadwicka.swac.edu